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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes</title><author><name sortKey="Hu, H" sort="Hu, H" uniqKey="Hu H" first="H" last="Hu">H. Hu</name><affiliation><nlm:aff id="aff1"><institution>Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Haas, S A" sort="Haas, S A" uniqKey="Haas S" first="S A" last="Haas">S A Haas</name><affiliation><nlm:aff id="aff2"><institution>Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Chelly, J" sort="Chelly, J" uniqKey="Chelly J" first="J" last="Chelly">J. Chelly</name><affiliation><nlm:aff id="aff3"><institution>University Paris Descartes</institution>, Paris,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff4"><institution>Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Institut National de la Santé et de la Recherche Médicale Unité 1016, Institut Cochin</institution>, Paris,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Van Esch, H" sort="Van Esch, H" uniqKey="Van Esch H" first="H" last="Van Esch">H. Van Esch</name><affiliation><nlm:aff id="aff5"><institution>Center for Human Genetics, University Hospitals Leuven</institution>, Leuven,<country>Belgium</country></nlm:aff></affiliation></author><author><name sortKey="Raynaud, M" sort="Raynaud, M" uniqKey="Raynaud M" first="M" last="Raynaud">M. Raynaud</name><affiliation><nlm:aff id="aff6"><institution>Inserm U930 ‘Imaging and Brain'</institution>, Tours,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff7"><institution>University François-Rabelais</institution>, Tours,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff8"><institution>Centre Hospitalier Régional Universitaire, Service de Génétique</institution>, Tours,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="De Brouwer, A P M" sort="De Brouwer, A P M" uniqKey="De Brouwer A" first="A P M" last="De Brouwer">A P M. De Brouwer</name><affiliation><nlm:aff id="aff9"><institution>Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour</institution>, Nijmegen,<country>The Netherlands</country></nlm:aff></affiliation></author><author><name sortKey="Weinert, S" sort="Weinert, S" uniqKey="Weinert S" first="S" last="Weinert">S. Weinert</name><affiliation><nlm:aff id="aff10"><institution>Max-Delbrück-Centrum für Molekulare Medizin</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff11"><institution>Leibniz-Institut für Molekulare Pharmakologie</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Froyen, G" sort="Froyen, G" uniqKey="Froyen G" first="G" last="Froyen">G. Froyen</name><affiliation><nlm:aff id="aff12"><institution>Human Genome Laboratory, VIB Center for the Biology of Disease</institution>, Leuven,<country>Belgium</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff13"><institution>Human Genome Laboratory, Department of Human Genetics, K.U. Leuven</institution>, Leuven,<country>Belgium</country></nlm:aff></affiliation></author><author><name sortKey="Frints, S G M" sort="Frints, S G M" uniqKey="Frints S" first="S G M" last="Frints">S G M. Frints</name><affiliation><nlm:aff id="aff14"><institution>Department of Clinical Genetics, Maastricht University Medical Center, azM</institution>, Maastricht,<country>The Netherlands</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff15"><institution>School for Oncology and Developmental Biology, GROW, Maastricht University</institution>, Maastricht,<country>The Netherlands</country></nlm:aff></affiliation></author><author><name sortKey="Laumonnier, F" sort="Laumonnier, F" uniqKey="Laumonnier F" first="F" last="Laumonnier">F. Laumonnier</name><affiliation><nlm:aff id="aff6"><institution>Inserm U930 ‘Imaging and Brain'</institution>, Tours,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff7"><institution>University François-Rabelais</institution>, Tours,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Zemojtel, T" sort="Zemojtel, T" uniqKey="Zemojtel T" first="T" last="Zemojtel">T. Zemojtel</name><affiliation><nlm:aff id="aff2"><institution>Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Love, M I" sort="Love, M I" uniqKey="Love M" first="M I" last="Love">M I Love</name><affiliation><nlm:aff id="aff2"><institution>Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Richard, H" sort="Richard, H" uniqKey="Richard H" first="H" last="Richard">H. Richard</name><affiliation><nlm:aff id="aff2"><institution>Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Emde, A K" sort="Emde, A K" uniqKey="Emde A" first="A-K" last="Emde">A-K Emde</name><affiliation><nlm:aff id="aff2"><institution>Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Bienek, M" sort="Bienek, M" uniqKey="Bienek M" first="M" last="Bienek">M. Bienek</name><affiliation><nlm:aff id="aff1"><institution>Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Jensen, C" sort="Jensen, C" uniqKey="Jensen C" first="C" last="Jensen">C. Jensen</name><affiliation><nlm:aff id="aff1"><institution>Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Hambrock, M" sort="Hambrock, M" uniqKey="Hambrock M" first="M" last="Hambrock">M. Hambrock</name><affiliation><nlm:aff id="aff1"><institution>Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Fischer, U" sort="Fischer, U" uniqKey="Fischer U" first="U" last="Fischer">U. Fischer</name><affiliation><nlm:aff id="aff1"><institution>Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Langnick, C" sort="Langnick, C" uniqKey="Langnick C" first="C" last="Langnick">C. Langnick</name><affiliation><nlm:aff id="aff10"><institution>Max-Delbrück-Centrum für Molekulare Medizin</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Feldkamp, M" sort="Feldkamp, M" uniqKey="Feldkamp M" first="M" last="Feldkamp">M. Feldkamp</name><affiliation><nlm:aff id="aff10"><institution>Max-Delbrück-Centrum für Molekulare Medizin</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Wissink Lindhout, W" sort="Wissink Lindhout, W" uniqKey="Wissink Lindhout W" first="W" last="Wissink-Lindhout">W. Wissink-Lindhout</name><affiliation><nlm:aff id="aff9"><institution>Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour</institution>, Nijmegen,<country>The Netherlands</country></nlm:aff></affiliation></author><author><name sortKey="Lebrun, N" sort="Lebrun, N" uniqKey="Lebrun N" first="N" last="Lebrun">N. Lebrun</name><affiliation><nlm:aff id="aff3"><institution>University Paris Descartes</institution>, Paris,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff4"><institution>Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Institut National de la Santé et de la Recherche Médicale Unité 1016, Institut Cochin</institution>, Paris,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Castelnau, L" sort="Castelnau, L" uniqKey="Castelnau L" first="L" last="Castelnau">L. Castelnau</name><affiliation><nlm:aff id="aff3"><institution>University Paris Descartes</institution>, Paris,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff4"><institution>Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Institut National de la Santé et de la Recherche Médicale Unité 1016, Institut Cochin</institution>, Paris,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Rucci, J" sort="Rucci, J" uniqKey="Rucci J" first="J" last="Rucci">J. Rucci</name><affiliation><nlm:aff id="aff3"><institution>University Paris Descartes</institution>, Paris,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff4"><institution>Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Institut National de la Santé et de la Recherche Médicale Unité 1016, Institut Cochin</institution>, Paris,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Montjean, R" sort="Montjean, R" uniqKey="Montjean R" first="R" last="Montjean">R. Montjean</name><affiliation><nlm:aff id="aff3"><institution>University Paris Descartes</institution>, Paris,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff4"><institution>Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Institut National de la Santé et de la Recherche Médicale Unité 1016, Institut Cochin</institution>, Paris,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Dorseuil, O" sort="Dorseuil, O" uniqKey="Dorseuil O" first="O" last="Dorseuil">O. Dorseuil</name><affiliation><nlm:aff id="aff3"><institution>University Paris Descartes</institution>, Paris,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff4"><institution>Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Institut National de la Santé et de la Recherche Médicale Unité 1016, Institut Cochin</institution>, Paris,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Billuart, P" sort="Billuart, P" uniqKey="Billuart P" first="P" last="Billuart">P. Billuart</name><affiliation><nlm:aff id="aff3"><institution>University Paris Descartes</institution>, Paris,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff4"><institution>Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Institut National de la Santé et de la Recherche Médicale Unité 1016, Institut Cochin</institution>, Paris,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Stuhlmann, T" sort="Stuhlmann, T" uniqKey="Stuhlmann T" first="T" last="Stuhlmann">T. Stuhlmann</name><affiliation><nlm:aff id="aff10"><institution>Max-Delbrück-Centrum für Molekulare Medizin</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff11"><institution>Leibniz-Institut für Molekulare Pharmakologie</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Shaw, M" sort="Shaw, M" uniqKey="Shaw M" first="M" last="Shaw">M. Shaw</name><affiliation><nlm:aff id="aff16"><institution>School of Paediatrics and Reproductive Health, The University of Adelaide</institution>, Adelaide, SA,<country>Australia</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff17"><institution>Robinson Research Institute, The University of Adelaide</institution>, Adelaide, SA,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Corbett, M A" sort="Corbett, M A" uniqKey="Corbett M" first="M A" last="Corbett">M A Corbett</name><affiliation><nlm:aff id="aff16"><institution>School of Paediatrics and Reproductive Health, The University of Adelaide</institution>, Adelaide, SA,<country>Australia</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff17"><institution>Robinson Research Institute, The University of Adelaide</institution>, Adelaide, SA,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Gardner, A" sort="Gardner, A" uniqKey="Gardner A" first="A" last="Gardner">A. Gardner</name><affiliation><nlm:aff id="aff16"><institution>School of Paediatrics and Reproductive Health, The University of Adelaide</institution>, Adelaide, SA,<country>Australia</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff17"><institution>Robinson Research Institute, The University of Adelaide</institution>, Adelaide, SA,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Willis Owen, S" sort="Willis Owen, S" uniqKey="Willis Owen S" first="S" last="Willis-Owen">S. Willis-Owen</name><affiliation><nlm:aff id="aff16"><institution>School of Paediatrics and Reproductive Health, The University of Adelaide</institution>, Adelaide, SA,<country>Australia</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff18"><institution>National Heart and Lung Institute, Imperial College London</institution>, London,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Tan, C" sort="Tan, C" uniqKey="Tan C" first="C" last="Tan">C. Tan</name><affiliation><nlm:aff id="aff16"><institution>School of Paediatrics and Reproductive Health, The University of Adelaide</institution>, Adelaide, SA,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Friend, K L" sort="Friend, K L" uniqKey="Friend K" first="K L" last="Friend">K L Friend</name><affiliation><nlm:aff id="aff19"><institution>SA Pathology, Women's and Children's Hospital</institution>, Adelaide, SA,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Belet, S" sort="Belet, S" uniqKey="Belet S" first="S" last="Belet">S. Belet</name><affiliation><nlm:aff id="aff12"><institution>Human Genome Laboratory, VIB Center for the Biology of Disease</institution>, Leuven,<country>Belgium</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff13"><institution>Human Genome Laboratory, Department of Human Genetics, K.U. Leuven</institution>, Leuven,<country>Belgium</country></nlm:aff></affiliation></author><author><name sortKey="Van Roozendaal, K E P" sort="Van Roozendaal, K E P" uniqKey="Van Roozendaal K" first="K E P" last="Van Roozendaal">K E P. Van Roozendaal</name><affiliation><nlm:aff id="aff14"><institution>Department of Clinical Genetics, Maastricht University Medical Center, azM</institution>, Maastricht,<country>The Netherlands</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff15"><institution>School for Oncology and Developmental Biology, GROW, Maastricht University</institution>, Maastricht,<country>The Netherlands</country></nlm:aff></affiliation></author><author><name sortKey="Jimenez Pocquet, M" sort="Jimenez Pocquet, M" uniqKey="Jimenez Pocquet M" first="M" last="Jimenez-Pocquet">M. Jimenez-Pocquet</name><affiliation><nlm:aff id="aff8"><institution>Centre Hospitalier Régional Universitaire, Service de Génétique</institution>, Tours,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Moizard, M P" sort="Moizard, M P" uniqKey="Moizard M" first="M-P" last="Moizard">M-P Moizard</name><affiliation><nlm:aff id="aff6"><institution>Inserm U930 ‘Imaging and Brain'</institution>, Tours,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff7"><institution>University François-Rabelais</institution>, Tours,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff8"><institution>Centre Hospitalier Régional Universitaire, Service de Génétique</institution>, Tours,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Ronce, N" sort="Ronce, N" uniqKey="Ronce N" first="N" last="Ronce">N. Ronce</name><affiliation><nlm:aff id="aff6"><institution>Inserm U930 ‘Imaging and Brain'</institution>, Tours,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff7"><institution>University François-Rabelais</institution>, Tours,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff8"><institution>Centre Hospitalier Régional Universitaire, Service de Génétique</institution>, Tours,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Sun, R" sort="Sun, R" uniqKey="Sun R" first="R" last="Sun">R. Sun</name><affiliation><nlm:aff id="aff2"><institution>Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="O Keeffe, S" sort="O Keeffe, S" uniqKey="O Keeffe S" first="S" last="O'Keeffe">S. O'Keeffe</name><affiliation><nlm:aff id="aff2"><institution>Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Chenna, R" sort="Chenna, R" uniqKey="Chenna R" first="R" last="Chenna">R. Chenna</name><affiliation><nlm:aff id="aff2"><institution>Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Van Bommel, A" sort="Van Bommel, A" uniqKey="Van Bommel A" first="A" last="Van Bömmel">A. Van Bömmel</name><affiliation><nlm:aff id="aff2"><institution>Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Goke, J" sort="Goke, J" uniqKey="Goke J" first="J" last="Göke">J. Göke</name><affiliation><nlm:aff id="aff2"><institution>Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Hackett, A" sort="Hackett, A" uniqKey="Hackett A" first="A" last="Hackett">A. Hackett</name><affiliation><nlm:aff id="aff20"><institution>Genetics of Learning and Disability Service, Hunter Genetics</institution>, Waratah, NSW,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Field, M" sort="Field, M" uniqKey="Field M" first="M" last="Field">M. Field</name><affiliation><nlm:aff id="aff20"><institution>Genetics of Learning and Disability Service, Hunter Genetics</institution>, Waratah, NSW,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Christie, L" sort="Christie, L" uniqKey="Christie L" first="L" last="Christie">L. Christie</name><affiliation><nlm:aff id="aff20"><institution>Genetics of Learning and Disability Service, Hunter Genetics</institution>, Waratah, NSW,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Boyle, J" sort="Boyle, J" uniqKey="Boyle J" first="J" last="Boyle">J. Boyle</name><affiliation><nlm:aff id="aff20"><institution>Genetics of Learning and Disability Service, Hunter Genetics</institution>, Waratah, NSW,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Haan, E" sort="Haan, E" uniqKey="Haan E" first="E" last="Haan">E. Haan</name><affiliation><nlm:aff id="aff16"><institution>School of Paediatrics and Reproductive Health, The University of Adelaide</institution>, Adelaide, SA,<country>Australia</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff19"><institution>SA Pathology, Women's and Children's Hospital</institution>, Adelaide, SA,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Nelson, J" sort="Nelson, J" uniqKey="Nelson J" first="J" last="Nelson">J. Nelson</name><affiliation><nlm:aff id="aff21"><institution>Genetic Services of Western Australia, King Edward Memorial Hospital</institution>, Perth, WA,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Turner, G" sort="Turner, G" uniqKey="Turner G" first="G" last="Turner">G. Turner</name><affiliation><nlm:aff id="aff20"><institution>Genetics of Learning and Disability Service, Hunter Genetics</institution>, Waratah, NSW,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Baynam, G" sort="Baynam, G" uniqKey="Baynam G" first="G" last="Baynam">G. Baynam</name><affiliation><nlm:aff id="aff21"><institution>Genetic Services of Western Australia, King Edward Memorial Hospital</institution>, Perth, WA,<country>Australia</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff22"><institution>School of Paediatrics and Child Health, University of Western Australia</institution>, Perth, WA,<country>Australia</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff23"><institution>Institute for Immunology and Infectious Diseases, Murdoch University</institution>, Perth, WA,<country>Australia</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff24"><institution>Telethon Kids Institute</institution>, Perth, WA,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Gillessen Kaesbach, G" sort="Gillessen Kaesbach, G" uniqKey="Gillessen Kaesbach G" first="G" last="Gillessen-Kaesbach">G. Gillessen-Kaesbach</name><affiliation><nlm:aff id="aff25"><institution>Institut für Humangenetik, Universität zu Lübeck</institution>, Lübeck,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Muller, U" sort="Muller, U" uniqKey="Muller U" first="U" last="Müller">U. Müller</name><affiliation><nlm:aff id="aff26"><institution>Institut für Humangenetik, Justus-Liebig-Universität Giessen</institution>, Giessen,<country>Germany</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff27"><institution>bio.logis Center for Human Genetics</institution>, Frankfurt a. M.,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Steinberger, D" sort="Steinberger, D" uniqKey="Steinberger D" first="D" last="Steinberger">D. Steinberger</name><affiliation><nlm:aff id="aff26"><institution>Institut für Humangenetik, Justus-Liebig-Universität Giessen</institution>, Giessen,<country>Germany</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff27"><institution>bio.logis Center for Human Genetics</institution>, Frankfurt a. M.,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Budny, B" sort="Budny, B" uniqKey="Budny B" first="B" last="Budny">B. Budny</name><affiliation><nlm:aff id="aff28"><institution>Chair and Department of Endocrinology, Metabolism and Internal Diseases</institution><institution>, Ponzan University of Medical Sciences,</institution> Poznan,<country>Poland</country></nlm:aff></affiliation></author><author><name sortKey="Badura Stronka, M" sort="Badura Stronka, M" uniqKey="Badura Stronka M" first="M" last="Badura-Stronka">M. Badura-Stronka</name><affiliation><nlm:aff id="aff29"><institution>Chair and Department of Medical Genetics, Poznan University of Medical Sciences</institution>, Poznan,<country>Poland</country></nlm:aff></affiliation></author><author><name sortKey="Latos Biele Ska, A" sort="Latos Biele Ska, A" uniqKey="Latos Biele Ska A" first="A" last="Latos-Biele Ska">A. Latos-Biele Ska</name><affiliation><nlm:aff id="aff29"><institution>Chair and Department of Medical Genetics, Poznan University of Medical Sciences</institution>, Poznan,<country>Poland</country></nlm:aff></affiliation></author><author><name sortKey="Ousager, L B" sort="Ousager, L B" uniqKey="Ousager L" first="L B" last="Ousager">L B Ousager</name><affiliation><nlm:aff id="aff30"><institution>Department of Clinical Genetics, Odense University Hospital</institution>, Odense,<country>Denmark</country></nlm:aff></affiliation></author><author><name sortKey="Wieacker, P" sort="Wieacker, P" uniqKey="Wieacker P" first="P" last="Wieacker">P. Wieacker</name><affiliation><nlm:aff id="aff31"><institution>Institut für Humangenetik, Universitätsklinikum Münster</institution>, Muenster,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Rodriguez Criado, G" sort="Rodriguez Criado, G" uniqKey="Rodriguez Criado G" first="G" last="Rodríguez Criado">G. Rodríguez Criado</name><affiliation><nlm:aff id="aff32"><institution>Unidad de Genética Clínica, Hospital Virgen del Rocío</institution>, Sevilla,<country>España</country></nlm:aff></affiliation></author><author><name sortKey="Bondeson, M L" sort="Bondeson, M L" uniqKey="Bondeson M" first="M-L" last="Bondeson">M-L Bondeson</name><affiliation><nlm:aff id="aff33"><institution>Department of Immunology, Genetics and Pathology, Uppsala University</institution>, Uppsala,<country>Sweden</country></nlm:aff></affiliation></author><author><name sortKey="Anneren, G" sort="Anneren, G" uniqKey="Anneren G" first="G" last="Annerén">G. Annerén</name><affiliation><nlm:aff id="aff33"><institution>Department of Immunology, Genetics and Pathology, Uppsala University</institution>, Uppsala,<country>Sweden</country></nlm:aff></affiliation></author><author><name sortKey="Dufke, A" sort="Dufke, A" uniqKey="Dufke A" first="A" last="Dufke">A. Dufke</name><affiliation><nlm:aff id="aff34"><institution>Institut für Medizinische Genetik und Angewandte Genomik</institution>, Tübingen,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Cohen, M" sort="Cohen, M" uniqKey="Cohen M" first="M" last="Cohen">M. Cohen</name><affiliation><nlm:aff id="aff35"><institution>Kinderzentrum München</institution>, München,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Van Maldergem, L" sort="Van Maldergem, L" uniqKey="Van Maldergem L" first="L" last="Van Maldergem">L. Van Maldergem</name><affiliation><nlm:aff id="aff36"><institution>Centre de Génétique Humaine, Université de Franche-Comté</institution>, Besançon,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Vincent Delorme, C" sort="Vincent Delorme, C" uniqKey="Vincent Delorme C" first="C" last="Vincent-Delorme">C. Vincent-Delorme</name><affiliation><nlm:aff id="aff37"><institution>Service de Génétique, Hôpital Jeanne de Flandre CHRU de Lilles</institution>, Lille,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Echenne, B" sort="Echenne, B" uniqKey="Echenne B" first="B" last="Echenne">B. Echenne</name><affiliation><nlm:aff id="aff38"><institution>Service de Neuro-Pédiatrie, CHU Montpellier</institution>, Montpellier,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Simon Bouy, B" sort="Simon Bouy, B" uniqKey="Simon Bouy B" first="B" last="Simon-Bouy">B. Simon-Bouy</name><affiliation><nlm:aff id="aff39"><institution>Laboratoire SESEP, Centre hospitalier de Versailles</institution>, Le Chesnay,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Kleefstra, T" sort="Kleefstra, T" uniqKey="Kleefstra T" first="T" last="Kleefstra">T. Kleefstra</name><affiliation><nlm:aff id="aff9"><institution>Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour</institution>, Nijmegen,<country>The Netherlands</country></nlm:aff></affiliation></author><author><name sortKey="Willemsen, M" sort="Willemsen, M" uniqKey="Willemsen M" first="M" last="Willemsen">M. Willemsen</name><affiliation><nlm:aff id="aff9"><institution>Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour</institution>, Nijmegen,<country>The Netherlands</country></nlm:aff></affiliation></author><author><name sortKey="Fryns, J P" sort="Fryns, J P" uniqKey="Fryns J" first="J-P" last="Fryns">J-P Fryns</name><affiliation><nlm:aff id="aff5"><institution>Center for Human Genetics, University Hospitals Leuven</institution>, Leuven,<country>Belgium</country></nlm:aff></affiliation></author><author><name sortKey="Devriendt, K" sort="Devriendt, K" uniqKey="Devriendt K" first="K" last="Devriendt">K. Devriendt</name><affiliation><nlm:aff id="aff5"><institution>Center for Human Genetics, University Hospitals Leuven</institution>, Leuven,<country>Belgium</country></nlm:aff></affiliation></author><author><name sortKey="Ullmann, R" sort="Ullmann, R" uniqKey="Ullmann R" first="R" last="Ullmann">R. Ullmann</name><affiliation><nlm:aff id="aff1"><institution>Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Vingron, M" sort="Vingron, M" uniqKey="Vingron M" first="M" last="Vingron">M. Vingron</name><affiliation><nlm:aff id="aff2"><institution>Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Wrogemann, K" sort="Wrogemann, K" uniqKey="Wrogemann K" first="K" last="Wrogemann">K. Wrogemann</name><affiliation><nlm:aff id="aff1"><institution>Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff40"><institution>Department of Biochemistry and Medical Genetics, University of Manitoba</institution>, Winnipeg, MB,<country>Canada</country></nlm:aff></affiliation></author><author><name sortKey="Wienker, T F" sort="Wienker, T F" uniqKey="Wienker T" first="T F" last="Wienker">T F Wienker</name><affiliation><nlm:aff id="aff1"><institution>Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Tzschach, A" sort="Tzschach, A" uniqKey="Tzschach A" first="A" last="Tzschach">A. Tzschach</name><affiliation><nlm:aff id="aff1"><institution>Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Van Bokhoven, H" sort="Van Bokhoven, H" uniqKey="Van Bokhoven H" first="H" last="Van Bokhoven">H. Van Bokhoven</name><affiliation><nlm:aff id="aff9"><institution>Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour</institution>, Nijmegen,<country>The Netherlands</country></nlm:aff></affiliation></author><author><name sortKey="Gecz, J" sort="Gecz, J" uniqKey="Gecz J" first="J" last="Gecz">J. Gecz</name><affiliation><nlm:aff id="aff16"><institution>School of Paediatrics and Reproductive Health, The University of Adelaide</institution>, Adelaide, SA,<country>Australia</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff17"><institution>Robinson Research Institute, The University of Adelaide</institution>, Adelaide, SA,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Jentsch, T J" sort="Jentsch, T J" uniqKey="Jentsch T" first="T J" last="Jentsch">T J Jentsch</name><affiliation><nlm:aff id="aff10"><institution>Max-Delbrück-Centrum für Molekulare Medizin</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff11"><institution>Leibniz-Institut für Molekulare Pharmakologie</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Chen, W" sort="Chen, W" uniqKey="Chen W" first="W" last="Chen">W. Chen</name><affiliation><nlm:aff id="aff1"><institution>Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff10"><institution>Max-Delbrück-Centrum für Molekulare Medizin</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Ropers, H H" sort="Ropers, H H" uniqKey="Ropers H" first="H-H" last="Ropers">H-H Ropers</name><affiliation><nlm:aff id="aff1"><institution>Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Kalscheuer, V M" sort="Kalscheuer, V M" uniqKey="Kalscheuer V" first="V M" last="Kalscheuer">V M Kalscheuer</name><affiliation><nlm:aff id="aff1"><institution>Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">25644381</idno><idno type="pmc">5414091</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5414091</idno><idno type="RBID">PMC:5414091</idno><idno type="doi">10.1038/mp.2014.193</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">000730</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000730</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes</title><author><name sortKey="Hu, H" sort="Hu, H" uniqKey="Hu H" first="H" last="Hu">H. Hu</name><affiliation><nlm:aff id="aff1"><institution>Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Haas, S A" sort="Haas, S A" uniqKey="Haas S" first="S A" last="Haas">S A Haas</name><affiliation><nlm:aff id="aff2"><institution>Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Chelly, J" sort="Chelly, J" uniqKey="Chelly J" first="J" last="Chelly">J. Chelly</name><affiliation><nlm:aff id="aff3"><institution>University Paris Descartes</institution>, Paris,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff4"><institution>Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Institut National de la Santé et de la Recherche Médicale Unité 1016, Institut Cochin</institution>, Paris,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Van Esch, H" sort="Van Esch, H" uniqKey="Van Esch H" first="H" last="Van Esch">H. Van Esch</name><affiliation><nlm:aff id="aff5"><institution>Center for Human Genetics, University Hospitals Leuven</institution>, Leuven,<country>Belgium</country></nlm:aff></affiliation></author><author><name sortKey="Raynaud, M" sort="Raynaud, M" uniqKey="Raynaud M" first="M" last="Raynaud">M. Raynaud</name><affiliation><nlm:aff id="aff6"><institution>Inserm U930 ‘Imaging and Brain'</institution>, Tours,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff7"><institution>University François-Rabelais</institution>, Tours,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff8"><institution>Centre Hospitalier Régional Universitaire, Service de Génétique</institution>, Tours,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="De Brouwer, A P M" sort="De Brouwer, A P M" uniqKey="De Brouwer A" first="A P M" last="De Brouwer">A P M. De Brouwer</name><affiliation><nlm:aff id="aff9"><institution>Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour</institution>, Nijmegen,<country>The Netherlands</country></nlm:aff></affiliation></author><author><name sortKey="Weinert, S" sort="Weinert, S" uniqKey="Weinert S" first="S" last="Weinert">S. Weinert</name><affiliation><nlm:aff id="aff10"><institution>Max-Delbrück-Centrum für Molekulare Medizin</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff11"><institution>Leibniz-Institut für Molekulare Pharmakologie</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Froyen, G" sort="Froyen, G" uniqKey="Froyen G" first="G" last="Froyen">G. Froyen</name><affiliation><nlm:aff id="aff12"><institution>Human Genome Laboratory, VIB Center for the Biology of Disease</institution>, Leuven,<country>Belgium</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff13"><institution>Human Genome Laboratory, Department of Human Genetics, K.U. Leuven</institution>, Leuven,<country>Belgium</country></nlm:aff></affiliation></author><author><name sortKey="Frints, S G M" sort="Frints, S G M" uniqKey="Frints S" first="S G M" last="Frints">S G M. Frints</name><affiliation><nlm:aff id="aff14"><institution>Department of Clinical Genetics, Maastricht University Medical Center, azM</institution>, Maastricht,<country>The Netherlands</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff15"><institution>School for Oncology and Developmental Biology, GROW, Maastricht University</institution>, Maastricht,<country>The Netherlands</country></nlm:aff></affiliation></author><author><name sortKey="Laumonnier, F" sort="Laumonnier, F" uniqKey="Laumonnier F" first="F" last="Laumonnier">F. Laumonnier</name><affiliation><nlm:aff id="aff6"><institution>Inserm U930 ‘Imaging and Brain'</institution>, Tours,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff7"><institution>University François-Rabelais</institution>, Tours,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Zemojtel, T" sort="Zemojtel, T" uniqKey="Zemojtel T" first="T" last="Zemojtel">T. Zemojtel</name><affiliation><nlm:aff id="aff2"><institution>Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Love, M I" sort="Love, M I" uniqKey="Love M" first="M I" last="Love">M I Love</name><affiliation><nlm:aff id="aff2"><institution>Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Richard, H" sort="Richard, H" uniqKey="Richard H" first="H" last="Richard">H. Richard</name><affiliation><nlm:aff id="aff2"><institution>Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Emde, A K" sort="Emde, A K" uniqKey="Emde A" first="A-K" last="Emde">A-K Emde</name><affiliation><nlm:aff id="aff2"><institution>Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Bienek, M" sort="Bienek, M" uniqKey="Bienek M" first="M" last="Bienek">M. Bienek</name><affiliation><nlm:aff id="aff1"><institution>Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Jensen, C" sort="Jensen, C" uniqKey="Jensen C" first="C" last="Jensen">C. Jensen</name><affiliation><nlm:aff id="aff1"><institution>Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Hambrock, M" sort="Hambrock, M" uniqKey="Hambrock M" first="M" last="Hambrock">M. Hambrock</name><affiliation><nlm:aff id="aff1"><institution>Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Fischer, U" sort="Fischer, U" uniqKey="Fischer U" first="U" last="Fischer">U. Fischer</name><affiliation><nlm:aff id="aff1"><institution>Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Langnick, C" sort="Langnick, C" uniqKey="Langnick C" first="C" last="Langnick">C. Langnick</name><affiliation><nlm:aff id="aff10"><institution>Max-Delbrück-Centrum für Molekulare Medizin</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Feldkamp, M" sort="Feldkamp, M" uniqKey="Feldkamp M" first="M" last="Feldkamp">M. Feldkamp</name><affiliation><nlm:aff id="aff10"><institution>Max-Delbrück-Centrum für Molekulare Medizin</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Wissink Lindhout, W" sort="Wissink Lindhout, W" uniqKey="Wissink Lindhout W" first="W" last="Wissink-Lindhout">W. Wissink-Lindhout</name><affiliation><nlm:aff id="aff9"><institution>Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour</institution>, Nijmegen,<country>The Netherlands</country></nlm:aff></affiliation></author><author><name sortKey="Lebrun, N" sort="Lebrun, N" uniqKey="Lebrun N" first="N" last="Lebrun">N. Lebrun</name><affiliation><nlm:aff id="aff3"><institution>University Paris Descartes</institution>, Paris,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff4"><institution>Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Institut National de la Santé et de la Recherche Médicale Unité 1016, Institut Cochin</institution>, Paris,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Castelnau, L" sort="Castelnau, L" uniqKey="Castelnau L" first="L" last="Castelnau">L. Castelnau</name><affiliation><nlm:aff id="aff3"><institution>University Paris Descartes</institution>, Paris,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff4"><institution>Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Institut National de la Santé et de la Recherche Médicale Unité 1016, Institut Cochin</institution>, Paris,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Rucci, J" sort="Rucci, J" uniqKey="Rucci J" first="J" last="Rucci">J. Rucci</name><affiliation><nlm:aff id="aff3"><institution>University Paris Descartes</institution>, Paris,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff4"><institution>Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Institut National de la Santé et de la Recherche Médicale Unité 1016, Institut Cochin</institution>, Paris,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Montjean, R" sort="Montjean, R" uniqKey="Montjean R" first="R" last="Montjean">R. Montjean</name><affiliation><nlm:aff id="aff3"><institution>University Paris Descartes</institution>, Paris,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff4"><institution>Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Institut National de la Santé et de la Recherche Médicale Unité 1016, Institut Cochin</institution>, Paris,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Dorseuil, O" sort="Dorseuil, O" uniqKey="Dorseuil O" first="O" last="Dorseuil">O. Dorseuil</name><affiliation><nlm:aff id="aff3"><institution>University Paris Descartes</institution>, Paris,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff4"><institution>Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Institut National de la Santé et de la Recherche Médicale Unité 1016, Institut Cochin</institution>, Paris,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Billuart, P" sort="Billuart, P" uniqKey="Billuart P" first="P" last="Billuart">P. Billuart</name><affiliation><nlm:aff id="aff3"><institution>University Paris Descartes</institution>, Paris,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff4"><institution>Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Institut National de la Santé et de la Recherche Médicale Unité 1016, Institut Cochin</institution>, Paris,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Stuhlmann, T" sort="Stuhlmann, T" uniqKey="Stuhlmann T" first="T" last="Stuhlmann">T. Stuhlmann</name><affiliation><nlm:aff id="aff10"><institution>Max-Delbrück-Centrum für Molekulare Medizin</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff11"><institution>Leibniz-Institut für Molekulare Pharmakologie</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Shaw, M" sort="Shaw, M" uniqKey="Shaw M" first="M" last="Shaw">M. Shaw</name><affiliation><nlm:aff id="aff16"><institution>School of Paediatrics and Reproductive Health, The University of Adelaide</institution>, Adelaide, SA,<country>Australia</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff17"><institution>Robinson Research Institute, The University of Adelaide</institution>, Adelaide, SA,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Corbett, M A" sort="Corbett, M A" uniqKey="Corbett M" first="M A" last="Corbett">M A Corbett</name><affiliation><nlm:aff id="aff16"><institution>School of Paediatrics and Reproductive Health, The University of Adelaide</institution>, Adelaide, SA,<country>Australia</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff17"><institution>Robinson Research Institute, The University of Adelaide</institution>, Adelaide, SA,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Gardner, A" sort="Gardner, A" uniqKey="Gardner A" first="A" last="Gardner">A. Gardner</name><affiliation><nlm:aff id="aff16"><institution>School of Paediatrics and Reproductive Health, The University of Adelaide</institution>, Adelaide, SA,<country>Australia</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff17"><institution>Robinson Research Institute, The University of Adelaide</institution>, Adelaide, SA,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Willis Owen, S" sort="Willis Owen, S" uniqKey="Willis Owen S" first="S" last="Willis-Owen">S. Willis-Owen</name><affiliation><nlm:aff id="aff16"><institution>School of Paediatrics and Reproductive Health, The University of Adelaide</institution>, Adelaide, SA,<country>Australia</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff18"><institution>National Heart and Lung Institute, Imperial College London</institution>, London,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Tan, C" sort="Tan, C" uniqKey="Tan C" first="C" last="Tan">C. Tan</name><affiliation><nlm:aff id="aff16"><institution>School of Paediatrics and Reproductive Health, The University of Adelaide</institution>, Adelaide, SA,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Friend, K L" sort="Friend, K L" uniqKey="Friend K" first="K L" last="Friend">K L Friend</name><affiliation><nlm:aff id="aff19"><institution>SA Pathology, Women's and Children's Hospital</institution>, Adelaide, SA,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Belet, S" sort="Belet, S" uniqKey="Belet S" first="S" last="Belet">S. Belet</name><affiliation><nlm:aff id="aff12"><institution>Human Genome Laboratory, VIB Center for the Biology of Disease</institution>, Leuven,<country>Belgium</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff13"><institution>Human Genome Laboratory, Department of Human Genetics, K.U. Leuven</institution>, Leuven,<country>Belgium</country></nlm:aff></affiliation></author><author><name sortKey="Van Roozendaal, K E P" sort="Van Roozendaal, K E P" uniqKey="Van Roozendaal K" first="K E P" last="Van Roozendaal">K E P. Van Roozendaal</name><affiliation><nlm:aff id="aff14"><institution>Department of Clinical Genetics, Maastricht University Medical Center, azM</institution>, Maastricht,<country>The Netherlands</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff15"><institution>School for Oncology and Developmental Biology, GROW, Maastricht University</institution>, Maastricht,<country>The Netherlands</country></nlm:aff></affiliation></author><author><name sortKey="Jimenez Pocquet, M" sort="Jimenez Pocquet, M" uniqKey="Jimenez Pocquet M" first="M" last="Jimenez-Pocquet">M. Jimenez-Pocquet</name><affiliation><nlm:aff id="aff8"><institution>Centre Hospitalier Régional Universitaire, Service de Génétique</institution>, Tours,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Moizard, M P" sort="Moizard, M P" uniqKey="Moizard M" first="M-P" last="Moizard">M-P Moizard</name><affiliation><nlm:aff id="aff6"><institution>Inserm U930 ‘Imaging and Brain'</institution>, Tours,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff7"><institution>University François-Rabelais</institution>, Tours,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff8"><institution>Centre Hospitalier Régional Universitaire, Service de Génétique</institution>, Tours,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Ronce, N" sort="Ronce, N" uniqKey="Ronce N" first="N" last="Ronce">N. Ronce</name><affiliation><nlm:aff id="aff6"><institution>Inserm U930 ‘Imaging and Brain'</institution>, Tours,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff7"><institution>University François-Rabelais</institution>, Tours,<country>France</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff8"><institution>Centre Hospitalier Régional Universitaire, Service de Génétique</institution>, Tours,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Sun, R" sort="Sun, R" uniqKey="Sun R" first="R" last="Sun">R. Sun</name><affiliation><nlm:aff id="aff2"><institution>Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="O Keeffe, S" sort="O Keeffe, S" uniqKey="O Keeffe S" first="S" last="O'Keeffe">S. O'Keeffe</name><affiliation><nlm:aff id="aff2"><institution>Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Chenna, R" sort="Chenna, R" uniqKey="Chenna R" first="R" last="Chenna">R. Chenna</name><affiliation><nlm:aff id="aff2"><institution>Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Van Bommel, A" sort="Van Bommel, A" uniqKey="Van Bommel A" first="A" last="Van Bömmel">A. Van Bömmel</name><affiliation><nlm:aff id="aff2"><institution>Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Goke, J" sort="Goke, J" uniqKey="Goke J" first="J" last="Göke">J. Göke</name><affiliation><nlm:aff id="aff2"><institution>Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Hackett, A" sort="Hackett, A" uniqKey="Hackett A" first="A" last="Hackett">A. Hackett</name><affiliation><nlm:aff id="aff20"><institution>Genetics of Learning and Disability Service, Hunter Genetics</institution>, Waratah, NSW,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Field, M" sort="Field, M" uniqKey="Field M" first="M" last="Field">M. Field</name><affiliation><nlm:aff id="aff20"><institution>Genetics of Learning and Disability Service, Hunter Genetics</institution>, Waratah, NSW,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Christie, L" sort="Christie, L" uniqKey="Christie L" first="L" last="Christie">L. Christie</name><affiliation><nlm:aff id="aff20"><institution>Genetics of Learning and Disability Service, Hunter Genetics</institution>, Waratah, NSW,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Boyle, J" sort="Boyle, J" uniqKey="Boyle J" first="J" last="Boyle">J. Boyle</name><affiliation><nlm:aff id="aff20"><institution>Genetics of Learning and Disability Service, Hunter Genetics</institution>, Waratah, NSW,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Haan, E" sort="Haan, E" uniqKey="Haan E" first="E" last="Haan">E. Haan</name><affiliation><nlm:aff id="aff16"><institution>School of Paediatrics and Reproductive Health, The University of Adelaide</institution>, Adelaide, SA,<country>Australia</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff19"><institution>SA Pathology, Women's and Children's Hospital</institution>, Adelaide, SA,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Nelson, J" sort="Nelson, J" uniqKey="Nelson J" first="J" last="Nelson">J. Nelson</name><affiliation><nlm:aff id="aff21"><institution>Genetic Services of Western Australia, King Edward Memorial Hospital</institution>, Perth, WA,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Turner, G" sort="Turner, G" uniqKey="Turner G" first="G" last="Turner">G. Turner</name><affiliation><nlm:aff id="aff20"><institution>Genetics of Learning and Disability Service, Hunter Genetics</institution>, Waratah, NSW,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Baynam, G" sort="Baynam, G" uniqKey="Baynam G" first="G" last="Baynam">G. Baynam</name><affiliation><nlm:aff id="aff21"><institution>Genetic Services of Western Australia, King Edward Memorial Hospital</institution>, Perth, WA,<country>Australia</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff22"><institution>School of Paediatrics and Child Health, University of Western Australia</institution>, Perth, WA,<country>Australia</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff23"><institution>Institute for Immunology and Infectious Diseases, Murdoch University</institution>, Perth, WA,<country>Australia</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff24"><institution>Telethon Kids Institute</institution>, Perth, WA,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Gillessen Kaesbach, G" sort="Gillessen Kaesbach, G" uniqKey="Gillessen Kaesbach G" first="G" last="Gillessen-Kaesbach">G. Gillessen-Kaesbach</name><affiliation><nlm:aff id="aff25"><institution>Institut für Humangenetik, Universität zu Lübeck</institution>, Lübeck,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Muller, U" sort="Muller, U" uniqKey="Muller U" first="U" last="Müller">U. Müller</name><affiliation><nlm:aff id="aff26"><institution>Institut für Humangenetik, Justus-Liebig-Universität Giessen</institution>, Giessen,<country>Germany</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff27"><institution>bio.logis Center for Human Genetics</institution>, Frankfurt a. M.,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Steinberger, D" sort="Steinberger, D" uniqKey="Steinberger D" first="D" last="Steinberger">D. Steinberger</name><affiliation><nlm:aff id="aff26"><institution>Institut für Humangenetik, Justus-Liebig-Universität Giessen</institution>, Giessen,<country>Germany</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff27"><institution>bio.logis Center for Human Genetics</institution>, Frankfurt a. M.,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Budny, B" sort="Budny, B" uniqKey="Budny B" first="B" last="Budny">B. Budny</name><affiliation><nlm:aff id="aff28"><institution>Chair and Department of Endocrinology, Metabolism and Internal Diseases</institution><institution>, Ponzan University of Medical Sciences,</institution> Poznan,<country>Poland</country></nlm:aff></affiliation></author><author><name sortKey="Badura Stronka, M" sort="Badura Stronka, M" uniqKey="Badura Stronka M" first="M" last="Badura-Stronka">M. Badura-Stronka</name><affiliation><nlm:aff id="aff29"><institution>Chair and Department of Medical Genetics, Poznan University of Medical Sciences</institution>, Poznan,<country>Poland</country></nlm:aff></affiliation></author><author><name sortKey="Latos Biele Ska, A" sort="Latos Biele Ska, A" uniqKey="Latos Biele Ska A" first="A" last="Latos-Biele Ska">A. Latos-Biele Ska</name><affiliation><nlm:aff id="aff29"><institution>Chair and Department of Medical Genetics, Poznan University of Medical Sciences</institution>, Poznan,<country>Poland</country></nlm:aff></affiliation></author><author><name sortKey="Ousager, L B" sort="Ousager, L B" uniqKey="Ousager L" first="L B" last="Ousager">L B Ousager</name><affiliation><nlm:aff id="aff30"><institution>Department of Clinical Genetics, Odense University Hospital</institution>, Odense,<country>Denmark</country></nlm:aff></affiliation></author><author><name sortKey="Wieacker, P" sort="Wieacker, P" uniqKey="Wieacker P" first="P" last="Wieacker">P. Wieacker</name><affiliation><nlm:aff id="aff31"><institution>Institut für Humangenetik, Universitätsklinikum Münster</institution>, Muenster,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Rodriguez Criado, G" sort="Rodriguez Criado, G" uniqKey="Rodriguez Criado G" first="G" last="Rodríguez Criado">G. Rodríguez Criado</name><affiliation><nlm:aff id="aff32"><institution>Unidad de Genética Clínica, Hospital Virgen del Rocío</institution>, Sevilla,<country>España</country></nlm:aff></affiliation></author><author><name sortKey="Bondeson, M L" sort="Bondeson, M L" uniqKey="Bondeson M" first="M-L" last="Bondeson">M-L Bondeson</name><affiliation><nlm:aff id="aff33"><institution>Department of Immunology, Genetics and Pathology, Uppsala University</institution>, Uppsala,<country>Sweden</country></nlm:aff></affiliation></author><author><name sortKey="Anneren, G" sort="Anneren, G" uniqKey="Anneren G" first="G" last="Annerén">G. Annerén</name><affiliation><nlm:aff id="aff33"><institution>Department of Immunology, Genetics and Pathology, Uppsala University</institution>, Uppsala,<country>Sweden</country></nlm:aff></affiliation></author><author><name sortKey="Dufke, A" sort="Dufke, A" uniqKey="Dufke A" first="A" last="Dufke">A. Dufke</name><affiliation><nlm:aff id="aff34"><institution>Institut für Medizinische Genetik und Angewandte Genomik</institution>, Tübingen,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Cohen, M" sort="Cohen, M" uniqKey="Cohen M" first="M" last="Cohen">M. Cohen</name><affiliation><nlm:aff id="aff35"><institution>Kinderzentrum München</institution>, München,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Van Maldergem, L" sort="Van Maldergem, L" uniqKey="Van Maldergem L" first="L" last="Van Maldergem">L. Van Maldergem</name><affiliation><nlm:aff id="aff36"><institution>Centre de Génétique Humaine, Université de Franche-Comté</institution>, Besançon,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Vincent Delorme, C" sort="Vincent Delorme, C" uniqKey="Vincent Delorme C" first="C" last="Vincent-Delorme">C. Vincent-Delorme</name><affiliation><nlm:aff id="aff37"><institution>Service de Génétique, Hôpital Jeanne de Flandre CHRU de Lilles</institution>, Lille,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Echenne, B" sort="Echenne, B" uniqKey="Echenne B" first="B" last="Echenne">B. Echenne</name><affiliation><nlm:aff id="aff38"><institution>Service de Neuro-Pédiatrie, CHU Montpellier</institution>, Montpellier,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Simon Bouy, B" sort="Simon Bouy, B" uniqKey="Simon Bouy B" first="B" last="Simon-Bouy">B. Simon-Bouy</name><affiliation><nlm:aff id="aff39"><institution>Laboratoire SESEP, Centre hospitalier de Versailles</institution>, Le Chesnay,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Kleefstra, T" sort="Kleefstra, T" uniqKey="Kleefstra T" first="T" last="Kleefstra">T. Kleefstra</name><affiliation><nlm:aff id="aff9"><institution>Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour</institution>, Nijmegen,<country>The Netherlands</country></nlm:aff></affiliation></author><author><name sortKey="Willemsen, M" sort="Willemsen, M" uniqKey="Willemsen M" first="M" last="Willemsen">M. Willemsen</name><affiliation><nlm:aff id="aff9"><institution>Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour</institution>, Nijmegen,<country>The Netherlands</country></nlm:aff></affiliation></author><author><name sortKey="Fryns, J P" sort="Fryns, J P" uniqKey="Fryns J" first="J-P" last="Fryns">J-P Fryns</name><affiliation><nlm:aff id="aff5"><institution>Center for Human Genetics, University Hospitals Leuven</institution>, Leuven,<country>Belgium</country></nlm:aff></affiliation></author><author><name sortKey="Devriendt, K" sort="Devriendt, K" uniqKey="Devriendt K" first="K" last="Devriendt">K. Devriendt</name><affiliation><nlm:aff id="aff5"><institution>Center for Human Genetics, University Hospitals Leuven</institution>, Leuven,<country>Belgium</country></nlm:aff></affiliation></author><author><name sortKey="Ullmann, R" sort="Ullmann, R" uniqKey="Ullmann R" first="R" last="Ullmann">R. Ullmann</name><affiliation><nlm:aff id="aff1"><institution>Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Vingron, M" sort="Vingron, M" uniqKey="Vingron M" first="M" last="Vingron">M. Vingron</name><affiliation><nlm:aff id="aff2"><institution>Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Wrogemann, K" sort="Wrogemann, K" uniqKey="Wrogemann K" first="K" last="Wrogemann">K. Wrogemann</name><affiliation><nlm:aff id="aff1"><institution>Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff40"><institution>Department of Biochemistry and Medical Genetics, University of Manitoba</institution>, Winnipeg, MB,<country>Canada</country></nlm:aff></affiliation></author><author><name sortKey="Wienker, T F" sort="Wienker, T F" uniqKey="Wienker T" first="T F" last="Wienker">T F Wienker</name><affiliation><nlm:aff id="aff1"><institution>Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Tzschach, A" sort="Tzschach, A" uniqKey="Tzschach A" first="A" last="Tzschach">A. Tzschach</name><affiliation><nlm:aff id="aff1"><institution>Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Van Bokhoven, H" sort="Van Bokhoven, H" uniqKey="Van Bokhoven H" first="H" last="Van Bokhoven">H. Van Bokhoven</name><affiliation><nlm:aff id="aff9"><institution>Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour</institution>, Nijmegen,<country>The Netherlands</country></nlm:aff></affiliation></author><author><name sortKey="Gecz, J" sort="Gecz, J" uniqKey="Gecz J" first="J" last="Gecz">J. Gecz</name><affiliation><nlm:aff id="aff16"><institution>School of Paediatrics and Reproductive Health, The University of Adelaide</institution>, Adelaide, SA,<country>Australia</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff17"><institution>Robinson Research Institute, The University of Adelaide</institution>, Adelaide, SA,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Jentsch, T J" sort="Jentsch, T J" uniqKey="Jentsch T" first="T J" last="Jentsch">T J Jentsch</name><affiliation><nlm:aff id="aff10"><institution>Max-Delbrück-Centrum für Molekulare Medizin</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff11"><institution>Leibniz-Institut für Molekulare Pharmakologie</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Chen, W" sort="Chen, W" uniqKey="Chen W" first="W" last="Chen">W. Chen</name><affiliation><nlm:aff id="aff1"><institution>Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff10"><institution>Max-Delbrück-Centrum für Molekulare Medizin</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Ropers, H H" sort="Ropers, H H" uniqKey="Ropers H" first="H-H" last="Ropers">H-H Ropers</name><affiliation><nlm:aff id="aff1"><institution>Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Kalscheuer, V M" sort="Kalscheuer, V M" uniqKey="Kalscheuer V" first="V M" last="Kalscheuer">V M Kalscheuer</name><affiliation><nlm:aff id="aff1"><institution>Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></nlm:aff></affiliation></author></analytic><series><title level="j">Molecular Psychiatry</title><idno type="ISSN">1359-4184</idno><idno type="eISSN">1476-5578</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>X-linked intellectual disability (XLID) is a clinically and genetically heterogeneous disorder. During the past two decades in excess of 100 X-chromosome ID genes have been identified. Yet, a large number of families mapping to the X-chromosome remained unresolved suggesting that more XLID genes or loci are yet to be identified. Here, we have investigated 405 unresolved families with XLID. We employed massively parallel sequencing of all X-chromosome exons in the index males. The majority of these males were previously tested negative for copy number variations and for mutations in a subset of known XLID genes by Sanger sequencing. In total, 745 X-chromosomal genes were screened. After stringent filtering, a total of 1297 non-recurrent exonic variants remained for prioritization. Co-segregation analysis of potential clinically relevant changes revealed that 80 families (20%) carried pathogenic variants in established XLID genes. In 19 families, we detected likely causative protein truncating and missense variants in 7 novel and validated XLID genes (<italic>CLCN4</italic>, <italic>CNKSR2</italic>, <italic>FRMPD4, KLHL15</italic>, <italic>LAS1L</italic>, <italic>RLIM</italic> and <italic>USP27X</italic>) and potentially deleterious variants in 2 novel candidate XLID genes (<italic>CDK16</italic> and <italic>TAF1</italic>). We show that the <italic>CLCN4</italic> and <italic>CNKSR2</italic> variants impair protein functions as indicated by electrophysiological studies and altered differentiation of cultured primary neurons from <italic>Clcn4</italic><sup>−/−</sup> mice or after mRNA knock-down. The newly identified and candidate XLID proteins belong to pathways and networks with established roles in cognitive function and intellectual disability in particular. We suggest that systematic sequencing of all X-chromosomal genes in a cohort of patients with genetic evidence for X-chromosome locus involvement may resolve up to 58% of Fragile X-negative cases.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Mol Psychiatry</journal-id><journal-id journal-id-type="iso-abbrev">Mol. Psychiatry</journal-id><journal-title-group><journal-title>Molecular Psychiatry</journal-title></journal-title-group><issn pub-type="ppub">1359-4184</issn><issn pub-type="epub">1476-5578</issn><publisher><publisher-name>Nature Publishing Group</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">25644381</article-id><article-id pub-id-type="pmc">5414091</article-id><article-id pub-id-type="pii">mp2014193</article-id><article-id pub-id-type="doi">10.1038/mp.2014.193</article-id><article-categories><subj-group subj-group-type="heading"><subject>Original Article</subject></subj-group></article-categories><title-group><article-title>X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes</article-title><alt-title alt-title-type="running">Novel X-linked intellectual disability genes</alt-title></title-group><contrib-group><contrib 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contrib-type="author"><name><surname>Vingron</surname><given-names>M</given-names></name><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Wrogemann</surname><given-names>K</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff40">40</xref></contrib><contrib contrib-type="author"><name><surname>Wienker</surname><given-names>T F</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Tzschach</surname><given-names>A</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>van Bokhoven</surname><given-names>H</given-names></name><xref ref-type="aff" rid="aff9">9</xref></contrib><contrib contrib-type="author"><name><surname>Gecz</surname><given-names>J</given-names></name><xref ref-type="aff" rid="aff16">16</xref><xref ref-type="aff" rid="aff17">17</xref><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0002-7884-6861</contrib-id></contrib><contrib contrib-type="author"><name><surname>Jentsch</surname><given-names>T J</given-names></name><xref ref-type="aff" rid="aff10">10</xref><xref ref-type="aff" rid="aff11">11</xref></contrib><contrib contrib-type="author"><name><surname>Chen</surname><given-names>W</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff10">10</xref></contrib><contrib contrib-type="author"><name><surname>Ropers</surname><given-names>H-H</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Kalscheuer</surname><given-names>V M</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="corresp" rid="caf1">*</xref></contrib><aff id="aff1"><label>1</label><institution>Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></aff><aff id="aff2"><label>2</label><institution>Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics</institution>, Berlin,<country>Germany</country></aff><aff id="aff3"><label>3</label><institution>University Paris Descartes</institution>, Paris,<country>France</country></aff><aff id="aff4"><label>4</label><institution>Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Institut National de la Santé et de la Recherche Médicale Unité 1016, Institut Cochin</institution>, Paris,<country>France</country></aff><aff id="aff5"><label>5</label><institution>Center for Human Genetics, University Hospitals Leuven</institution>, Leuven,<country>Belgium</country></aff><aff id="aff6"><label>6</label><institution>Inserm U930 ‘Imaging and Brain'</institution>, Tours,<country>France</country></aff><aff id="aff7"><label>7</label><institution>University François-Rabelais</institution>, Tours,<country>France</country></aff><aff id="aff8"><label>8</label><institution>Centre Hospitalier Régional Universitaire, Service de Génétique</institution>, Tours,<country>France</country></aff><aff id="aff9"><label>9</label><institution>Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour</institution>, Nijmegen,<country>The Netherlands</country></aff><aff id="aff10"><label>10</label><institution>Max-Delbrück-Centrum für Molekulare Medizin</institution>, Berlin,<country>Germany</country></aff><aff id="aff11"><label>11</label><institution>Leibniz-Institut für Molekulare Pharmakologie</institution>, Berlin,<country>Germany</country></aff><aff id="aff12"><label>12</label><institution>Human Genome Laboratory, VIB Center for the Biology of Disease</institution>, Leuven,<country>Belgium</country></aff><aff id="aff13"><label>13</label><institution>Human Genome Laboratory, Department of Human Genetics, K.U. Leuven</institution>, Leuven,<country>Belgium</country></aff><aff id="aff14"><label>14</label><institution>Department of Clinical Genetics, Maastricht University Medical Center, azM</institution>, Maastricht,<country>The Netherlands</country></aff><aff id="aff15"><label>15</label><institution>School for Oncology and Developmental Biology, GROW, Maastricht University</institution>, Maastricht,<country>The Netherlands</country></aff><aff id="aff16"><label>16</label><institution>School of Paediatrics and Reproductive Health, The University of Adelaide</institution>, Adelaide, SA,<country>Australia</country></aff><aff id="aff17"><label>17</label><institution>Robinson Research Institute, The University of Adelaide</institution>, Adelaide, SA,<country>Australia</country></aff><aff id="aff18"><label>18</label><institution>National Heart and Lung Institute, Imperial College London</institution>, London,<country>UK</country></aff><aff id="aff19"><label>19</label><institution>SA Pathology, Women's and Children's Hospital</institution>, Adelaide, SA,<country>Australia</country></aff><aff id="aff20"><label>20</label><institution>Genetics of Learning and Disability Service, Hunter Genetics</institution>, Waratah, NSW,<country>Australia</country></aff><aff id="aff21"><label>21</label><institution>Genetic Services of Western Australia, King Edward Memorial Hospital</institution>, Perth, WA,<country>Australia</country></aff><aff id="aff22"><label>22</label><institution>School of Paediatrics and Child Health, University of Western Australia</institution>, Perth, WA,<country>Australia</country></aff><aff id="aff23"><label>23</label><institution>Institute for Immunology and Infectious Diseases, Murdoch University</institution>, Perth, WA,<country>Australia</country></aff><aff id="aff24"><label>24</label><institution>Telethon Kids Institute</institution>, Perth, WA,<country>Australia</country></aff><aff id="aff25"><label>25</label><institution>Institut für Humangenetik, Universität zu Lübeck</institution>, Lübeck,<country>Germany</country></aff><aff id="aff26"><label>26</label><institution>Institut für Humangenetik, Justus-Liebig-Universität Giessen</institution>, Giessen,<country>Germany</country></aff><aff id="aff27"><label>27</label><institution>bio.logis Center for Human Genetics</institution>, Frankfurt a. M.,<country>Germany</country></aff><aff id="aff28"><label>28</label><institution>Chair and Department of Endocrinology, Metabolism and Internal Diseases</institution><institution>, Ponzan University of Medical Sciences,</institution> Poznan,<country>Poland</country></aff><aff id="aff29"><label>29</label><institution>Chair and Department of Medical Genetics, Poznan University of Medical Sciences</institution>, Poznan,<country>Poland</country></aff><aff id="aff30"><label>30</label><institution>Department of Clinical Genetics, Odense University Hospital</institution>, Odense,<country>Denmark</country></aff><aff id="aff31"><label>31</label><institution>Institut für Humangenetik, Universitätsklinikum Münster</institution>, Muenster,<country>Germany</country></aff><aff id="aff32"><label>32</label><institution>Unidad de Genética Clínica, Hospital Virgen del Rocío</institution>, Sevilla,<country>España</country></aff><aff id="aff33"><label>33</label><institution>Department of Immunology, Genetics and Pathology, Uppsala University</institution>, Uppsala,<country>Sweden</country></aff><aff id="aff34"><label>34</label><institution>Institut für Medizinische Genetik und Angewandte Genomik</institution>, Tübingen,<country>Germany</country></aff><aff id="aff35"><label>35</label><institution>Kinderzentrum München</institution>, München,<country>Germany</country></aff><aff id="aff36"><label>36</label><institution>Centre de Génétique Humaine, Université de Franche-Comté</institution>, Besançon,<country>France</country></aff><aff id="aff37"><label>37</label><institution>Service de Génétique, Hôpital Jeanne de Flandre CHRU de Lilles</institution>, Lille,<country>France</country></aff><aff id="aff38"><label>38</label><institution>Service de Neuro-Pédiatrie, CHU Montpellier</institution>, Montpellier,<country>France</country></aff><aff id="aff39"><label>39</label><institution>Laboratoire SESEP, Centre hospitalier de Versailles</institution>, Le Chesnay,<country>France</country></aff><aff id="aff40"><label>40</label><institution>Department of Biochemistry and Medical Genetics, University of Manitoba</institution>, Winnipeg, MB,<country>Canada</country></aff></contrib-group><author-notes><corresp id="caf1"><label>*</label><institution>Max Planck Institute for Molecular Genetics</institution>, Ihnestrasse 73, Berlin 14195, <country>Germany</country>. E-mail: <email>kalscheu@molgen.mpg.de</email></corresp><fn id="note1" fn-type="equal"><label>41</label><p>These authors contributed equally to this work.</p></fn><fn id="note2" fn-type="present-address"><label>42</label><p>Present address: Institut für Radiobiologie der Bundeswehr in Verbindung mit der Universität Ulm, 80937 München, Germany</p></fn></author-notes><pub-date pub-type="ppub"><month>01</month><year>2016</year></pub-date><pub-date pub-type="epub"><day>03</day><month>02</month><year>2015</year></pub-date><volume>21</volume><issue>1</issue><fpage>133</fpage><lpage>148</lpage><history><date date-type="received"><day>04</day><month>08</month><year>2014</year></date><date date-type="rev-recd"><day>17</day><month>11</month><year>2014</year></date><date date-type="accepted"><day>08</day><month>12</month><year>2014</year></date></history><permissions><copyright-statement>Copyright © 2016 Macmillan Publishers Limited</copyright-statement><copyright-year>2016</copyright-year><copyright-holder>Macmillan Publishers Limited</copyright-holder><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by-nc-nd/4.0/"><pmc-comment>author-paid</pmc-comment>
<license-p>This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc-nd/4.0/">http://creativecommons.org/licenses/by-nc-nd/4.0/</ext-link></license-p></license></permissions><abstract><p>X-linked intellectual disability (XLID) is a clinically and genetically heterogeneous disorder. During the past two decades in excess of 100 X-chromosome ID genes have been identified. Yet, a large number of families mapping to the X-chromosome remained unresolved suggesting that more XLID genes or loci are yet to be identified. Here, we have investigated 405 unresolved families with XLID. We employed massively parallel sequencing of all X-chromosome exons in the index males. The majority of these males were previously tested negative for copy number variations and for mutations in a subset of known XLID genes by Sanger sequencing. In total, 745 X-chromosomal genes were screened. After stringent filtering, a total of 1297 non-recurrent exonic variants remained for prioritization. Co-segregation analysis of potential clinically relevant changes revealed that 80 families (20%) carried pathogenic variants in established XLID genes. In 19 families, we detected likely causative protein truncating and missense variants in 7 novel and validated XLID genes (<italic>CLCN4</italic>, <italic>CNKSR2</italic>, <italic>FRMPD4, KLHL15</italic>, <italic>LAS1L</italic>, <italic>RLIM</italic> and <italic>USP27X</italic>) and potentially deleterious variants in 2 novel candidate XLID genes (<italic>CDK16</italic> and <italic>TAF1</italic>). We show that the <italic>CLCN4</italic> and <italic>CNKSR2</italic> variants impair protein functions as indicated by electrophysiological studies and altered differentiation of cultured primary neurons from <italic>Clcn4</italic><sup>−/−</sup> mice or after mRNA knock-down. The newly identified and candidate XLID proteins belong to pathways and networks with established roles in cognitive function and intellectual disability in particular. We suggest that systematic sequencing of all X-chromosomal genes in a cohort of patients with genetic evidence for X-chromosome locus involvement may resolve up to 58% of Fragile X-negative cases.</p></abstract></article-meta></front><body><sec><title>Introduction</title><p>Intellectual disability (ID), which affects 1–2% of the general population, is characterized by significant sub-average cognitive functioning, commonly defined by an IQ of lower than 70, and deficits in adaptive behavior, such as social and daily-living skills with an onset before 18 years of age. Most severe forms have a single genetic cause, and males are more often affected than females. Therefore, for many years, research has focused on the molecular elucidation of X-linked forms of ID which are thought to account for 10–12% of all males with ID.<sup><xref ref-type="bibr" rid="bib1">1</xref></sup> Until 2007, mutations in XLID genes known at that time had been detected in 42% of the Fragile X-negative families studied.<sup><xref ref-type="bibr" rid="bib2">2</xref></sup> Afterwards, a large-scale, comprehensive Sanger sequencing study was performed to identify the missing genes and mutations in a cohort of 208 families.<sup><xref ref-type="bibr" rid="bib3">3</xref></sup> This study was complemented by high-resolution array CGH profiling on the same set of families<sup><xref ref-type="bibr" rid="bib4">4</xref></sup> and by further genetic and functional evidence for some of the unique missense variants.<sup><xref ref-type="bibr" rid="bib5">5</xref>, <xref ref-type="bibr" rid="bib6">6</xref>, <xref ref-type="bibr" rid="bib7">7</xref></sup> However, in excess of 50% XLID families remained without plausible gene defects further indicating genetic heterogeneity of XLID. Since then, several novel XLID genes have been reported in the medical literature, including <italic>HUWE1</italic> [MIM 300697],<sup><xref ref-type="bibr" rid="bib8">8</xref></sup><italic>SLC9A6</italic> [MIM 300231],<sup><xref ref-type="bibr" rid="bib9">9</xref></sup><italic>PCDH19</italic> [MIM 300460],<sup><xref ref-type="bibr" rid="bib10">10</xref></sup><italic>RAB39B</italic> [MIM 300774],<sup><xref ref-type="bibr" rid="bib11">11</xref></sup><italic>HDAC8</italic> [MIM 300269],<sup><xref ref-type="bibr" rid="bib12">12</xref></sup><italic>HCFC1</italic> [MIM 300019],<sup><xref ref-type="bibr" rid="bib13">13</xref></sup><italic>CCDC22</italic> [MIM 300859],<sup><xref ref-type="bibr" rid="bib14">14</xref>, <xref ref-type="bibr" rid="bib15">15</xref></sup><italic>USP9X</italic> [MIM 300072],<sup><xref ref-type="bibr" rid="bib6">6</xref></sup><italic>PIGA</italic> [MIM 311770],<sup><xref ref-type="bibr" rid="bib16">16</xref></sup><italic>WDR45</italic> [MIM 300526],<sup><xref ref-type="bibr" rid="bib17">17</xref></sup><italic>KDM6A</italic> [MIM 300128],<sup><xref ref-type="bibr" rid="bib18">18</xref></sup><italic>BCAP31</italic> [MIM 300398],<sup><xref ref-type="bibr" rid="bib19">19</xref></sup><italic>ZC4H2</italic> [MIM 300897],<sup><xref ref-type="bibr" rid="bib20">20</xref></sup><italic>KIAA2022</italic> [MIM 300524]<sup><xref ref-type="bibr" rid="bib21">21</xref></sup> and <italic>MID2</italic> [MIM 300204].<sup><xref ref-type="bibr" rid="bib22">22</xref></sup></p><p>In this study, we aimed to (i) identify the molecular causes of XLID in a large group of unresolved families, (ii) define the number of XLID genes that can be identified by performing targeted sequencing of all X chromosome-specific exons, (iii) gain knowledge about ID-related pathways and networks and (iv) estimate the proportion of families with XLID that can be solved using X-exome sequencing. For this, we initially focused on 248 families collected by the EUROMRX consortium and associated groups that remained unresolved by pre-screening for mutations in selected known XLID genes and by array CGH. In follow-up work we investigated an additional cohort of 157 similarly pre-screened families. We took advantage of next-generation sequencing (NGS) technology to substantially improve the coverage of X-chromosomal coding sequences compared with previous studies. We identified likely pathogenic variants in a range of previously established XLID genes as well as several novel and candidate XLID genes.</p></sec><sec><title>Subjects and methods</title><sec><title>Subjects</title><p>All index cases had a normal karyotype, were negative for <italic>FMR1</italic> repeat expansion, and in most of these large indels had been excluded using array CGH. The study was approved by all institutional review boards of the participating institutions, and written informed consent was obtained from all participants or their legal guardians.</p></sec><sec><title>Methods</title><p>For each family, DNA from one affected male was used for constructing a sequencing library using the Illumina Genomic DNA Single End Sample Prep kit (Illumina, San Diego, CA, USA). Enrichment of the X-chromosomal exome was then performed for each library using the Agilent SureSelect Human X Chromosome Kit (Agilent, Santa Clara, CA, USA), which contains 47 657 RNA baits for 7591 exons of 745 genes of the human X chromosome. Single-end deep sequencing was performed on the Illumina Genome Analyzer GAIIx (Illumina, San Diego, CA, USA). Read length was 76 nucleotides. For a subset of families of the second cohort, we performed droplet-based multiplex PCR (7367 amplicons, 757 genes, 1.54 Mb) similarly to the previously described study.<sup><xref ref-type="bibr" rid="bib23">23</xref></sup> Paired-end deep sequencing was performed on the HiSeq2000 platform (ATLAS, Berlin, Germay). A scheme outlining the variant discovery workflow is presented in <xref ref-type="supplementary-material" rid="sup1">Supplementary Figure 1</xref>.</p><p>Reads were extracted from qseq-files provided by the Illumina GAII system (Illumina). Reads containing ambiguous base calls were not considered for further analysis. The remaining reads were subsequently mapped to the human reference genome (hg18 without random fragments) with RazerS<sup><xref ref-type="bibr" rid="bib24">24</xref></sup> (parameters: -mcl 25 -pa -m 1 -dr 0 -i 93 -s 110101111001100010111 -t 4 -lm) tolerating up to 5 bp differences to the reference sequence per read. Only unique best matches were kept, whereas all remaining reads and those containing indels were subjected to a split mapping procedure of single end reads (SplazerS version 1.0,<sup><xref ref-type="bibr" rid="bib25">25</xref></sup> parameters: -m 1 -pa -i 95 -sm 23 -s 111001110011100111 -t 2 -maxG 50000) to detect short insertions (⩽30 bp) and larger deletions (<50 kb). For detecting large insertions/deletions by analyzing changes in depth of coverage along the targeted regions we used ExomeCopy.<sup><xref ref-type="bibr" rid="bib26">26</xref></sup> We performed a quality-based clipping of reads after mapping but before calling variants to minimize the number of false-positive calls. Starting from each end of a read with a sliding window of 10 bp we trimmed the read until we observed a window with all 10 phred base quality values >10. If there was a variant within 3 bp distance to the clipped region then the trimming was expanded up to this potential sequencing error. For both mapping procedures (RazerS+SplazerS) the calling of a variant required at least three reads with different mapping coordinates to exclude potential amplification artifacts. Single-nucleotide polymorphisms (SNPs) and short indels (⩽5 bp) were called with snpStore (parameters: -reb 0 -fc 10 -m 1 -mmp -mc 3 -oa -mp 1 -th 0.85 -mmq 10 -hr 0.001 -re -pws 1000), performing a realignment of the clipped mapped reads whenever at least three indel-containing reads were observed within close proximity. For an indel to be called no more than 75% of the spanning reads were allowed to contradict it. For single base variants we used the Maq consensus statistics<sup><xref ref-type="bibr" rid="bib27">27</xref></sup> integrated into the snpStore code. Larger deletions and small insertions were identified by examining the split mapping results for potential breakpoint positions. In case of multiple such positions implying varying indel lengths within a 20-bp range such candidate calls were assumed to be unreliable and were therefore discarded. To detect potential retrocopies, the boundaries of split read mappings were compared with known exon boundaries allowing a tolerance of ±5 bp. When both split ends coincided with exon boundaries these exons were defined as being part of a retrocopy event. Completeness of the retrocopy was defined by the highest fraction of exons per transcript for which exon-spanning reads were detected. One example is shown in <xref ref-type="supplementary-material" rid="sup1">Supplementary Figure 2</xref>. In a parallel approach, we processed the sequencing reads using an alternative software, Medical Resequencing Analysis Pipeline (MERAP), for mapping, variant calling, and annotation.<sup><xref ref-type="bibr" rid="bib28">28</xref></sup> Here, the mapping was performed using SOAP2.20<sup><xref ref-type="bibr" rid="bib29">29</xref></sup> allowing at most two mismatches. For the calling of single-nucleotide variants (SNVs) and indels a minimum of four reads and a more stringent Phred-like quality score of ⩾20 were required. Finally, only those variants called by both approaches were kept to yield high-confidence candidate variants.</p><p>For <italic>in silico</italic> prioritization of variants, we integrated the following features: (a) gene/transcript annotations (downloaded from UCSC Genome Browser, hg19); (b) known sequence variants from the following data sources: dbSNP, 1000 Genomes project, 200 Danish exomes,<sup><xref ref-type="bibr" rid="bib30">30</xref></sup> NHLBI Exome Sequencing Project (ESP6500, version without indels). Base exchanges were considered as 'known' (with exception of SNVs observed as only heterozygous in ESP6500 and 1000 Genomes project) if position and type of the nucleotide were identical to entries in the reference databases. We did not use a cutoff based on minor allele frequency. In case of short indels, a tolerance in positional matching was applied based on repetitiveness of the deleted/inserted sequence in the SNV flanking sequence; (c) variants detected in the screen performed by Tarpey <italic>et al.</italic><sup><xref ref-type="bibr" rid="bib3">3</xref></sup> were located in transcripts derived from ENSEMBL version 54. We defined the amino-acid coordinate shared by most transcripts of a gene as reference, which is sometimes different from the one annotated by Tarpey <italic>et al.</italic><sup><xref ref-type="bibr" rid="bib3">3</xref></sup> Conversion of coordinates was successful for 1647 variants; (d) evolutionary conservation across 44 vertebrate species;<sup><xref ref-type="bibr" rid="bib31">31</xref></sup> (e) splice site detection for defining potential cryptic splice sites (software NNSplice; cutoff 0.9 (ref. <xref ref-type="bibr" rid="bib32">32</xref>)); (f) potential functional impact: PolyPhen2,<sup><xref ref-type="bibr" rid="bib33">33</xref></sup> SIFT<sup><xref ref-type="bibr" rid="bib34">34</xref></sup> and (g) Human Gene Mutation Database (HGMD): known variants with Pubmed entries were treated as potentially disease causing if they were listed in HGMD Professional and annotated in maximally one reference SNV database.</p><p>We thus defined a prioritization score (PS) based on basic, computationally tractable criteria like type of variant or evolutionary conservation. Polyphen2/SIFT produces a categorical output (benign/tolerated, possibly damaging/low confidence, probably damaging/damaging), which was assigned to ordinal variables 1, 2 or 3. Numbers are decreasing with decreasing functional impact, missing values are scored nil. Whenever only one of the methods scored >0, the zero score was set to 1 to avoid underestimation of the functional impact. PhyloP values were rounded down to decimal numbers, values >5 were set to PHY=5, for values <2 PHY= 1, for values <0 PHY= 0. Since deletions/insertions are usually not scored by PolyPhen2/SIFT, we defined the following adhoc weighting scheme: non-sense/frameshift: TYPE=20 (maximal PS), deletions (>50 bp): TYPE=9 (similar to maximal impact prediction by PolyPhen2 and SIFT), duplications, in-frame deletions, potential splice site variants: TYPE=3. The score for a change identified in a gene known to have a role in XLID before this study was set to 3. PS=PP2 * Sift+PHY+TYPE+XLID; if PS>20, PS=20.</p><p>We also used CADD (Combined Annotation-Dependent Depletion)<sup><xref ref-type="bibr" rid="bib35">35</xref></sup> as an additional tool for annotating and interpreting SNVs as well as small indels (see <xref ref-type="supplementary-material" rid="sup1">Supplementary Figure 3</xref> for comparison of the scores).</p></sec><sec><title>Analysis of human <italic>CLCN4</italic> SNVs in Xenopus oocytes</title><p><italic>CLCN4</italic> SNVs were introduced into human <italic>CLCN4</italic> (NM_001830.3; Gene ID: 118) cDNA cloned into pTLN and pCIneo<sup><xref ref-type="bibr" rid="bib36">36</xref></sup> by recombinant PCR. We assessed the expression level and stability of wild-type and mutants with p.Gly78Ser, p.Leu221Val, p.Val536Met or p.Gly731Arg substitutions by western blot analysis of lysates from transiently transfected cells using standard methods. <italic>Xenopus laevis</italic> oocytes were injected with 23 ng cRNA, which was transcribed with the mMessage Machine kit (Ambion, Thermo Fisher Scientific Inc., Waltham, MA, USA) from pTLN.<sup><xref ref-type="bibr" rid="bib37">37</xref></sup> After 3 days incubation at 17 °C, currents were measured at room temperature using standard two-electrode voltage clamp employing TurboTEC amplifiers (npi electronic, Tamm, Germany) and pClamp10.2 software (Molecular Devices, Sunnyvale, CA, USA). Oocytes were superfused with modified ND96 saline (96 m<sc>M</sc> NaCl, 2 m<sc>M</sc> K-gluconate, 1.8 m<sc>M</sc> Ca-gluconate, 1 m<sc>M</sc> Mg-gluconate, 5 m<sc>M</sc> HEPES pH 7.5) and clamped in 20-mV steps to voltages between −100 and +80 mV. The holding potential was −30 mV.</p></sec><sec><title>Morphological studies of mouse hippocampal neurons</title><p>Mouse embryos were dissected at embryonic day 16.5 (E16.5), tissue was dissociated by trypsin as well as by mechanical treatment, and primary cultures of hippocampal neurons were established at 37 °C by plating on coated-glass coverslips (poly-L-Lysine and Laminin) at a density of 100 000 per 16 mm Petri dish. Neurons were differentiated for 18 days <italic>in vitro</italic> (18 DIV) using Neurobasal/B27 medium and antibiotics (Mycozap, Lonza, Basel, Switzerland), replacing half of the media each third day for maintenance according to standard procedures.<sup><xref ref-type="bibr" rid="bib38">38</xref>, <xref ref-type="bibr" rid="bib39">39</xref></sup> Short-hairpin RNA (shRNA) design was made by targeting the 3′UTR of each specific gene using Promega shRNA designer tools (Promega BioSciences, San Luis Obispo, CA, USA) or informations based on The RNAi Consortium (TCR) shRNA Library. A control shRNA-producing plasmid was used in control experiments as previously described.<sup><xref ref-type="bibr" rid="bib40">40</xref></sup> Three independent shRNA-producing and GFP-expressing plasmids, based on pSystrike vector (Promega), were produced for each gene and used as a pool. Sequences targeted by shRNAs for <italic>Cnksr2</italic> and <italic>Clcn4–2</italic> (<italic>Clcn4</italic>) genes and control sequences are GGAGCAGAGGATGGCAGTCATTCA, GGTGGGAAGGCTAGCTCTGTTACT, GCGCGGCGTATCAGGGCAAAGCTT, GGGTATGTGGGAGGGTGTAAATGA, GGGAGAGGCGAGTACGAAGATGAA, GTGGTCTACTCATGGCCATCTCAT and GCTCACCCTTCCTACTCTC. Full-length murine <italic>Cnksr2</italic> (NCBI reference sequence NM_177751.2) and <italic>Clcn4</italic> (NCBI reference sequence NM_011334.4) cDNAs were cloned into pFN21A HaloTag® CMV Flexi® vector (Promega). For rescue experiments, pool of plasmids encoding shRNAs were cotransfected with pFN21A HaloTag® fused to either <italic>Cnksr2</italic> or <italic>Clcn4</italic>. All constructs were sequence verified and plasmids were purified using an endotoxin-free kit (Macherey Nagel, Düren, Germany). Transfections were carried out using Lipofectamine (Invitrogen, Life Technologies, Carlsbad, CA, USA) at 11 DIV and cells were fixed at a later stage of differentiation for analysis (DIV 18). Individual neurons were directly imaged under fluorescence and confocal microscopy (spinning disk microscope, Leica, Leica Microsystems, Wetzlar, Germany) using GFP labeling as a tracer of morphology. Immunocytochemistry to detect GFP (goat antibody, Abcam, Cambridge, UK) and HaloTag constructs (HaloTag TMR Ligand, Promega) was also realized according to standard procedures. Image analysis was done using Imaris software with ‘Filament tracer' plugin (Bitplane Scientific Software, Bitplane AG, Zürich, Switzerland) and ImageJ software (Wayne Rasband, Bethesda, NIH). It allowed quantifying total arborization of neurites (dendrites and axon) for each neuron (total length of neurites, numbers of branches, branching complexity), see <xref ref-type="supplementary-material" rid="sup1">Supplementary Figure 4</xref> for details on branching analysis. Quantification was based on three independent experiments with more than 15 cells of each type per experiment analyzed. Mann-Whitney statistical test was used to compare total neuritic length as well as number of branches, whereas Chi-square test was used to evaluate significance of variations in branching complexity. Primary cultures of hippocampal neurons from wild-type and <italic>Clcn4</italic><sup>−/−</sup> mice<sup><xref ref-type="bibr" rid="bib41">41</xref></sup> were obtained as described above with some minor differences. Animals were dissected at postnatal day 1 (P1), papain was used for dissociation of tissue, and glass coverslips were coated with poly-L-Lysine and collagen. At DIV 11, neurons were transfected with pEGFP-C1 vector (Clontech, Mountain View, CA, USA) using Lipofectamine-2000 according to the manufacturer's instructions. Cells were fixed and stained at DIV15 or DIV18 as described previously.<sup><xref ref-type="bibr" rid="bib42">42</xref></sup> Primary antibodies were chicken anti-GFP (Aves Lab, Tigard, Oregon, USA) and mouse anti-microtubule associated protein 2 (Chemicon/Millipore, Merck/Millipore, Darmstadt, Germany) as a neuronal marker. Secondary antibodies conjugated to Alexa Fluor 488 or 546 were from Molecular Probes. Images were taken using a LSM510 laser scanning confocal microscope equipped with a × 10 lens (Zeiss). Image analysis was performed in a blinded manner using ImageJ and its plugin NeuronJ: ns (non-statistically different), *<italic>P</italic><0.05, **<italic>P</italic><0.01, ***<italic>P</italic><0.001 for validation.</p></sec></sec><sec><title>Results</title><p>Initially, using genome partitioning and NGS we investigated a cohort of 248 unresolved families with suggestive X-chromosome involvement. Each of the families has at least 2 affected males and in 210 families affected males were present in separate sibships. Before this study, 125 of the index patients had been prescreened for different (per case) known XLID genes.<sup><xref ref-type="bibr" rid="bib2">2</xref>, <xref ref-type="bibr" rid="bib23">23</xref></sup> For 1/3 of the 248 families, linkage data were available. For enrichment, we used probes covering 745 X-chromosome genes, including 1 224 575 bp in coding regions and 2 400 136 bp in exonic regions. In all, 92% of the target sequences were covered by at least three sequence reads, and 94.2% were covered by at least one read (<xref ref-type="supplementary-material" rid="sup1">Supplementary Figures 5, 6, 7 and 8</xref>). In total, we identified 3378 recurrent and 1299 non-recurrent exonic variants, which were also found in control populations (<xref rid="tbl1" ref-type="table">Table 1</xref>). After filtering against variants from >7000 controls, present in publicly available databases as well as our in-house database, 28 recurrent and 765 non-recurrent exonic variants, as well as 16 potential splice site variants remained (<xref rid="tbl1" ref-type="table">Tables 1</xref>, <xref rid="tbl2" ref-type="table">2</xref>, <xref rid="tbl3" ref-type="table">3</xref>, <xref ref-type="supplementary-material" rid="sup1">Supplementary Tables 1, 2, 3 and 4</xref>).</p><p>As a follow-up study we investigated an additional cohort of 157 unresolved, similarly pre-screened XLID families. For this cohort, we present data on pathogenic variants identified in known XLID genes, likely or potentially pathogenic variants in novel and candidate XLID genes and truncating variants unlikely implicated in XLID.</p><p>For validation and segregation analyses, we prioritized variants by defining a prioritization score (PS). This score incorporates several computationally tractable pieces of information including the type of variant, evolutionary conservation and (if available) evidence that the gene has a role in XLID. Except for duplications and small in-frame indels, variants with a PS of ⩾5 were considered as strong candidates for follow-up studies. More recently, we also assigned C-scores obtained by applying CADD<sup><xref ref-type="bibr" rid="bib35">35</xref></sup> for ranking SNVs and short indels.</p><sec><title>Pathogenic variants identified in known XLID genes</title><p>A critical survey of the medical literature suggests that there are currently ~90 well-established XLID genes (79 previously known genes proposed as ‘confirmed' by Piton <italic>et al.</italic><sup><xref ref-type="bibr" rid="bib43">43</xref></sup> plus <italic>HCFC1</italic>,<sup><xref ref-type="bibr" rid="bib13">13</xref></sup><italic>MAOA</italic>,<sup><xref ref-type="bibr" rid="bib44">44</xref></sup><italic>CCDC22</italic>,<sup><xref ref-type="bibr" rid="bib14">14</xref></sup><italic>USP9X</italic>,<sup><xref ref-type="bibr" rid="bib6">6</xref></sup><italic>PIGA</italic>,<sup><xref ref-type="bibr" rid="bib16">16</xref></sup><italic>WDR45,</italic><sup><xref ref-type="bibr" rid="bib17">17</xref></sup><italic>KDM6A</italic>,<sup><xref ref-type="bibr" rid="bib18">18</xref></sup><italic>BCAP31</italic>,<sup><xref ref-type="bibr" rid="bib19">19</xref></sup><italic>ZC4H2</italic>,<sup><xref ref-type="bibr" rid="bib20">20</xref></sup><italic>KIAA2022</italic>,<sup><xref ref-type="bibr" rid="bib21">21</xref></sup><italic>MID2</italic><sup><xref ref-type="bibr" rid="bib22">22</xref></sup>). In these genes, we identified likely pathogenic variants in 39 of the 248 families (16%) and in 16 of the 157 families (10%), which together with the 24 families from these two cohorts that were resolved through this screen and were published earlier,<sup><xref ref-type="bibr" rid="bib7">7</xref>, <xref ref-type="bibr" rid="bib20">20</xref>, <xref ref-type="bibr" rid="bib21">21</xref>, <xref ref-type="bibr" rid="bib23">23</xref>, <xref ref-type="bibr" rid="bib45">45</xref>, <xref ref-type="bibr" rid="bib46">46</xref>, <xref ref-type="bibr" rid="bib47">47</xref>, <xref ref-type="bibr" rid="bib48">48</xref>, <xref ref-type="bibr" rid="bib49">49</xref>, <xref ref-type="bibr" rid="bib50">50</xref></sup> account for 21 and 18% of the cohorts (for details, see <xref ref-type="supplementary-material" rid="sup1">Supplementary Tables 5 and 6</xref>). The variants include co-segregating protein truncating variants, in-frame deletions or missense changes and none of them were reported in 61 486 unrelated individuals (ExAC Browser). According to the current literature and HGMD (as of May 2014), for some of these XLID genes only very few families with pathogenic variants have so far been reported, suggesting that mutations in these genes are very rare. One example is <italic>ACSL4</italic> (previously known as <italic>FACL4</italic> [MIM 300157]), which has a role in long-fatty-acid metabolism. Its involvement in XLID was discovered more than 10 years ago.<sup><xref ref-type="bibr" rid="bib51">51</xref></sup> Yet, until today a total of only four unrelated families with pathogenic point variants in <italic>ACSL4</italic> have been published. These include one recurrent amino-acid change and one splicing variant.<sup><xref ref-type="bibr" rid="bib51">51</xref>, <xref ref-type="bibr" rid="bib52">52</xref>, <xref ref-type="bibr" rid="bib53">53</xref></sup> We identified a non-sense variant in this gene (chrX:108902601G>A, p.Arg654*) present in one family (<xref ref-type="supplementary-material" rid="sup1">Supplementary Table 5</xref>). Our results strongly support that <italic>ACSL4</italic> mutations cause XLID. In <italic>NLGN3</italic> [MIM 300336], that is known as ‘autism' gene with currently two likely pathogenic missense and two potentially disease relevant splicing variants reported in the literature,<sup><xref ref-type="bibr" rid="bib54">54</xref>, <xref ref-type="bibr" rid="bib55">55</xref>, <xref ref-type="bibr" rid="bib56">56</xref></sup> we identified a likely deleterious stop codon (p.Arg162*) which is expected to remove most part of the protein. The variant could not be tested for segregation because additional family members were unavailable. The 29-year-old affected is the first and only child of unrelated and healthy parents. He presented with moderate ID, severe behavioral problems, especially abnormal sexual behavior and aggression. There was no formal diagnosis of autism. We have also identified pathogenic variants in ID genes with widely varying phenotypes, which are difficult to diagnose by clinical examination alone. One example is <italic>PQBP1</italic> [MIM 300463] in which we found a pathogenic single nucleotide deletion that causes a frameshift resulting in a premature stop codon (p.Phe240Serfs*26, <xref ref-type="supplementary-material" rid="sup1">Supplementary Table 5</xref>). As a result of this molecular diagnosis, careful reexamination of the affected boys revealed subtle dysmorphic features that are in good agreement with the currently known <italic>PQBP1</italic> clinical spectrum.</p><p>One of the established XLID genes with several likely pathogenic variants identified in our study groups is <italic>MED12</italic> [MIM 300188]. Missense variants in this gene have been linked with Lujan-Fryns syndrome<sup><xref ref-type="bibr" rid="bib57">57</xref></sup> [MIM 309520], Opitz-Kaveggia syndrome<sup><xref ref-type="bibr" rid="bib58">58</xref></sup> [MIM 305450] and Ohdo syndrome<sup><xref ref-type="bibr" rid="bib59">59</xref></sup> [MIM 300895]. In addition to the previously published large family with a protein truncating variant associated with a profound phenotype in males and several heterozygous female carriers with variable cognitive impairment,<sup><xref ref-type="bibr" rid="bib28">28</xref></sup> we identified segregating likely pathogenic missense variants in three families (<xref ref-type="supplementary-material" rid="sup1">Supplementary Table 5</xref>). Similarly, eight XLID families carry pathogenic variants in <italic>CUL4B</italic> [MIM 300304] (<xref ref-type="supplementary-material" rid="sup1">Supplementary Table 5</xref>).<sup><xref ref-type="bibr" rid="bib50">50</xref></sup></p></sec><sec><title>Likely pathogenic variants in novel XLID genes and previously proposed candidate genes</title><p>We identified likely deleterious variants in four novel XLID genes and validated three previously suggested candidates, described here in more detail, including <italic>CLCN4</italic> [MIM 302910], <italic>CNKSR2</italic> [MIM 300724], <italic>FRMPD4</italic> [MIM 300838], <italic>KLHL15</italic>, <italic>LAS1L</italic>, <italic>RLIM</italic> [MIM 300379] and <italic>USP27X</italic>. We propose these genes to be confirmed or novel X-chromosome ID genes based on our genetic, bioinformatic and functional evidence as well as current knowledge extracted from the literature. All but one variant identified in these genes co-segregated with ID in the relevant families (<xref rid="tbl2" ref-type="table">Table 2</xref>, <xref ref-type="fig" rid="fig1">Figures 1</xref> and <xref ref-type="fig" rid="fig2">2</xref>).</p><p>In <italic>CLCN4</italic>, that encodes the electrogenic chloride/proton exchanger ClC-4,<sup><xref ref-type="bibr" rid="bib60">60</xref></sup> we discovered a protein truncating variant (p.Asp15Serfs*18, family MRX49<sup><xref ref-type="bibr" rid="bib61">61</xref></sup>) and four missense variants (p.Gly731Arg, family MRX15,<sup><xref ref-type="bibr" rid="bib62">62</xref></sup> p.Leu221Val, p.Val536Met, p.Gly78Ser) (<xref ref-type="fig" rid="fig1">Figure 1a</xref>). ID of the affected males was variable, even within families, ranging from mild to severe. Similarly, intra- and interfamilial variable clinical features include epilepsy, dysmorphic face, scoliosis and strabismus (for detailed clinical information, see <xref ref-type="supplementary-material" rid="sup1">Supplementary Table 7</xref>). All affected amino-acid residues lie within the transmembrane part or in the cytoplasmic, carboxy terminus of the protein (<xref ref-type="fig" rid="fig1">Figure 1c</xref>). To provide further evidence that the missense variants identified impair ClC-4 protein function, we performed analyses in <italic>Xenopus laevis</italic> oocytes. Compared with the strong outwardly-rectifying currents of wild-type CLC-4 (refs. <xref ref-type="bibr" rid="bib36">36</xref>, <xref ref-type="bibr" rid="bib60">60</xref>) currents were much smaller or even absent with ClC-4 constructs carrying the point variants, showing that these substitutions markedly impaired the function of the ClC-4 protein (<xref ref-type="fig" rid="fig1">Figure 1b</xref>). In the crystal structure of algal CmClC,<sup><xref ref-type="bibr" rid="bib63">63</xref></sup> p.Gly731 is located just at the contact sites of the cytosolic cystathionine-β-synthase (CBS) domains of the different subunits of the ClC-4 homodimer. Since CBS domains have been implicated in the gating of CLC channels,<sup><xref ref-type="bibr" rid="bib64">64</xref>, <xref ref-type="bibr" rid="bib65">65</xref></sup> the p.Gly731Arg substitution may interfere with this process. We additionally analyzed the effects of the mouse counterpart, <italic>Clcn4</italic>, on neuronal differentiation by transfecting hippocampal neurons at day-in-vitro 11 (DIV11) with knock-down constructs targeting this gene and evaluated the cells at a later stage of differentiation (DIV18). At this stage, neuronal differentiation is complete and was clearly affected in <italic>Clcn4</italic>-depleted cells. Indeed, compared with controls that were transfected with a non-silencing construct, in <italic>Clcn4</italic> depleted cultures neurons were less branched, that is, the total length of neuritic branches was decreased by 30% corresponding to less dendritic branches per cell. However, there was no effect on the complexity of dendritic branching. Introduction of ClC-4 protein in knock-down cells using RNAi-insensitive cDNA rescued both dendritic phenotypes to control levels, thus highlighting the specificity of the phenotype truly associated with the loss of ClC-4 protein (<xref ref-type="fig" rid="fig3">Figure 3a</xref>). Primary neurons derived from <italic>Clcn4</italic><sup>−/−</sup> mice<sup><xref ref-type="bibr" rid="bib41">41</xref></sup> confirmed these findings (<xref ref-type="fig" rid="fig3">Figure 3b</xref>). Although the observed morphological changes were more subtle when compared with those obtained with the shRNA-mediated knock-down, they were statistically significant.</p><p>In <italic>CNKSR2</italic> (also known as <italic>CNK2</italic>, <italic>KSR2</italic>, <italic>MAGUIN</italic>), we identified a likely pathogenic frameshift variant (p.Asp152Argfs*8) in a family with four affected males. This variant was present in three affected brothers tested and their mother (<xref ref-type="fig" rid="fig2">Figure 2a</xref>). That <italic>CNKSR2</italic> is implicated in ID is further supported by an unrelated intellectually impaired female who carries a balanced translocation with a chromosomal breakpoint that disrupts <italic>CNKSR2</italic> (J Chelly <italic>et al.</italic>, unpublished result). To assess whether the loss of the mouse ortholog, <italic>Cnksr2</italic>, has a functional impact, we depleted it in primary hippocampal neurons fully differentiated <italic>in vitro</italic>. Reduction of <italic>Cnksr2</italic> had a profound effect on the number of dendritic branches, as well as on total length of neurites per neuron, which were all reduced by 65–75% (<xref ref-type="fig" rid="fig3">Figure 3c</xref>). These two drastic phenotypes were partially, but highly significantly rescued in neurons by expression of a shRNA-resistant cDNA plasmid encoding HaloTag-fused Cnksr2 protein. Furthermore, dendritic branching complexity was largely affected due to loss of terminal branches (level 4 30%, level 5 50% and level 6 70%). This phenotype could be restored in the rescue experiment (<xref ref-type="fig" rid="fig3">Figure 3c</xref>).</p><p>In <italic>FRMPD4</italic> we identified a protein truncating variant (p.Cys618Valfs*8) in a single XLID family with five affected males in different sibships (<xref ref-type="fig" rid="fig2">Figure 2b</xref>) and a <italic>de novo</italic> missense mutation in an unrelated male who at the age of 17 years presented with significant developmental delay, the absence of speech and autism spectrum disorder. His brother and a half-brother did not carry the mutation, and upon re-examination it appeared that they had much milder phenotypes characterized by learning problems at school.</p><p>In the poorly characterized <italic>KLHL15</italic> gene, encoding a member of the kelch-like protein family, we identified a protein-truncating variant (p.Tyr394Ilefs*61) that co-segregates with ID in a large family with eight affected males in three different sibships (<xref ref-type="fig" rid="fig2">Figure 2c</xref>). Further support for KLHL15 being implicated in XLID comes from an unrelated XLID family, which carries a small deletion that removes part of <italic>KLHL15</italic> and is expected to result either in a C-terminally truncated protein or in a complete loss of KLHL15 (J Gecz, V Kalscheuer and F McKenzie <italic>et al.</italic>, unpublished result).</p><p>Two likely causative missense variants potentially affecting protein biosynthesis or transcription regulation involved <italic>LAS1L,</italic> encoding the human homolog of the highly evolutionary conserved <italic>S. cerevisiae</italic> protein Las1 (lethal in the absence of SSD1-v1). The p.Ala269Gly substitution was identified in the large original family described as Wilson-Turner syndrome (WTS, MIM 309585) with mild to moderate ID and obesity (<xref ref-type="fig" rid="fig2">Figure 2d</xref>). <sup><xref ref-type="bibr" rid="bib66">66</xref></sup> More than half of the affecteds had speech disability (mutism or stuttering), small or undescended testes and relatively small feet. The p.Arg415Trp substitution was present in an unrelated family from France with five affected males in three different sibships (<xref ref-type="fig" rid="fig2">Figure 2d</xref>). Upon clinical re-examination of affected males from this family, they all turned out to have ID with speech impairment, obesity and hypogonadism, too.</p><p>For <italic>RLIM</italic>, which encodes the RING-H2 zinc finger protein 12, we identified three families who carry unique missense variants that resulted in single amino-acid substitutions (D72, p.Arg387Cys; T11/MRX61, p.Pro587Arg; AU31, p.Arg599Cys). All variants co-segregated with XLID in these large families (<xref ref-type="fig" rid="fig2">Figure 2e</xref>) and affected highly conserved amino-acid residues. Both p.Pro587Arg and p.Arg599Cys substitutions affect amino acids of the zinc-finger domain of RLIM. In addition, HOPE<sup><xref ref-type="bibr" rid="bib67">67</xref></sup> predicts that the differences in amino-acid properties disturb this domain.</p><p>Family D177 with three affected males in different sibships carries a 5-bp deletion (g.AAGTA) in <italic>USP27X</italic> encoding ubiquitin-specific peptidase 27. The deletion was also present in their mothers (<xref ref-type="fig" rid="fig2">Figure 2f</xref>). The variant results in a frameshift and premature stop codon (p.Ser342Argfs*14) that is expected to remove the C-terminal part of the corresponding protein. The unrelated family L75 with four affected males (<xref ref-type="fig" rid="fig2">Figure 2f</xref>) carries a potentially deleterious missense variant in <italic>USP27X</italic>, which substitutes a highly conserved tryptophane by a histidine residue (p.Trp381His).</p></sec><sec><title>Variants identified in novel candidate XLID genes</title><p>In <italic>CDK16</italic> (also frequently named in the literature as <italic>PCTK1</italic> and <italic>PCTAIRE1</italic>, [MIM 311550]), which is highly expressed in brain and testis, we identified a dinucleotide deletion in the index male of family L56. The deletion affects all three known RNA isoforms and results in a frameshift and a premature stop codon before the N-terminal kinase domain (p.Trp326Valfs*5). The deletion was also present in his affected brother and two affected male cousins (<xref ref-type="fig" rid="fig2">Figure 2g</xref>) who, in addition to ID, all suffered from spastic diplegia. It is currently unclear whether another dinucleotide deletion (g.TG, chrX:47085594-47085595, p.Phe322Trpfs*12), which would truncate the C-terminus of only one CDK16 protein isoform (non RefSeq variant), and was identified in a single family is a rare neutral variant. CDK16 is a poorly characterized atypical member of the cyclin-dependent kinase family. It is particularly abundant in postmitotic neurons,<sup><xref ref-type="bibr" rid="bib68">68</xref></sup> and has been implicated in the regulation of neurite outgrowth,<sup><xref ref-type="bibr" rid="bib69">69</xref></sup> neuronal migration, vesicular transport and exocytosis.<sup><xref ref-type="bibr" rid="bib70">70</xref>, <xref ref-type="bibr" rid="bib71">71</xref>, <xref ref-type="bibr" rid="bib72">72</xref></sup> Depletion of Cdk16 abolished dendrite development in primary neuron cultures,<sup><xref ref-type="bibr" rid="bib73">73</xref></sup> and in <italic>C. elegans</italic> it is important for localizing presynaptic components.<sup><xref ref-type="bibr" rid="bib74">74</xref></sup> Thus, it is plausible to assume that loss of CDK16 function could have a role in ID, but more evidence is required to accept <italic>CDK16</italic> as a novel XLID gene.</p><p>In <italic>TAF1</italic> [MIM 313650] we identified segregating missense variants in two unrelated families (<xref ref-type="fig" rid="fig2">Figure 2h</xref>), both of which affect highly conserved amino acids of proteins encoded by the longest transcript isoforms encoding the TATA box binding protein-associated factor, 250 kD (TAF1), which is a subunit of a complex with a key role in transcription initiation. Additionally, TAF1 is part of the H3K4 methyltransferase MLL1, which also contains CHD8 that is implicated in autism.<sup><xref ref-type="bibr" rid="bib75">75</xref>, <xref ref-type="bibr" rid="bib76">76</xref></sup> Reduced expression of <italic>TAF1</italic> has been shown in brain tissues from patients with X-linked Dystonia-Parkinsonism [MIM 314250], a movement disorder endemic to the Philippines.<sup><xref ref-type="bibr" rid="bib77">77</xref></sup> Furthermore, variants in <italic>TAF2</italic> have been associated with autosomal recessive ID.<sup><xref ref-type="bibr" rid="bib78">78</xref>, <xref ref-type="bibr" rid="bib79">79</xref></sup> Although additional evidence for <italic>TAF1</italic> being implicated in XLID is currently missing, these data indicate that loss of <italic>TAF1</italic> function could affect cognition.</p></sec><sec><title>Variants with unlikely effect on brain function</title><p>We also identified protein truncating or read-through changes in 40 genes which we considered as unlikely to cause ID because these were (i) outside the linkage intervals in the respective families and therefore expected not to co-segregate with the phenotype, (ii) did not co-segregate with ID, (iii) previously reported in healthy males<sup><xref ref-type="bibr" rid="bib3">3</xref>, <xref ref-type="bibr" rid="bib80">80</xref></sup> or (iv) involved in phenotypes distinct from ID. From these, protein truncating variants that have not been reported in controls are presented in <xref rid="tbl3" ref-type="table">Table 3</xref>. The <italic>ARSF</italic> [MIM 300003] variant is present in a family with two affected males. Other <italic>ARSF</italic> truncations were reported in controls.<sup><xref ref-type="bibr" rid="bib3">3</xref></sup> The index patient sequenced here additionally carries a non-segregating truncating variant in <italic>MAGIX</italic>, but we currently cannot entirely rule out that this proband is a phenocopy. Single truncating variants in <italic>COL4A6</italic> [MIM 303631], <italic>CXorf61</italic> [MIM 300625] and <italic>MAP3K15</italic> [MIM 300820] are outside the linkage intervals of the respective families and therefore unlikely co-segregate with XLID in the families in which they were found. Similarly, the <italic>GUCY2F</italic> [MIM 300041] and <italic>SLC25A43</italic> [MIM 300641] truncating variants did not co-segregate with XLID in the family in which they were identified and other rare protein truncating variants were reported in ESP6500 and in other healthy male controls.<sup><xref ref-type="bibr" rid="bib81">81</xref>, <xref ref-type="bibr" rid="bib82">82</xref></sup> Furthermore, <italic>COL4A6</italic> is part of a contiguous gene deletion causing Alport syndrome [MIM 301050], a childhood onset progressive haematuric glomerulopathy with high-frequency sensorineural hearing loss and typical ocular signs, and for <italic>MAP3K15</italic> other stop-gain variants have been identified in male controls.<sup><xref ref-type="bibr" rid="bib3">3</xref></sup><italic>CXorf64</italic> and <italic>FATE1</italic> [MIM 300450] truncating variants were identified in the same family and both did not co-segregate with XLID. Variants in <italic>FRMD7</italic> [MIM 300628] cause idiopathic infantile nystagmus [MIM 310700]. Similarly, a non-segregating stop-gain variant in <italic>GPR112</italic> and a non-segregating stop-loss variant in the XLID gene <italic>HDAC8</italic> [MIM 300269] (<xref rid="tbl3" ref-type="table">Table 3</xref>) were found in a family with a co-segregating protein truncating variant in the XLID gene <italic>UPF3B</italic> [MIM 300298], which was considered as the cause of ID (<xref ref-type="supplementary-material" rid="sup1">Supplementary Table 5</xref>). For <italic>HS6ST2</italic> [MIM 300545], our follow-up study revealed that this deletion is recurrent and also present in a family with a pathogenic variant in the known XLID gene <italic>KDM5C</italic> (previously known as <italic>JARID1C</italic> [MIM 314690]). Similarly, other <italic>HS6ST2</italic> truncating variants were identified in normal males.<sup><xref ref-type="bibr" rid="bib30">30</xref></sup> Furthermore, a recurrent <italic>RAB40AL</italic> dinucleotide missense variant (p.Asp59Gly) previously reported to cause Martin-Probst syndrome<sup><xref ref-type="bibr" rid="bib83">83</xref></sup> [MIM 300519] and published as causal in an unrelated male<sup><xref ref-type="bibr" rid="bib84">84</xref></sup> was identified in four unrelated index patients and did not segregate in two of the families. In another family, a protein truncating variant was present on both X-chromosomes of healthy females, as recently reported.<sup><xref ref-type="bibr" rid="bib85">85</xref></sup></p></sec></sec><sec><title>Discussion</title><p>For many years, research into the molecular causes of ID has focused on the X-chromosome, prompted by the observation that males are more often affected than females.<sup><xref ref-type="bibr" rid="bib86">86</xref>, <xref ref-type="bibr" rid="bib87">87</xref></sup> Cumulatively, sequencing of positional and functional candidate genes as well as high-resolution array CGH led to the identification of apparently causative defects in more than 100 X-linked genes, but after the advent of high-throughput sequencing techniques, mutations inactivating some of these genes were also observed in healthy individuals, thereby questioning the identity of several of the previously identified XLID genes.<sup><xref ref-type="bibr" rid="bib43">43</xref></sup></p><p>Despite the large number of established XLID genes, more than half of the XLID families remained unsolved,<sup><xref ref-type="bibr" rid="bib2">2</xref>, <xref ref-type="bibr" rid="bib3">3</xref></sup> suggesting further heterogeneity. This prompted us to investigate a cohort of 405 XLID families by NGS. 74 (18%) of the families carry variants in established XLID genes that we consider as causative. Six families (1.5%) carry potentially causative XLID variants which, in our opinion, have to be studied in more detail before qualifying for carrier testing or prenatal diagnosis. Some of these variants are recurrent and were previously reported in other XLID families (for example, <italic>ATRX</italic>, <italic>CUL4B</italic>, <italic>HUWE1</italic>, for more details see our previously unpublished variants showing the respective HGMD entries in <xref ref-type="supplementary-material" rid="sup1">Supplementary Table 5</xref>). We did not identify any pathogenic variants in genes with an unclear role in XLID,<sup><xref ref-type="bibr" rid="bib43">43</xref></sup> apart from a co-segregating missense variant identified in <italic>ARHGEF6</italic> [MIM 300267] the functional relevance of which remains to be established. This does not disprove a possible role of these genes in ID.</p><p>In 5% of the families, we identified likely deleterious variants in novel XLID genes and previously proposed candidate genes. In 2% of the families, mutations were observed in XLID genes that emerged from this screen and have been or will be reported in detail elsewhere, for example, <italic>ZC4H2</italic>,<sup><xref ref-type="bibr" rid="bib20">20</xref></sup><italic>KIAA2022</italic>,<sup><xref ref-type="bibr" rid="bib21">21</xref></sup><italic>THOC2</italic> [MIM 300395] (Kumar <italic>et al.</italic>, manuscript in preparation) and <italic>EIF2S3</italic> [MIM 300161] (manuscript in preparation). None of these variants was found in >61 486 ‘healthy' controls except for 3 heterozygous females with RLIM protein truncating variants, and none of these genes carry loss-of-function variants in these controls (dbSNP138, ExAC Browser<sup><xref ref-type="bibr" rid="bib30">30</xref>, <xref ref-type="bibr" rid="bib81">81</xref>, <xref ref-type="bibr" rid="bib88">88</xref>, <xref ref-type="bibr" rid="bib89">89</xref>, <xref ref-type="bibr" rid="bib90">90</xref></sup>).</p><p>One of the novel XLID genes discovered in this study is <italic>CLCN4</italic> in which we identified protein truncating and missense variants in five unrelated families, including families MRX15 (ref. <xref ref-type="bibr" rid="bib62">62</xref>) and MRX49 (ref. <xref ref-type="bibr" rid="bib61">61</xref>) with non-syndromic XLID. Electrophysiological studies in <italic>Xenopus laevis</italic> oocytes showed that the amino-acid substitutions present in the affected males markedly impaired ClC-4 function and primary mouse neurons depleted of <italic>Clcn4</italic>, the mouse counterpart of <italic>CLCN4</italic>. As well, primary neurons derived from <italic>Clcn4</italic> knock-out mice showed a significant effect on neuronal differentiation thereby corroborating that ClC-4 is important for cognition. Our results further support pathogenicity of a <italic>de novo CLCN4</italic> missense variant identified in a boy with epilepsy and cognitive dysfunction.<sup><xref ref-type="bibr" rid="bib91">91</xref></sup> Very little is known about the physiological role of ClC-4. It is a member of the CLC family and most homologous to ClC-3 and ClC-5. Similar to ClC-4, other members of this family are also required for normal brain function, for example, ClC-2 variants have been described in individuals with leukoencephalopathy and MRI abnormalities,<sup><xref ref-type="bibr" rid="bib92">92</xref></sup> and loss of ClC-7 leads to neurodegeneration associated with lysosomal storage and osteopetrosis, respectively.<sup><xref ref-type="bibr" rid="bib93">93</xref>, <xref ref-type="bibr" rid="bib94">94</xref>, <xref ref-type="bibr" rid="bib95">95</xref></sup><italic>Clcn4</italic><sup>−/−</sup> mice do not display an obvious phenotype,<sup><xref ref-type="bibr" rid="bib41">41</xref></sup> whereas <italic>Clcn3</italic><sup>−/−</sup> mice are developmentally retarded, show neurological manifestations and severe postnatal degeneration of the hippocampus,<sup><xref ref-type="bibr" rid="bib96">96</xref></sup> and <italic>Clcn</italic>6<sup>−/−</sup> mice display lysosomal storage in neurons.<sup><xref ref-type="bibr" rid="bib97">97</xref></sup> Thus, direct and indirect evidence point to a vital role for ClC proteins, including ClC-4, in the central nervous system.</p><p>Interestingly, the proteins encoded by the now confirmed XLID genes <italic>CNKSR2</italic> and <italic>FRMPD4</italic> (also termed PDZD10, PDZK10, Preso and Preso1) interact with PSD95 (<xref ref-type="fig" rid="fig4">Figure 4</xref>), the major scaffold protein of the postsynaptic density, which has an important role in neuronal plasticity. In <italic>CNKSR2</italic>, we identified a deleterious variant in a single family. This result was conducive to interprete a previously reported intragenic deletion identified in a boy with non-syndromic XLID<sup><xref ref-type="bibr" rid="bib98">98</xref></sup> and of two additional <italic>CNKSR2</italic> gene deletions present in unrelated families.<sup><xref ref-type="bibr" rid="bib99">99</xref></sup> In addition, depletion of Cnksr2 in primary hippocampal neurons resulted in reduced number and complexity of dendritic branches. CNKSR2 is also connected with the XLID protein DLG3 and the ID/autism protein SHANK3 (ref. <xref ref-type="bibr" rid="bib100">100</xref>) is involved in the assembly of synaptic junction components,<sup><xref ref-type="bibr" rid="bib101">101</xref></sup> and modulates Rac cycling during spine morphogenesis.<sup><xref ref-type="bibr" rid="bib102">102</xref></sup></p><p>For <italic>FRMPD4</italic>, the first evidence for its involvement in XLID came from a duplication that likely disrupted this gene in a male with mild ID and autism.<sup><xref ref-type="bibr" rid="bib103">103</xref></sup> Depletion of the FRMPD4 ortholog in the mouse decreases spine density and excitatory synaptic transmission,<sup><xref ref-type="bibr" rid="bib104">104</xref></sup> similarly to what has been described for other proteins important for normal brain function and, when deficient result in cognitive impairment.</p><p>Four of the novel and validated XLID genes are potentially directly or indirectly implicated in the regulation of protein turnover (<xref ref-type="fig" rid="fig4">Figure 4</xref>). One of these is <italic>KLHL15</italic>, in which we identified a deleterious variant in a large family and a deletion that likely affects its normal function in an unrelated family (unpublished results). Our results support pathogenicity of a partial deletion of <italic>KLHL15</italic>, which has very recently been described in a single proband with severe ID, epilepsy and anomalies of cortical development.<sup><xref ref-type="bibr" rid="bib105">105</xref></sup> KLHL15 is a member of the Kelch-like proteins, many of which are adaptors for the recruitment of substrates to Cul3-based E3 ubiquitin ligases for degradation by the 26S proteasome. KLHL15-Cul3 specifically targets a brain-specific regulatory subunit of the protein phosphatase 2A (PP2A/B'ß) and thereby promotes its proteasomal degradation, resulting in the formation of alternative PP2A holoenzymes.<sup><xref ref-type="bibr" rid="bib106">106</xref></sup> PP2A/B'ß has been shown to inactivate CAMKII, which is a key mediator of long-term potentiation. Thus, aberrant turnover of PP2A/B'ß caused by KLHL15 protein-truncating variants could contribute to XLID.</p><p>Little is currently known about the functional role of the ubiquitin specific peptidase USP27X. It was among the top 50 genes with enriched expression in mouse embryonic serotonin neurons and thus may be important for serotonergic function.<sup><xref ref-type="bibr" rid="bib107">107</xref></sup> The only known interaction partner of USP27X is USP22, which has been shown to be required for glial cell and neuronal development in flies.<sup><xref ref-type="bibr" rid="bib108">108</xref></sup> It is an integral component of a Pol II coactivator complex that, in addition to its histone acetyltransferase activity, has a role in the turnover of histone modifications by specifically removing the ubiquitin moiety from histones H2A and B, and it functions as a positive cofactor for activation by nuclear receptors.<sup><xref ref-type="bibr" rid="bib109">109</xref></sup> Several previously identified ID genes code for subunits of the same complex, for example, proteins from the mediator complex, for example, MED12 and MED13L [MIM 608771], and a range of proteins that regulate transcription by modulation of the chromatin structure.<sup><xref ref-type="bibr" rid="bib110">110</xref></sup> Furthermore, variants in another member of the peptidase C19 family, USP9X, are also associated with XLID.<sup><xref ref-type="bibr" rid="bib6">6</xref></sup></p><p>Three unrelated families carry co-segregating point mutations in the E3 ubiquitin ligase RLIM, which were all predicted as disease causing.<sup><xref ref-type="bibr" rid="bib111">111</xref></sup> Two of the amino-acid substitutions lie in the C-terminal zinc finger domain and could disturb its function. RLIM has an important role in embryonic development by acting as a negative regulator of LIM homeodomain transcription factors through two distinct and complementary mechanisms: recruitment of the Sin3A/histone deacetylase corepressor complex and targeting the coactivator of LIM homeodomain proteins for degradation,<sup><xref ref-type="bibr" rid="bib112">112</xref>, <xref ref-type="bibr" rid="bib113">113</xref></sup> suggesting that it has critical functions in regulating associated transcriptional activity.</p><p>LAS1L in which we identified likely pathogenic missense variants in two families with a syndromic form of XLID (WTS,<sup><xref ref-type="bibr" rid="bib66">66</xref></sup> [MIM 309585]) is involved in ribosome biogenesis. It is required for the synthesis of the 60S ribosomal subunit and maturation of 28S rRNA. Depletion of LAS1L results in a p53-dependent cell-cycle arrest, defective pre-rRNA processing and failure to synthesize mature 60S ribosomal subunits.<sup><xref ref-type="bibr" rid="bib114">114</xref>, <xref ref-type="bibr" rid="bib115">115</xref></sup> Additionally, LAS1L is part of a large nuclear complex (Five Friend of Methylated chromatin target of protein-arginine-methyltransferase-1) that has a role in transcription regulation by affecting the sumoylation status and transactivation potential of the zinc-finger transcription factor Zbp-89,<sup><xref ref-type="bibr" rid="bib116">116</xref>, <xref ref-type="bibr" rid="bib117">117</xref></sup> and is a component of the CoREST1/HDAC1 corepressor complex.<sup><xref ref-type="bibr" rid="bib117">117</xref></sup> It remains to be determined which of the LAS1L functions are compromised by the missense variants. Interestingly, another missense variant in this gene has recently been identified in a boy with congenital lethal motor neuron disease,<sup><xref ref-type="bibr" rid="bib118">118</xref></sup> suggesting that <italic>LAS1L</italic> variants are associated with a variable phenotype. Similarly, a family with a phenotype resembling WTS carries a missense variant in the known XLID gene <italic>HDAC8</italic>,<sup><xref ref-type="bibr" rid="bib119">119</xref></sup> in which loss-of-function variants are associated with Cornelia de Lange syndrome (CDLS5 [MIM 300882]).<sup><xref ref-type="bibr" rid="bib12">12</xref></sup></p><p>Our investigation has led to the identification of several novel ID genes that are mutated in up to 7% of the XLID families. There are still many ID families with evidence for X-linkage that remain unresolved, including 75 families with 4 and more affected males in separate sibships connected through female carriers, suggesting several yet to be identified genes or loci on the X-chromosome involved in ID. The ‘diagnostic' yield of 26% obtained by performing X-exome resequencing on a pre-screened cohort contrasts with our previous experience that defects in XLID genes known until 2007 account for more than half of the families screened.<sup><xref ref-type="bibr" rid="bib2">2</xref></sup> This discrepancy can be explained by the fact that in the present study, most of the families had already undergone prior FraX testing, array CGH and targeted analysis of many previously known genes. Indeed, <italic>KDM5C</italic> variants and disease-causing variants in three other most common XLID genes, namely <italic>MECP2</italic> [MIM 300005], <italic>IL1RAPL1</italic> [MIM 300206] and <italic>PQBP1</italic>, turned out to be strongly under-represented in the families included here (<xref ref-type="supplementary-material" rid="sup1">Supplementary Table 10</xref>). To estimate the diagnostic yield of sequencing all X-chromosomal exons in novel, not previously examined XLID families, we selected 222 EUROMRX consortium families with convincing evidence for X-linkage, as evidenced by two or more affected males in two generations connected through healthy female carriers. In all, 97 of these 222 families had been resolved by mutation screening of single genes or by array CGH before this study (unpublished results).<sup><xref ref-type="bibr" rid="bib2">2</xref></sup> Of the remaining 125 families, 32 could be solved and 3 potentially solved by NGS-based sequencing of all X-chromosomal genes, but 90 remained unsolved, with half of them having four or more affected males in separate sibships. Assuming that we would have detected all previously identified defects by NGS, this indicates that mutations in coding regions of all presently known XLID genes account for 58% of the (EUROMRX) Fragile X-negative families (<xref ref-type="supplementary-material" rid="sup1">Supplementary Figure 9</xref>). Combined with Fragile X, which is seen in about 15% of XLID families, NGS and Fragile X testing allows a molecular diagnosis in 64% of all families with XLID (<xref ref-type="supplementary-material" rid="sup1">Supplementary Figure 10</xref>).</p><p>There are several explanations why about one-third of all XLID families cannot be solved by Fragile X testing combined with X-exome sequencing, (1) technical limitations because of poor enrichment and coverage that may account for a small number of the families, (2) non-coding variants or yet to be annotated regions of X-chromosome, (3) also, it is rather likely that at least some of the families might have autosomal ID instead of XLID, (4) the unique DNA missense variants with currently unknown causality are pathogenic, (5) at least some of the cases might be due to multigenic variations, or (6) deleterious variants are located in yet undiscovered regulatory elements. Although there is no reliable information about the proportion of disease-causing mutations located outside coding exons, their frequency may be considerable. A recent effort to annotate the non-coding sequence showed that around 80% of the genome contains elements linked to a biochemical function.<sup><xref ref-type="bibr" rid="bib120">120</xref></sup> Nowadays, whole genome sequencing or targeted genomic sequencing of linkage intervals combined with sophisticated computational tools that predict such potentially functionally relevant sequences, in principle, allow finding disease-relevant variants outside coding exons. One example is a family with non-syndromic XLID in which we failed to identify the causative mutation by exome sequencing. Subsequent massively parallel resequencing of the non-repetitive genomic linkage interval identified a regulatory variant that leads to overexpression of the transcriptional regulator HCFC1.<sup><xref ref-type="bibr" rid="bib7">7</xref></sup> Though the numbers of non-coding sequences in the human genome are comparably large, interpreting non-protein coding variants is a new challenge for the next years.</p><p>In conclusion, we have been able to identify numerous pathogenic variants in known XLID genes, previously proposed and novel XLID genes and two XLID candidates. The results provide a molecular diagnosis for the families involved and will be useful for interpreting variants that will be identified in other patients and families in these genes in the future. It will also help to better understand the genetic complexity underlying ID and the functional complexity underlying normal brain function, which is amazingly diverse. There is a growing body of evidence demonstrating that genetic lesions identified in XLID genes are also associated with other brain/neurological disorders, many of these often co-occurring with ID including autism, epilepsy, schizophrenia or other neuropsychiatric and neurobehavioral problems. Therefore, further investigations of the XLID genes in the context of their functional and regulatory networks will not only deepen our insight into the pathogenesis of ID but also shed more light into the etiology of related neurological disorders and into human brain development.</p></sec></body><back><ack><p>We thank all the families who participated in this research. We also thank Susanne Freier, Ines Müller, Rien Blok, Carolien Oosterhoud, Roel Brandts, Demis Tserpelis, Evelyn Douglas, Lynne Hobson, Pia Winter and Sara Ekvall for excellent technical assistance; Dagmar Wieczorek, Vincent Desportes, Jean-Paul Bonnefont, Valerie Biancalana, Daniel Amram, Stanislas Lyonnet, Jacqueline Vigneron, Veronica Cusin, Philippe Jonveaux, Laurence-Olivier Faivre, Lydie Burglen, Yves Alembik, Sophie Scheidecker, Aurelia Jacquette, Delphine Heron, Cyril Goizet, Marie Ange Delrue, Didier Lacombe, Odile Boute, Andre Megarbane, Anne Moncla, Brigitte Gilbert Tiong Tan, Sharron Townshend, Michael Gabbett, Zornitza Stark, Mac Gardner, Joanne Dixon, Ian Glass, Martin Delatycki, Salim Aftimos, Felicity Collins, Paul James, George McGillivray, Kate Pope, Judith Allanson, Claude Moraine, Christine Francannet, Annick Toutain, James Lespinasse, Brigitte Gilbert, Isabelle Mortemousque, Anne Moncla, Etienne Mornet, Albert David, Connie Schrander-Stumpel, Christine de Die-Smulders, Yvonne Arens, Eric Smeets, Dominique Marcus-Soekarman, Ute Moog, Bert Smeets, Marzena Wiśniewska, Renata Glazar, Maciej Robert Krawczyński, Barbara Leube, Magdalena Nawara, Agnieszka Charzewska, Irma Järvelä, Barbara Oehl-Jaschkowitz, Marco Henneke, Peter Propping, Gholamali Tariverdian, Almuth Caliebe, Dorothea Wand, Jürgen Mücke, Eva Seemanova, Birgit Zirn, Jörg Müsebeck, Rudolf Mallmann, Christiane Zweier, Rami Abou Jamra and Anita Rauch for contributing families with XLID. We would like to thank the Exome Aggregation Consortium and the groups that provided exome variant data for comparison. A full list of contributing groups can be found at <ext-link ext-link-type="uri" xlink:href="http://exac.broadinstitute.org/about">http://exac.broadinstitute.org/about</ext-link>. This work was financed by a grant of the German Ministry of Education and Research through the MRNET (to HHR); the EU FP7 project GENCODYS, grant number 241995; the Max Planck Innovation Funds (to HHR), NWO VENI grant: 91666017 to SGMF, grant 2009(2)-81 from the Dutch Brain Foundation to AdB, WCH Foundation and Australian NHMRC to JG, grant from Fondation pour la Recherche Médicale (FRM, J Chelly-Equipe FRM 2013: DEQ2000326477).</p><p>Web Resources</p><p>1000 Genomes Project Consortium, <ext-link ext-link-type="uri" xlink:href="http://www.1000genomes.org/data">http://www.1000genomes.org/data</ext-link>.</p><p>SplazerS, <ext-link ext-link-type="uri" xlink:href="http://www.seqan.de/projects/splazers.html">http://www.seqan.de/projects/splazers.html</ext-link>.</p><p>SnpStore, <ext-link ext-link-type="uri" xlink:href="http://www.seqan.de/projects/snpstore.html">http://www.seqan.de/projects/snpstore.html</ext-link>.</p><p>Online Mendelian Inheritance in Man (OMIM), <ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/omim">http://www.ncbi.nlm.nih.gov/omim</ext-link>.</p><p>PolyPhen2, <ext-link ext-link-type="uri" xlink:href="http://genetics.bwh.harvard.edu/pph2/">http://genetics.bwh.harvard.edu/pph2/</ext-link>.</p><p>SIFT, <ext-link ext-link-type="uri" xlink:href="http://sift.jcvi.org/">http://sift.jcvi.org/</ext-link>.</p><p>NHLBI Exome Variant Server (ESP6500), <ext-link ext-link-type="uri" xlink:href="http://evs.gs.washington.edu/EVS/">http://evs.gs.washington.edu/EVS/</ext-link>.</p><p>dbSNP135, dbSNP138, <ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/snp">http://www.ncbi.nlm.nih.gov/snp</ext-link>.</p><p>Ingenuity tool, <ext-link ext-link-type="uri" xlink:href="http://www.ingenuity.com">http://www.ingenuity.com</ext-link>.</p><p>HOPE server, <ext-link ext-link-type="uri" xlink:href="http://www.cmbi.ru.nl/hope/home">http://www.cmbi.ru.nl/hope/home</ext-link>.</p><p>shRNA designer tools, <ext-link ext-link-type="uri" xlink:href="http://france.promega.com/resources/tools/">http://france.promega.com/resources/tools/</ext-link>.</p><p>Decipher, <ext-link ext-link-type="uri" xlink:href="http://decipher.sanger.ac.uk/">http://decipher.sanger.ac.uk/</ext-link>.</p><p>RNAi Consortium (TCR) shRNA Library, <ext-link ext-link-type="uri" xlink:href="http://www.broadinstitute.org/rnai/trc/lib">http://www.broadinstitute.org/rnai/trc/lib</ext-link>.</p><p>MutationTaster, <ext-link ext-link-type="uri" xlink:href="http://www.mutationtaster.org/">http://www.mutationtaster.org/</ext-link>.</p><p>The Human Gene Mutation Database, <ext-link ext-link-type="uri" xlink:href="http://www.hgmd.org/">http://www.hgmd.org/</ext-link>.</p><p>Exome Aggregation Consortium (ExAC), Cambridge, MA, <ext-link ext-link-type="uri" xlink:href="http://exac.broadinstitute.org/">http://exac.broadinstitute.org/</ext-link>.</p><p>[November, 2014 accessed].</p></ack><fn-group><fn><p><xref ref-type="supplementary-material" rid="sup1">Supplementary Information</xref> accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)</p></fn><fn fn-type="COI-statement"><p>The authors declare no conflict of interest.</p></fn></fn-group><ref-list><ref id="bib1"><mixed-citation publication-type="journal">Ropers HH, Hamel BC. <article-title>X-linked mental retardation</article-title>. <source>Nat Rev Genet</source><year>2005</year>; 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(<bold>a</bold>) Pedigrees of families with <italic>CLCN4</italic> likely pathogenic mutations. Individuals tested for co-segregation with X-linked intellectual disability (XLID) and the results are indicated, *=mutation carrier, wt=subject does not carry the mutation. (<bold>b</bold>) Current–voltage relationships of the electrogenic Cl<sup>−</sup>/H<sup>+</sup> exchanger protein ClC-4 and its mutants expressed in <italic>Xenopus</italic> oocytes, shown as mean values of normalized steady-state currents from several oocytes (numbers indicated in figure, in parentheses: number of frogs). Compared with the strongly outwardly-rectifying currents of wild-type ClC-4,<sup><xref ref-type="bibr" rid="bib36">36</xref>, <xref ref-type="bibr" rid="bib121">121</xref></sup> currents were much smaller or even absent with CIC-4 mutant proteins carrying p.Gly78Ser, p.Leu221Val, p.Val536Met and p.Gly731Arg substitutions. ctr, non-injected controls; error bars, s.e.m. Two-tailed <italic>t</italic>-test was used for statistical comparisons (**<italic>P</italic><0.01, ***<italic>P</italic><0.001 compared with wild-type ClC-4 currents). (<bold>c</bold>) Analogous positions of amino acids mutated in ClC-4 highlighted in the crystal structure of CmClC.<sup><xref ref-type="bibr" rid="bib63">63</xref></sup> Amino acids are displayed as spheres in colors like in (<bold>b</bold>). The small green spheres represent Cl<sup>−</sup> ions. CLC transporters form dimers of identical subunits (shown in different shades) and include a transmembrane domain (TMD) and two cytosolic cystathionine-β-synthase (CBS) domains.</p></caption><graphic xlink:href="mp2014193f1"></graphic></fig><fig id="fig2"><label>Figure 2</label><caption><p>Pedigrees of families with co-segregating truncating and missense variants in novel and previously suggested candidate X-linked intellectual disability (XLID) genes validated through this study. (<bold>a</bold>) In the postsynaptic density protein <italic>CNKSR2</italic>, we observed a protein truncating variant in family P180. (<bold>b</bold>) In <italic>FRMPD4</italic>, we detected a unique protein truncating variant in family P58 with five affected males. (<bold>c</bold>) In <italic>KLHL15</italic>, we identified a protein truncating variant in family D60 with eight affected males. (<bold>d</bold>) In <italic>LAS1L</italic>, we found unique missense variants in families MRXS6 (ref. <xref ref-type="bibr" rid="bib66">66</xref>) and T50, both with Wilson-Turner (WTS) syndrome. (<bold>e</bold>) In <italic>RLIM</italic>, we identified missense variants in three large families D72, T11 and AU31. (<bold>f</bold>) In <italic>USPX27</italic>, we found a protein truncating variant in family D177 and a missense variant in family L75. (<bold>g</bold>) In the novel candidate XLID gene <italic>CDK16</italic>, we detected a protein truncating variant in family L56. (<bold>h</bold>) In the novel candidate XLID gene <italic>TAF1</italic>, we identified missense variants in families D185 and N67. *=mutation carrier, wt=wild type.</p></caption><graphic xlink:href="mp2014193f2"></graphic></fig><fig id="fig3"><label>Figure 3</label><caption><p>Effects of <italic>Clcn4</italic> or <italic>Cnksr2</italic> downregulation on morphology of mouse hippocampal neurons. Typical arborization of GFP-labeled neurons cultured for 18 days <italic>in vitro</italic> (DIV) after targeting by non-silencing (NS) or gene-specific shRNA (<italic>Clcn4</italic> or <italic>Cnksr2</italic>) at 11 DIV. Quantification of transfected neurons, for total length of neuritic branches, total number of branches (a branch is considered as the segment between two branching points) and for dendritic branching complexity (levels were quantified per neuron from 1 to 6, each time a branching point is met from nucleus toward the distal part of each dendrite). Detection of co-transfections of shRNA and cDNA encoding plasmids for rescue experiments is shown as overlap of GFP (green) and Halotag (red) signals. <italic>Clcn4</italic> experiment is shown in (<bold>a</bold>) and <italic>Cnksr2</italic> in (<bold>c</bold>). More than 15 representative cells of each type were analyzed per experiment, with three independent experiments conducted. (<bold>b</bold>) Quantification of neuritic arborization in GFP expressing primary hippocampal neurons derived from <italic>Clcn4</italic><sup>+/+</sup> and <italic>Clcn4</italic><sup>−/−</sup> mice as described above. Two independent experiments with>30 cells per genotype of five wild-type and four knock-out mice were analyzed. ClC-4-deficient neurons showed a significant reduction in the total number and total length of neuritic branches compared with wild-type cells. Average values with s.e.m. are shown (i) in histograms for neuritic length and number of branches and (ii) in curves for complexity levels of branching. Mann-Whitney and Chi2 tests were respectively used for statistical comparisons (ns: non-statistically significant, *<italic>P</italic><0.05, **<italic>P</italic><0.01, ***<italic>P</italic><0.001). Scale bar represents 10 μm.</p></caption><graphic xlink:href="mp2014193f3"></graphic></fig><fig id="fig4"><label>Figure 4</label><caption><p>Novel X-linked intellectual disability (XLID) genes and candidates that emerged from this study encode components of key cellular protein networks. All available protein–protein interactions involving known intellectual disability (ID) proteins and the proteins likely implicated in XLID identified in this study were first extracted from the literature and then connected into a set of protein–protein interaction networks via the Ingenuity tool. Functional cellular subnetworks were extracted by using the available annotations of the interacting proteins (e.g., defined by functional category ‘translation/transcription') and by performing literature searches. (<bold>a</bold>) PSD-95 (postsynaptic density protein 95)/Ras/Rho interaction network. CNKSR2 (CNK2, MAGUIN1, validated XLID protein) that likely functions as an adapter protein or regulator of Ras signaling pathways interacts with PSD-95 in synaptosomes.<sup><xref ref-type="bibr" rid="bib122">122</xref></sup> FRMPD4 (Preso, validated XLID protein), which is a positive regulator of dendritic spine morphogenesis and density and is required for the maintenance of excitatory synaptic transmission, interacts with PSD-95,<sup><xref ref-type="bibr" rid="bib104">104</xref></sup> and together with its binding partner ARHGEF7 (βPix) localizes in dendritic growth cones.<sup><xref ref-type="bibr" rid="bib123">123</xref></sup> (<bold>b</bold>) Transcriptional/translational interaction network. Known protein complexes are highlighted. RNA Polymerase II (RNAPII) complex with the core component TAF1 (novel candidate XLID protein). ATN1 (known ID protein) interacts with TAF4 and negatively regulates transcription of RNAPII.<sup><xref ref-type="bibr" rid="bib124">124</xref></sup> Large ribosomal subunit (60S) contains RPL10 (known candidate XLID/autism protein). LAS1L (novel XLID protein) is essential for the biogenesis of the ribosomal subunit 60S.<sup><xref ref-type="bibr" rid="bib114">114</xref></sup> Eukaryotic translation initiation factor, EIF2S3 (novel XLID protein), is a component of the translation initiation complex and promotes binding of the initiator methionyl-tRNA to the 40S ribosomal subunit.<sup><xref ref-type="bibr" rid="bib125">125</xref></sup> POLDIP3 (SKAR), involved in positive regulation of translation, associates with THOC2 (novel XLID protein) as a part of the TREX complex (functioning in mRNA export),<sup><xref ref-type="bibr" rid="bib126">126</xref></sup> with mRNA surveillance factor UPF3B (known XLID protein), as well as with a core component of the exon junction complex, EIF4A3.<sup><xref ref-type="bibr" rid="bib127">127</xref></sup> CDK16 (novel candidate XLID protein) and Synapsin 1 (Syn1, known XLID protein) were shown to interact in a membrane fraction from brain.<sup><xref ref-type="bibr" rid="bib71">71</xref></sup> Cdk16 associates with 14-3-3 zeta in Neuro-2A cells.<sup><xref ref-type="bibr" rid="bib69">69</xref></sup> Mediator complex, which functions as a transcriptional coactivator, contains MED12 (known XLID protein) and MED13L (known ID protein). NIPBL (known ID protein) is involved in loading of cohesin and associates with the mediator-cohesin complex, which interfaces gene expression and chromatin structure. Histone methyltransferase MLL2 (known ID protein) associates with a core component of Pol II, POLR2B, and activates transcription.<sup><xref ref-type="bibr" rid="bib128">128</xref></sup> Deubiquitinating enzyme USP27X (novel XLID protein) interacts with USP22 that is required for histone deubiquitination,<sup><xref ref-type="bibr" rid="bib129">129</xref></sup> and which associates together with TAF10 as part of the TBP-free TAF complex (TFTC).<sup><xref ref-type="bibr" rid="bib109">109</xref></sup> ADRA2B, G-protein coupled receptor, by interacting with EIF2B<sup><xref ref-type="bibr" rid="bib130">130</xref></sup> and 14-3-3 zeta<sup><xref ref-type="bibr" rid="bib131">131</xref></sup> links G protein-mediated signaling network and cellular control of protein synthesis. (<bold>c</bold>) Ubiquitination interaction network. KLHL15 (validated XLID protein) with a function in protein ubiquitination interacts with a component of an ubiquitin E3 ligase, CUL3.<sup><xref ref-type="bibr" rid="bib132">132</xref></sup> RLIM (novel XLID protein) is an E3 ubiquitin protein ligase<sup><xref ref-type="bibr" rid="bib113">113</xref></sup> and associates with UBE2D1.<sup><xref ref-type="bibr" rid="bib133">133</xref></sup></p></caption><graphic xlink:href="mp2014193f4"></graphic></fig><table-wrap id="tbl1"><label>Table 1</label><caption><title>Overview of sequence variants identified in 248 index patients with XLID</title></caption><table frame="hsides" rules="groups" border="1"><colgroup><col align="left"></col><col align="char" char="."></col><col align="char" char="."></col><col align="char" char="."></col><col align="char" char="."></col><col align="char" char="."></col><col align="char" char="."></col></colgroup><thead valign="bottom"><tr><th align="left" valign="top" charoff="50"><italic>Variant class</italic></th><th colspan="3" align="center" valign="top" char="." charoff="50"><italic>Variants found in the study cohort and present in control populations</italic><xref ref-type="fn" rid="t1-fn2">a</xref><hr></hr></th><th colspan="3" align="center" valign="top" char="." charoff="50"><italic>Variants found in the study cohort and absent in control populations</italic><xref ref-type="fn" rid="t1-fn2">a</xref><hr></hr></th></tr><tr><th align="left" valign="top" charoff="50"> </th><th align="center" valign="top" char="." charoff="50"><italic>Recurrent</italic></th><th align="center" valign="top" char="." charoff="50"><italic>Non-recurrent</italic></th><th align="center" valign="top" char="." charoff="50"><italic>Total</italic></th><th align="center" valign="top" char="." charoff="50"><italic>Recurrent</italic></th><th align="center" valign="top" char="." charoff="50"><italic>Non-recurrent</italic></th><th align="center" valign="top" char="." charoff="50"><italic>Total</italic></th></tr></thead><tbody valign="top"><tr><td align="left" valign="top" charoff="50">Synonymous</td><td align="char" valign="top" char="." charoff="50">602</td><td align="char" valign="top" char="." charoff="50">262</td><td align="char" valign="top" char="." charoff="50">864</td><td align="char" valign="top" char="." charoff="50">9</td><td align="char" valign="top" char="." charoff="50">235</td><td align="char" valign="top" char="." charoff="50">244</td></tr><tr><td align="left" valign="top" charoff="50">Missense</td><td align="char" valign="top" char="." charoff="50">606</td><td align="char" valign="top" char="." charoff="50">356</td><td align="char" valign="top" char="." charoff="50">962</td><td align="center" valign="top" char="." charoff="50">15 (1)</td><td align="center" valign="top" char="." charoff="50">461 (9)</td><td align="char" valign="top" char="." charoff="50">476</td></tr><tr><td align="left" valign="top" charoff="50">Non-sense</td><td align="char" valign="top" char="." charoff="50">6</td><td align="char" valign="top" char="." charoff="50">4</td><td align="char" valign="top" char="." charoff="50">10</td><td align="char" valign="top" char="." charoff="50">0</td><td align="char" valign="top" char="." charoff="50">13</td><td align="char" valign="top" char="." charoff="50">13</td></tr><tr><td align="left" valign="top" charoff="50">In-frame indels (<50 kb)</td><td align="char" valign="top" char="." charoff="50">13</td><td align="char" valign="top" char="." charoff="50">4</td><td align="char" valign="top" char="." charoff="50">17</td><td align="char" valign="top" char="." charoff="50">1</td><td align="center" valign="top" char="." charoff="50">18 (1)</td><td align="char" valign="top" char="." charoff="50">19</td></tr><tr><td align="left" valign="top" charoff="50">Small frameshift indels (⩽50 kb)</td><td align="char" valign="top" char="." charoff="50">12</td><td align="char" valign="top" char="." charoff="50">7</td><td align="char" valign="top" char="." charoff="50">19</td><td align="char" valign="top" char="." charoff="50">3</td><td align="center" valign="top" char="." charoff="50">29 (1)</td><td align="char" valign="top" char="." charoff="50">32</td></tr><tr><td align="left" valign="top" charoff="50">Large indels (>50 kb)</td><td align="char" valign="top" char="." charoff="50">0</td><td align="char" valign="top" char="." charoff="50">0</td><td align="char" valign="top" char="." charoff="50">0</td><td align="char" valign="top" char="." charoff="50">0</td><td align="center" valign="top" char="." charoff="50">9<xref ref-type="fn" rid="t1-fn3">b</xref></td><td align="char" valign="top" char="." charoff="50">9</td></tr><tr><td align="left" valign="top" charoff="50">Total</td><td align="char" valign="top" char="." charoff="50">1239</td><td align="char" valign="top" char="." charoff="50">633</td><td align="char" valign="top" char="." charoff="50">1872</td><td align="char" valign="top" char="." charoff="50">28</td><td align="char" valign="top" char="." charoff="50">765</td><td align="char" valign="top" char="." charoff="50">793</td></tr><tr><td align="left" valign="top" charoff="50">Canonical splice sites</td><td align="char" valign="top" char="." charoff="50">7</td><td align="char" valign="top" char="." charoff="50">3</td><td align="char" valign="top" char="." charoff="50">10</td><td align="char" valign="top" char="." charoff="50">2</td><td align="char" valign="top" char="." charoff="50">10</td><td align="char" valign="top" char="." charoff="50">12</td></tr><tr><td align="left" valign="top" charoff="50">Retrocopies</td><td align="char" valign="top" char="." charoff="50">0</td><td align="char" valign="top" char="." charoff="50">0</td><td align="char" valign="top" char="." charoff="50">0</td><td align="char" valign="top" char="." charoff="50">3</td><td align="char" valign="top" char="." charoff="50">5</td><td align="char" valign="top" char="." charoff="50">8</td></tr><tr><td align="left" valign="top" charoff="50">Potential cryptic splice sites</td><td align="char" valign="top" char="." charoff="50">0</td><td align="char" valign="top" char="." charoff="50">0</td><td align="char" valign="top" char="." charoff="50">0</td><td align="char" valign="top" char="." charoff="50">0</td><td align="char" valign="top" char="." charoff="50">4</td><td align="char" valign="top" char="." charoff="50">4</td></tr><tr><td align="left" valign="top" charoff="50">Non-coding exons</td><td align="char" valign="top" char="." charoff="50">2132</td><td align="char" valign="top" char="." charoff="50">663</td><td align="char" valign="top" char="." charoff="50">2795</td><td align="char" valign="top" char="." charoff="50">342</td><td align="char" valign="top" char="." charoff="50">1468</td><td align="char" valign="top" char="." charoff="50">1810</td></tr><tr><td align="left" valign="top" charoff="50">Total</td><td align="char" valign="top" char="." charoff="50">3378</td><td align="char" valign="top" char="." charoff="50">1299</td><td align="char" valign="top" char="." charoff="50">4677</td><td align="char" valign="top" char="." charoff="50">375</td><td align="char" valign="top" char="." charoff="50">2252</td><td align="char" valign="top" char="." charoff="50">2627</td></tr></tbody></table><table-wrap-foot><fn id="t1-fn1"><p>Abbreviations: HGMD, Human Gene Mutation Database; XLID, X-linked intellectual disability.</p></fn><fn id="t1-fn2"><label>a</label><p>Variants present in HGMD with PubMed entries (numbers shown in parentheses) were treated as potentially disease relevant and therefore were excluded from filtering against control populations (dbSNP 135, Exome Variant Server, NHLBI Exome Sequencing Project (ESP), Seattle, WA, 1000 Genomes Project, 200 Danish exomes<sup><xref ref-type="bibr" rid="bib3">3</xref></sup>). Indels=insertions and deletions.</p></fn><fn id="t1-fn3"><label>b</label><p>Three duplications were only detected by using a Hidden–Markov Model-based method.<sup><xref ref-type="bibr" rid="bib30">30</xref></sup></p></fn></table-wrap-foot></table-wrap><table-wrap id="tbl2"><label>Table 2</label><caption><title>Variants identified in novel XLID genes and candidates</title></caption><table frame="hsides" rules="groups" border="1"><colgroup><col align="left"></col><col align="left"></col><col align="left"></col><col align="char" char="."></col><col align="char" char="."></col><col align="left"></col><col align="left"></col></colgroup><thead valign="bottom"><tr><th align="left" valign="top" charoff="50"><italic>Family ID</italic></th><th align="left" valign="top" charoff="50"><italic>Gene</italic></th><th align="left" valign="top" charoff="50"><italic>Variant</italic></th><th align="center" valign="top" char="." charoff="50"><italic>PS score</italic></th><th align="center" valign="top" char="." charoff="50"><italic>C score</italic></th><th align="left" valign="top" charoff="50"><italic>Additional information (numbers indicate informative affected/unaffected males tested for segregation/obligate female carriers)</italic></th><th align="left" valign="top" charoff="50"><italic>Summary of clinical information for families per gene</italic></th></tr></thead><tbody valign="top"><tr><td colspan="7" align="left" valign="top" charoff="50"><italic>Likely pathogenic variants in novel and validated XLID genes</italic></td></tr><tr><td align="left" valign="top" charoff="50"> MRX49<sup><xref ref-type="bibr" rid="bib61">61</xref></sup>/L19</td><td align="left" valign="top" charoff="50"><italic>CLCN4</italic></td><td align="left" valign="top" charoff="50">p.Asp15Serfs*18</td><td align="char" valign="top" char="." charoff="50">20</td><td align="char" valign="top" char="." charoff="50">36</td><td align="left" valign="top" charoff="50">4/2/2, F, encodes a proton-chloride antiporter</td><td align="left" valign="top" charoff="50">Non-specific borderline to profound ID</td></tr><tr><td align="left" valign="top" charoff="50"> MRX15<sup><xref ref-type="bibr" rid="bib62">62</xref></sup>/T8</td><td align="left" valign="top" charoff="50"><italic>CLCN4</italic></td><td align="left" valign="top" charoff="50">p.Gly731Arg</td><td align="char" valign="top" char="." charoff="50">8</td><td align="char" valign="top" char="." charoff="50">29</td><td align="left" valign="top" charoff="50">F, cytosolic cystathionine-β-synthase domain, may impair transporter opening</td><td align="left" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> N70</td><td align="left" valign="top" charoff="50"><italic>CLCN4</italic></td><td align="left" valign="top" charoff="50">p.Gly78Ser</td><td align="char" valign="top" char="." charoff="50">14</td><td align="char" valign="top" char="." charoff="50">25</td><td align="left" valign="top" charoff="50">1/0/1, F, transmembrane domain</td><td align="left" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> AU27</td><td align="left" valign="top" charoff="50"><italic>CLCN4</italic></td><td align="left" valign="top" charoff="50">p.Leu221Val</td><td align="char" valign="top" char="." charoff="50">8</td><td align="char" valign="top" char="." charoff="50">25</td><td align="left" valign="top" charoff="50">2/0/4, F, transmembrane domain</td><td align="left" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> AU9</td><td align="left" valign="top" charoff="50"><italic>CLCN4</italic></td><td align="left" valign="top" charoff="50">p.Val536Met</td><td align="char" valign="top" char="." charoff="50">14</td><td align="char" valign="top" char="." charoff="50">27</td><td align="left" valign="top" charoff="50">3/0/7, F, transmembrane domain</td><td align="left" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> P180</td><td align="left" valign="top" charoff="50"><italic>CNKSR2</italic></td><td align="left" valign="top" charoff="50">p.Asp152Argfs*8</td><td align="char" valign="top" char="." charoff="50">20</td><td align="char" valign="top" char="." charoff="50">19</td><td align="left" valign="top" charoff="50">3/0/1, F, C, encodes connector enhancer of kinase suppressor of Ras 2, interacts with PSD95, XLID protein DLG3, ID/autism protein SHANK3</td><td align="left" valign="top" charoff="50">ID, attentional problems, hyperactivity, language loss, seizures<sup><xref ref-type="bibr" rid="bib99">99</xref></sup></td></tr><tr><td align="left" valign="top" charoff="50"> P58</td><td align="left" valign="top" charoff="50"><italic>FRMPD4</italic></td><td align="left" valign="top" charoff="50">p.Cys618Valfs*8</td><td align="char" valign="top" char="." charoff="50">20</td><td align="char" valign="top" char="." charoff="50">38</td><td align="left" valign="top" charoff="50">5/2/2, encodes FERM and PDZ domain containing 4, interacts with PSD95, with ARHGEF7, a guanine nucleotide exchange factor with a role in the regulation of spine morphogenesis, and with actin filaments<sup><xref ref-type="bibr" rid="bib104">104</xref>, <xref ref-type="bibr" rid="bib123">123</xref></sup></td><td align="left" valign="top" charoff="50">Mild to severe ID with variable seizures, lack of speech or poor speech, behavioral problems</td></tr><tr><td align="left" valign="top" charoff="50"> L87</td><td align="left" valign="top" charoff="50"><italic>FRMPD4</italic></td><td align="left" valign="top" charoff="50">p.Cys553Arg</td><td align="char" valign="top" char="." charoff="50">4</td><td align="char" valign="top" char="." charoff="50">16</td><td align="left" valign="top" charoff="50"><italic>De novo</italic></td><td align="left" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> D60</td><td align="left" valign="top" charoff="50"><italic>KLHL15</italic></td><td align="left" valign="top" charoff="50">p.Tyr394Ilefs*61</td><td align="char" valign="top" char="." charoff="50">20</td><td align="char" valign="top" char="." charoff="50">33</td><td align="left" valign="top" charoff="50">8/1/4, encodes kelch-like 15, large family with 8 affected in three generations</td><td align="left" valign="top" charoff="50">Mild to moderate ID, mild facial features</td></tr><tr><td align="left" valign="top" charoff="50"> MRXS6<sup><xref ref-type="bibr" rid="bib66">66</xref></sup>/AU10</td><td align="left" valign="top" charoff="50"><italic>LAS1L</italic></td><td align="left" valign="top" charoff="50">p.Ala269Gly</td><td align="char" valign="top" char="." charoff="50">10</td><td align="char" valign="top" char="." charoff="50">18</td><td align="left" valign="top" charoff="50">5/0/19, C, encodes Las1-like, ribosome biogenesis</td><td align="left" valign="top" charoff="50">Wilson-Turner syndrome,<sup><xref ref-type="bibr" rid="bib66">66</xref></sup> mild to moderate ID, obesity, facial features, speech impairment, variable behavioral problems, gynecomastia, small/undescended testes/hypogonadism, tapering fingers</td></tr><tr><td align="left" valign="top" charoff="50"> T50</td><td align="left" valign="top" charoff="50"><italic>LAS1L</italic></td><td align="left" valign="top" charoff="50">p.Arg415Trp</td><td align="char" valign="top" char="." charoff="50">11</td><td align="char" valign="top" char="." charoff="50">14</td><td align="left" valign="top" charoff="50">3/2/3, C</td><td align="left" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> MRX61/T11</td><td align="left" valign="top" charoff="50"><italic>RLIM</italic></td><td align="left" valign="top" charoff="50">p.Pro587Arg</td><td align="char" valign="top" char="." charoff="50">11</td><td align="char" valign="top" char="." charoff="50">13</td><td align="left" valign="top" charoff="50">3/1/3, encodes ring finger protein, LIM domain interacting, E3 ubiquitin-protein ligase, binds to transcription factors that play important roles for the development of neuronal structures and cell types</td><td align="left" valign="top" charoff="50">Non-specific mild to profound ID in two families with variable behavior problems, ID, microcephaly, micrognathia and cryptorchidism in all affected of one family</td></tr><tr><td align="left" valign="top" charoff="50"> D72</td><td align="left" valign="top" charoff="50"><italic>RLIM</italic></td><td align="left" valign="top" charoff="50">p.Arg387Cys</td><td align="char" valign="top" char="." charoff="50">12</td><td align="char" valign="top" char="." charoff="50">12</td><td align="left" valign="top" charoff="50">1/2/8</td><td align="left" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> AU31</td><td align="left" valign="top" charoff="50"><italic>RLIM</italic></td><td align="left" valign="top" charoff="50">p.Arg599Cys</td><td align="char" valign="top" char="." charoff="50">14</td><td align="char" valign="top" char="." charoff="50">18</td><td align="left" valign="top" charoff="50">2/3/3</td><td align="left" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> D177</td><td align="left" valign="top" charoff="50"><italic>USP27X</italic></td><td align="left" valign="top" charoff="50">p.Ser342Argfs*14</td><td align="char" valign="top" char="." charoff="50">20</td><td align="char" valign="top" char="." charoff="50">10</td><td align="left" valign="top" charoff="50">3/0/2, encodes ubiquitin-specific peptidase 27, interacts with USP22 which deubiquitinates core histones H2A and H2B, USP22 interacts with ARID gene KIF7</td><td align="left" valign="top" charoff="50">Borderline to moderate ID, variable absent or poor speech and behavioral problems</td></tr><tr><td align="left" valign="top" charoff="50"> L75</td><td align="left" valign="top" charoff="50"><italic>USP27X</italic></td><td align="left" valign="top" charoff="50">p.Tyr381His</td><td align="char" valign="top" char="." charoff="50">12</td><td align="char" valign="top" char="." charoff="50">11</td><td align="left" valign="top" charoff="50">1/1/2, this residue is part of a domain (IPR001394) and using HOPE web server (see URLs) the variant is predicted to cause an empty space in the core of the protein or protein complex and to cause loss of hydrophobic interactions</td><td align="left" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> </td><td align="left" valign="top" charoff="50"> </td><td align="left" valign="top" charoff="50"> </td><td align="char" valign="top" char="." charoff="50"> </td><td align="char" valign="top" char="." charoff="50"> </td><td align="left" valign="top" charoff="50"> </td><td align="left" valign="top" charoff="50"> </td></tr><tr><td colspan="7" align="left" valign="top" charoff="50"><italic>Potentially deleterious changes in novel candidate genes</italic></td></tr><tr><td align="left" valign="top" charoff="50"> L56</td><td align="left" valign="top" charoff="50"><italic>CDK16</italic></td><td align="left" valign="top" charoff="50">p.Trp326Valfs*5</td><td align="char" valign="top" char="." charoff="50">20</td><td align="char" valign="top" char="." charoff="50">37</td><td align="left" valign="top" charoff="50">4/1/3, encodes cyclin-dependent kinase 16, also known as PCTK1, PCTAIRE1, and PCT-1</td><td align="left" valign="top" charoff="50">ID, spastic paraplegia</td></tr><tr><td align="left" valign="top" charoff="50"> N67</td><td align="left" valign="top" charoff="50"><italic>TAF1</italic></td><td align="left" valign="top" charoff="50">p.Asn493Asp</td><td align="char" valign="top" char="." charoff="50">13</td><td align="char" valign="top" char="." charoff="50">19</td><td align="left" valign="top" charoff="50">2/0/2, encodes TATA box binding protein (TBP)-associated factor, 250 kDa, subunit of TAFIID which plays a key role transcription initiation. Drosophila homolog phosphorylates histone H2B, variants in <italic>TAF2</italic> cause ARID<sup><xref ref-type="bibr" rid="bib78">78</xref>, <xref ref-type="bibr" rid="bib79">79</xref></sup></td><td align="left" valign="top" charoff="50">Mild to severe ID, facial features</td></tr><tr><td align="left" valign="top" charoff="50"> D185</td><td align="left" valign="top" charoff="50"><italic>TAF1</italic></td><td align="left" valign="top" charoff="50">p.Arg1190Cys</td><td align="char" valign="top" char="." charoff="50">14</td><td align="char" valign="top" char="." charoff="50">27</td><td align="left" valign="top" charoff="50">2/4/7</td><td align="left" valign="top" charoff="50"> </td></tr></tbody></table><table-wrap-foot><fn id="t2-fn1"><p>Abbreviations: C, clinical evidence; F, functional evidence from this study; HGMD, Human Gene Mutation Database; ID, intellectual disability; PS, prioritization score, includes type of variant, evolutionary conservation and predictions from Polyphen2 and SIFT; C score obtained by using Combined Annotation-Dependent Depletion (CADD);<sup><xref ref-type="bibr" rid="bib35">35</xref></sup> XLID, X-linked intellectual disability.</p></fn></table-wrap-foot></table-wrap><table-wrap id="tbl3"><label>Table 3</label><caption><title>Potentially non-XLID causing recurrent and non-recurrent transcript and protein truncating variants identified in the screen and not present in controls (dbSNP 135, 1000 Genomes Project, 200 Danish exomes, NHLBI Exome Sequencing Project (ESP6500, Exome Variant Server))</title></caption><table frame="hsides" rules="groups" border="1"><colgroup><col align="left"></col><col align="left"></col><col align="left"></col><col align="char" char="."></col><col align="left"></col></colgroup><thead valign="bottom"><tr><th align="left" valign="top" charoff="50"><italic>Recurrence in 248 probands</italic></th><th align="left" valign="top" charoff="50"><italic>Gene</italic></th><th align="left" valign="top" charoff="50"><italic>Variant</italic></th><th align="center" valign="top" char="." charoff="50"><italic>Protein length</italic></th><th align="left" valign="top" charoff="50"><italic>Genomic location (Hg19)</italic></th></tr></thead><tbody valign="top"><tr><td align="left" valign="top" charoff="50">1</td><td align="left" valign="top" charoff="50"><italic>ARSF</italic></td><td align="left" valign="top" charoff="50">del5bp, p.F283Sfs*30</td><td align="char" valign="top" char="." charoff="50">591</td><td align="left" valign="top" charoff="50">X:3007551-3007555</td></tr><tr><td align="left" valign="top" charoff="50">1</td><td align="left" valign="top" charoff="50"><italic>COL4A6</italic></td><td align="left" valign="top" charoff="50">del1bp, p.L891Sfs*14</td><td align="char" valign="top" char="." charoff="50">1691</td><td align="left" valign="top" charoff="50">X:107420086-107420086</td></tr><tr><td align="left" valign="top" charoff="50">1</td><td align="left" valign="top" charoff="50"><italic>CXorf61</italic></td><td align="left" valign="top" charoff="50">C>T, p.W19*</td><td align="char" valign="top" char="." charoff="50">114</td><td align="left" valign="top" charoff="50">X:115593961-115593961</td></tr><tr><td align="left" valign="top" charoff="50">1</td><td align="left" valign="top" charoff="50"><italic>CXorf64</italic></td><td align="left" valign="top" charoff="50">C>T, p.R201*</td><td align="char" valign="top" char="." charoff="50">299</td><td align="left" valign="top" charoff="50">X:125955222-125955222</td></tr><tr><td align="left" valign="top" charoff="50">3</td><td align="left" valign="top" charoff="50"><italic>FAM58A</italic></td><td align="left" valign="top" charoff="50">ins1bp, p.Q18Afs*39<xref ref-type="fn" rid="t3-fn2">a</xref></td><td align="char" valign="top" char="." charoff="50">248</td><td align="left" valign="top" charoff="50">X:152864477-152864478</td></tr><tr><td align="left" valign="top" charoff="50">1</td><td align="left" valign="top" charoff="50"><italic>FATE1</italic></td><td align="left" valign="top" charoff="50">ins7bp, p.M38*</td><td align="char" valign="top" char="." charoff="50">184</td><td align="left" valign="top" charoff="50">X:150885749-150885750</td></tr><tr><td align="left" valign="top" charoff="50">1</td><td align="left" valign="top" charoff="50"><italic>FRMD7</italic></td><td align="left" valign="top" charoff="50">del1bp, p.L713*</td><td align="char" valign="top" char="." charoff="50">715</td><td align="left" valign="top" charoff="50">X:131211907-131211907</td></tr><tr><td align="left" valign="top" charoff="50">1</td><td align="left" valign="top" charoff="50"><italic>GPR112</italic></td><td align="left" valign="top" charoff="50">ins2bp, p.A1156Gfs*7</td><td align="char" valign="top" char="." charoff="50">3081</td><td align="left" valign="top" charoff="50">X:135429330-135429331</td></tr><tr><td align="left" valign="top" charoff="50">1</td><td align="left" valign="top" charoff="50"><italic>GUCY2F</italic></td><td align="left" valign="top" charoff="50">G>A, p.R628*</td><td align="char" valign="top" char="." charoff="50">1109</td><td align="left" valign="top" charoff="50">X:108652307-108652307</td></tr><tr><td align="left" valign="top" charoff="50">1</td><td align="left" valign="top" charoff="50"><italic>HDAC8</italic></td><td align="left" valign="top" charoff="50">A>G, p.*257QKQLPQLVFPHLHSLV</td><td align="char" valign="top" char="." charoff="50">257</td><td align="left" valign="top" charoff="50">X:71694548-71694548</td></tr><tr><td align="left" valign="top" charoff="50">1</td><td align="left" valign="top" charoff="50"><italic>HS6ST2</italic></td><td align="left" valign="top" charoff="50">del1bp, p.V8Afs*27</td><td align="char" valign="top" char="." charoff="50">606</td><td align="left" valign="top" charoff="50">X:132092608-132092608</td></tr><tr><td align="left" valign="top" charoff="50">1</td><td align="left" valign="top" charoff="50"><italic>MAGIX</italic></td><td align="left" valign="top" charoff="50">ins1bp, p.G316Rfs*20</td><td align="char" valign="top" char="." charoff="50">335</td><td align="left" valign="top" charoff="50">X:49022676-49022677</td></tr><tr><td align="left" valign="top" charoff="50">1</td><td align="left" valign="top" charoff="50"><italic>MAP3K15</italic></td><td align="left" valign="top" charoff="50">A>T, p.Y645*</td><td align="char" valign="top" char="." charoff="50">1314</td><td align="left" valign="top" charoff="50">X:19416475-19416475</td></tr><tr><td align="left" valign="top" charoff="50">1</td><td align="left" valign="top" charoff="50"><italic>SLC25A43</italic></td><td align="left" valign="top" charoff="50">C>T, p.R196*</td><td align="char" valign="top" char="." charoff="50">342</td><td align="left" valign="top" charoff="50">X:118544221-118544221</td></tr></tbody></table><table-wrap-foot><fn id="t3-fn1"><p>Abbreviation: XLID, X-linked intellectual disability.</p></fn><fn id="t3-fn2"><label>a</label><p>This variant is reported in dbSNP138.</p></fn></table-wrap-foot></table-wrap></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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