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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en"><italic>ZC4H2</italic> Mutations Are Associated with Arthrogryposis Multiplex Congenita and Intellectual Disability through Impairment of Central and Peripheral Synaptic Plasticity</title><author><name sortKey="Hirata, Hiromi" sort="Hirata, Hiromi" uniqKey="Hirata H" first="Hiromi" last="Hirata">Hiromi Hirata</name><affiliation><nlm:aff id="aff1">Center for Frontier Research, National Institute of Genetics, Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Mishima 411-8540, Japan</nlm:aff></affiliation></author><author><name sortKey="Nanda, Indrajit" sort="Nanda, Indrajit" uniqKey="Nanda I" first="Indrajit" last="Nanda">Indrajit Nanda</name><affiliation><nlm:aff id="aff2">Institute of Human Genetics, University of Würzburg, Biocenter, 97047 Würzburg, Germany</nlm:aff></affiliation></author><author><name sortKey="Van Riesen, Anne" sort="Van Riesen, Anne" uniqKey="Van Riesen A" first="Anne" last="Van Riesen">Anne Van Riesen</name><affiliation><nlm:aff id="aff3">Department of Neuropediatrics and NeuroCure Clinical Research Center, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Mcmichael, Gai" sort="Mcmichael, Gai" uniqKey="Mcmichael G" first="Gai" last="Mcmichael">Gai Mcmichael</name><affiliation><nlm:aff id="aff4">Robinson Institute, The University of Adelaide, Adelaide, SA 5000, Australia</nlm:aff></affiliation></author><author><name sortKey="Hu, Hao" sort="Hu, Hao" uniqKey="Hu H" first="Hao" last="Hu">Hao Hu</name><affiliation><nlm:aff id="aff5">Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Hambrock, Melanie" sort="Hambrock, Melanie" uniqKey="Hambrock M" first="Melanie" last="Hambrock">Melanie Hambrock</name><affiliation><nlm:aff id="aff5">Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Papon, Marie Amelie" sort="Papon, Marie Amelie" uniqKey="Papon M" first="Marie-Amélie" last="Papon">Marie-Amélie Papon</name><affiliation><nlm:aff id="aff6">Université François-Rabelais, 37032 Tours, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff7">Institut National de la Santé et de la Recherche Médicale Unité 930, 37032 Tours, France</nlm:aff></affiliation></author><author><name sortKey="Fischer, Ute" sort="Fischer, Ute" uniqKey="Fischer U" first="Ute" last="Fischer">Ute Fischer</name><affiliation><nlm:aff id="aff5">Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Marouillat, Sylviane" sort="Marouillat, Sylviane" uniqKey="Marouillat S" first="Sylviane" last="Marouillat">Sylviane Marouillat</name><affiliation><nlm:aff id="aff6">Université François-Rabelais, 37032 Tours, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff7">Institut National de la Santé et de la Recherche Médicale Unité 930, 37032 Tours, France</nlm:aff></affiliation></author><author><name sortKey="Ding, Can" sort="Ding, Can" uniqKey="Ding C" first="Can" last="Ding">Can Ding</name><affiliation><nlm:aff id="aff3">Department of Neuropediatrics and NeuroCure Clinical Research Center, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Alirol, Servane" sort="Alirol, Servane" uniqKey="Alirol S" first="Servane" last="Alirol">Servane Alirol</name><affiliation><nlm:aff id="aff6">Université François-Rabelais, 37032 Tours, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff7">Institut National de la Santé et de la Recherche Médicale Unité 930, 37032 Tours, France</nlm:aff></affiliation></author><author><name sortKey="Bienek, Melanie" sort="Bienek, Melanie" uniqKey="Bienek M" first="Melanie" last="Bienek">Melanie Bienek</name><affiliation><nlm:aff id="aff5">Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Preisler Adams, Sabine" sort="Preisler Adams, Sabine" uniqKey="Preisler Adams S" first="Sabine" last="Preisler-Adams">Sabine Preisler-Adams</name><affiliation><nlm:aff id="aff8">Institute of Human Genetics, Westfälische Wilhelms Universität Münster, 48149 Münster, Germany</nlm:aff></affiliation></author><author><name sortKey="Grimme, Astrid" sort="Grimme, Astrid" uniqKey="Grimme A" first="Astrid" last="Grimme">Astrid Grimme</name><affiliation><nlm:aff id="aff5">Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Seelow, Dominik" sort="Seelow, Dominik" uniqKey="Seelow D" first="Dominik" last="Seelow">Dominik Seelow</name><affiliation><nlm:aff id="aff3">Department of Neuropediatrics and NeuroCure Clinical Research Center, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Webster, Richard" sort="Webster, Richard" uniqKey="Webster R" first="Richard" last="Webster">Richard Webster</name><affiliation><nlm:aff id="aff9">The Department of Neurology and Neurosurgery, The Children’s Hospital at Westmead, Sydney, NSW 2145, Australia</nlm:aff></affiliation></author><author><name sortKey="Haan, Eric" sort="Haan, Eric" uniqKey="Haan E" first="Eric" last="Haan">Eric Haan</name><affiliation><nlm:aff id="aff10">South Australian Clinical Genetics Service, SA Pathology, Adelaide, SA 5000, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff11">School of Paediatrics and Reproductive Health, The University of Adelaide, Adelaide, SA 5000, Australia</nlm:aff></affiliation></author><author><name sortKey="Maclennan, Alastair" sort="Maclennan, Alastair" uniqKey="Maclennan A" first="Alastair" last="Maclennan">Alastair Maclennan</name><affiliation><nlm:aff id="aff4">Robinson Institute, The University of Adelaide, Adelaide, SA 5000, Australia</nlm:aff></affiliation></author><author><name sortKey="Stenzel, Werner" sort="Stenzel, Werner" uniqKey="Stenzel W" first="Werner" last="Stenzel">Werner Stenzel</name><affiliation><nlm:aff id="aff12">Institute of Neuropathology, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Yap, Tzu Ying" sort="Yap, Tzu Ying" uniqKey="Yap T" first="Tzu Ying" last="Yap">Tzu Ying Yap</name><affiliation><nlm:aff id="aff11">School of Paediatrics and Reproductive Health, The University of Adelaide, Adelaide, SA 5000, Australia</nlm:aff></affiliation></author><author><name sortKey="Gardner, Alison" sort="Gardner, Alison" uniqKey="Gardner A" first="Alison" last="Gardner">Alison Gardner</name><affiliation><nlm:aff id="aff13">Neurogenetics, SA Pathology, Adelaide, SA 5000, Australia</nlm:aff></affiliation></author><author><name sortKey="Nguyen, Lam Son" sort="Nguyen, Lam Son" uniqKey="Nguyen L" first="Lam Son" last="Nguyen">Lam Son Nguyen</name><affiliation><nlm:aff id="aff11">School of Paediatrics and Reproductive Health, The University of Adelaide, Adelaide, SA 5000, Australia</nlm:aff></affiliation></author><author><name sortKey="Shaw, Marie" sort="Shaw, Marie" uniqKey="Shaw M" first="Marie" last="Shaw">Marie Shaw</name><affiliation><nlm:aff id="aff11">School of Paediatrics and Reproductive Health, The University of Adelaide, Adelaide, SA 5000, Australia</nlm:aff></affiliation></author><author><name sortKey="Lebrun, Nicolas" sort="Lebrun, Nicolas" uniqKey="Lebrun N" first="Nicolas" last="Lebrun">Nicolas Lebrun</name><affiliation><nlm:aff id="aff14">University Paris Descartes, 75006 Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff15">Institut National de la Santé et de la Recherche Médicale Unité 1016, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Institut Cochin, 75014 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Haas, Stefan A" sort="Haas, Stefan A" uniqKey="Haas S" first="Stefan A." last="Haas">Stefan A. Haas</name><affiliation><nlm:aff id="aff16">Department of Computational Biology, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Kress, Wolfram" sort="Kress, Wolfram" uniqKey="Kress W" first="Wolfram" last="Kress">Wolfram Kress</name><affiliation><nlm:aff id="aff2">Institute of Human Genetics, University of Würzburg, Biocenter, 97047 Würzburg, Germany</nlm:aff></affiliation></author><author><name sortKey="Haaf, Thomas" sort="Haaf, Thomas" uniqKey="Haaf T" first="Thomas" last="Haaf">Thomas Haaf</name><affiliation><nlm:aff id="aff2">Institute of Human Genetics, University of Würzburg, Biocenter, 97047 Würzburg, Germany</nlm:aff></affiliation></author><author><name sortKey="Schellenberger, Elke" sort="Schellenberger, Elke" uniqKey="Schellenberger E" first="Elke" last="Schellenberger">Elke Schellenberger</name><affiliation><nlm:aff id="aff17">Kinderklinik am Mönchberg, Kinderfachabteilung der Missionsärztlichen Klinik Würzburg, 97067 Würzburg, Germany</nlm:aff></affiliation></author><author><name sortKey="Chelly, Jamel" sort="Chelly, Jamel" uniqKey="Chelly J" first="Jamel" last="Chelly">Jamel Chelly</name><affiliation><nlm:aff id="aff14">University Paris Descartes, 75006 Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff15">Institut National de la Santé et de la Recherche Médicale Unité 1016, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Institut Cochin, 75014 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Viot, Geraldine" sort="Viot, Geraldine" uniqKey="Viot G" first="Géraldine" last="Viot">Géraldine Viot</name><affiliation><nlm:aff id="aff18">Department of Gynecology-Obstetrics, Cochin Hospital, Assistance Publique – Hôpitaux de Paris, 75014 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Shaffer, Lisa G" sort="Shaffer, Lisa G" uniqKey="Shaffer L" first="Lisa G." last="Shaffer">Lisa G. Shaffer</name><affiliation><nlm:aff id="aff19">Signature Genomic Laboratories, PerkinElmer, Inc., Spokane, WA 99207, USA</nlm:aff></affiliation></author><author><name sortKey="Rosenfeld, Jill A" sort="Rosenfeld, Jill A" uniqKey="Rosenfeld J" first="Jill A." last="Rosenfeld">Jill A. Rosenfeld</name><affiliation><nlm:aff id="aff19">Signature Genomic Laboratories, PerkinElmer, Inc., Spokane, WA 99207, USA</nlm:aff></affiliation></author><author><name sortKey="Kramer, Nancy" sort="Kramer, Nancy" uniqKey="Kramer N" first="Nancy" last="Kramer">Nancy Kramer</name><affiliation><nlm:aff id="aff20">Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA</nlm:aff></affiliation></author><author><name sortKey="Falk, Rena" sort="Falk, Rena" uniqKey="Falk R" first="Rena" last="Falk">Rena Falk</name><affiliation><nlm:aff id="aff21">Medical Genetics Institute and Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA</nlm:aff></affiliation></author><author><name sortKey="El Khechen, Dima" sort="El Khechen, Dima" uniqKey="El Khechen D" first="Dima" last="El-Khechen">Dima El-Khechen</name><affiliation><nlm:aff id="aff22">Medical Genetics and Neurodevelopmental Center, Peyton Manning St. Vincent Children’s Hospital, Indianapolis, IN 46260, USA</nlm:aff></affiliation></author><author><name sortKey="Escobar, Luis F" sort="Escobar, Luis F" uniqKey="Escobar L" first="Luis F." last="Escobar">Luis F. Escobar</name><affiliation><nlm:aff id="aff22">Medical Genetics and Neurodevelopmental Center, Peyton Manning St. Vincent Children’s Hospital, Indianapolis, IN 46260, USA</nlm:aff></affiliation></author><author><name sortKey="Hennekam, Raoul" sort="Hennekam, Raoul" uniqKey="Hennekam R" first="Raoul" last="Hennekam">Raoul Hennekam</name><affiliation><nlm:aff id="aff23">Department of Pediatrics and Clinical Genetics, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Wieacker, Peter" sort="Wieacker, Peter" uniqKey="Wieacker P" first="Peter" last="Wieacker">Peter Wieacker</name><affiliation><nlm:aff id="aff8">Institute of Human Genetics, Westfälische Wilhelms Universität Münster, 48149 Münster, Germany</nlm:aff></affiliation></author><author><name sortKey="Hubner, Christoph" sort="Hubner, Christoph" uniqKey="Hubner C" first="Christoph" last="Hübner">Christoph Hübner</name><affiliation><nlm:aff id="aff3">Department of Neuropediatrics and NeuroCure Clinical Research Center, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Ropers, Hans Hilger" sort="Ropers, Hans Hilger" uniqKey="Ropers H" first="Hans-Hilger" last="Ropers">Hans-Hilger Ropers</name><affiliation><nlm:aff id="aff5">Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Gecz, Jozef" sort="Gecz, Jozef" uniqKey="Gecz J" first="Jozef" last="Gecz">Jozef Gecz</name><affiliation><nlm:aff id="aff11">School of Paediatrics and Reproductive Health, The University of Adelaide, Adelaide, SA 5000, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff13">Neurogenetics, SA Pathology, Adelaide, SA 5000, Australia</nlm:aff></affiliation></author><author><name sortKey="Schuelke, Markus" sort="Schuelke, Markus" uniqKey="Schuelke M" first="Markus" last="Schuelke">Markus Schuelke</name><affiliation><nlm:aff id="aff3">Department of Neuropediatrics and NeuroCure Clinical Research Center, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Laumonnier, Frederic" sort="Laumonnier, Frederic" uniqKey="Laumonnier F" first="Frédéric" last="Laumonnier">Frédéric Laumonnier</name><affiliation><nlm:aff id="aff6">Université François-Rabelais, 37032 Tours, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff7">Institut National de la Santé et de la Recherche Médicale Unité 930, 37032 Tours, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff24">Department of Medical Genetics, Centre Hospitalier Régional Universitaire, 37044 Tours, France</nlm:aff></affiliation></author><author><name sortKey="Kalscheuer, Vera M" sort="Kalscheuer, Vera M" uniqKey="Kalscheuer V" first="Vera M." last="Kalscheuer">Vera M. Kalscheuer</name><affiliation><nlm:aff id="aff5">Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">23623388</idno><idno type="pmc">3644645</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3644645</idno><idno type="RBID">PMC:3644645</idno><idno type="doi">10.1016/j.ajhg.2013.03.021</idno><date when="2013">2013</date><idno type="wicri:Area/Pmc/Corpus">001684</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001684</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main"><italic>ZC4H2</italic> Mutations Are Associated with Arthrogryposis Multiplex Congenita and Intellectual Disability through Impairment of Central and Peripheral Synaptic Plasticity</title><author><name sortKey="Hirata, Hiromi" sort="Hirata, Hiromi" uniqKey="Hirata H" first="Hiromi" last="Hirata">Hiromi Hirata</name><affiliation><nlm:aff id="aff1">Center for Frontier Research, National Institute of Genetics, Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Mishima 411-8540, Japan</nlm:aff></affiliation></author><author><name sortKey="Nanda, Indrajit" sort="Nanda, Indrajit" uniqKey="Nanda I" first="Indrajit" last="Nanda">Indrajit Nanda</name><affiliation><nlm:aff id="aff2">Institute of Human Genetics, University of Würzburg, Biocenter, 97047 Würzburg, Germany</nlm:aff></affiliation></author><author><name sortKey="Van Riesen, Anne" sort="Van Riesen, Anne" uniqKey="Van Riesen A" first="Anne" last="Van Riesen">Anne Van Riesen</name><affiliation><nlm:aff id="aff3">Department of Neuropediatrics and NeuroCure Clinical Research Center, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Mcmichael, Gai" sort="Mcmichael, Gai" uniqKey="Mcmichael G" first="Gai" last="Mcmichael">Gai Mcmichael</name><affiliation><nlm:aff id="aff4">Robinson Institute, The University of Adelaide, Adelaide, SA 5000, Australia</nlm:aff></affiliation></author><author><name sortKey="Hu, Hao" sort="Hu, Hao" uniqKey="Hu H" first="Hao" last="Hu">Hao Hu</name><affiliation><nlm:aff id="aff5">Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Hambrock, Melanie" sort="Hambrock, Melanie" uniqKey="Hambrock M" first="Melanie" last="Hambrock">Melanie Hambrock</name><affiliation><nlm:aff id="aff5">Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Papon, Marie Amelie" sort="Papon, Marie Amelie" uniqKey="Papon M" first="Marie-Amélie" last="Papon">Marie-Amélie Papon</name><affiliation><nlm:aff id="aff6">Université François-Rabelais, 37032 Tours, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff7">Institut National de la Santé et de la Recherche Médicale Unité 930, 37032 Tours, France</nlm:aff></affiliation></author><author><name sortKey="Fischer, Ute" sort="Fischer, Ute" uniqKey="Fischer U" first="Ute" last="Fischer">Ute Fischer</name><affiliation><nlm:aff id="aff5">Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Marouillat, Sylviane" sort="Marouillat, Sylviane" uniqKey="Marouillat S" first="Sylviane" last="Marouillat">Sylviane Marouillat</name><affiliation><nlm:aff id="aff6">Université François-Rabelais, 37032 Tours, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff7">Institut National de la Santé et de la Recherche Médicale Unité 930, 37032 Tours, France</nlm:aff></affiliation></author><author><name sortKey="Ding, Can" sort="Ding, Can" uniqKey="Ding C" first="Can" last="Ding">Can Ding</name><affiliation><nlm:aff id="aff3">Department of Neuropediatrics and NeuroCure Clinical Research Center, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Alirol, Servane" sort="Alirol, Servane" uniqKey="Alirol S" first="Servane" last="Alirol">Servane Alirol</name><affiliation><nlm:aff id="aff6">Université François-Rabelais, 37032 Tours, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff7">Institut National de la Santé et de la Recherche Médicale Unité 930, 37032 Tours, France</nlm:aff></affiliation></author><author><name sortKey="Bienek, Melanie" sort="Bienek, Melanie" uniqKey="Bienek M" first="Melanie" last="Bienek">Melanie Bienek</name><affiliation><nlm:aff id="aff5">Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Preisler Adams, Sabine" sort="Preisler Adams, Sabine" uniqKey="Preisler Adams S" first="Sabine" last="Preisler-Adams">Sabine Preisler-Adams</name><affiliation><nlm:aff id="aff8">Institute of Human Genetics, Westfälische Wilhelms Universität Münster, 48149 Münster, Germany</nlm:aff></affiliation></author><author><name sortKey="Grimme, Astrid" sort="Grimme, Astrid" uniqKey="Grimme A" first="Astrid" last="Grimme">Astrid Grimme</name><affiliation><nlm:aff id="aff5">Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Seelow, Dominik" sort="Seelow, Dominik" uniqKey="Seelow D" first="Dominik" last="Seelow">Dominik Seelow</name><affiliation><nlm:aff id="aff3">Department of Neuropediatrics and NeuroCure Clinical Research Center, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Webster, Richard" sort="Webster, Richard" uniqKey="Webster R" first="Richard" last="Webster">Richard Webster</name><affiliation><nlm:aff id="aff9">The Department of Neurology and Neurosurgery, The Children’s Hospital at Westmead, Sydney, NSW 2145, Australia</nlm:aff></affiliation></author><author><name sortKey="Haan, Eric" sort="Haan, Eric" uniqKey="Haan E" first="Eric" last="Haan">Eric Haan</name><affiliation><nlm:aff id="aff10">South Australian Clinical Genetics Service, SA Pathology, Adelaide, SA 5000, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff11">School of Paediatrics and Reproductive Health, The University of Adelaide, Adelaide, SA 5000, Australia</nlm:aff></affiliation></author><author><name sortKey="Maclennan, Alastair" sort="Maclennan, Alastair" uniqKey="Maclennan A" first="Alastair" last="Maclennan">Alastair Maclennan</name><affiliation><nlm:aff id="aff4">Robinson Institute, The University of Adelaide, Adelaide, SA 5000, Australia</nlm:aff></affiliation></author><author><name sortKey="Stenzel, Werner" sort="Stenzel, Werner" uniqKey="Stenzel W" first="Werner" last="Stenzel">Werner Stenzel</name><affiliation><nlm:aff id="aff12">Institute of Neuropathology, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Yap, Tzu Ying" sort="Yap, Tzu Ying" uniqKey="Yap T" first="Tzu Ying" last="Yap">Tzu Ying Yap</name><affiliation><nlm:aff id="aff11">School of Paediatrics and Reproductive Health, The University of Adelaide, Adelaide, SA 5000, Australia</nlm:aff></affiliation></author><author><name sortKey="Gardner, Alison" sort="Gardner, Alison" uniqKey="Gardner A" first="Alison" last="Gardner">Alison Gardner</name><affiliation><nlm:aff id="aff13">Neurogenetics, SA Pathology, Adelaide, SA 5000, Australia</nlm:aff></affiliation></author><author><name sortKey="Nguyen, Lam Son" sort="Nguyen, Lam Son" uniqKey="Nguyen L" first="Lam Son" last="Nguyen">Lam Son Nguyen</name><affiliation><nlm:aff id="aff11">School of Paediatrics and Reproductive Health, The University of Adelaide, Adelaide, SA 5000, Australia</nlm:aff></affiliation></author><author><name sortKey="Shaw, Marie" sort="Shaw, Marie" uniqKey="Shaw M" first="Marie" last="Shaw">Marie Shaw</name><affiliation><nlm:aff id="aff11">School of Paediatrics and Reproductive Health, The University of Adelaide, Adelaide, SA 5000, Australia</nlm:aff></affiliation></author><author><name sortKey="Lebrun, Nicolas" sort="Lebrun, Nicolas" uniqKey="Lebrun N" first="Nicolas" last="Lebrun">Nicolas Lebrun</name><affiliation><nlm:aff id="aff14">University Paris Descartes, 75006 Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff15">Institut National de la Santé et de la Recherche Médicale Unité 1016, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Institut Cochin, 75014 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Haas, Stefan A" sort="Haas, Stefan A" uniqKey="Haas S" first="Stefan A." last="Haas">Stefan A. Haas</name><affiliation><nlm:aff id="aff16">Department of Computational Biology, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Kress, Wolfram" sort="Kress, Wolfram" uniqKey="Kress W" first="Wolfram" last="Kress">Wolfram Kress</name><affiliation><nlm:aff id="aff2">Institute of Human Genetics, University of Würzburg, Biocenter, 97047 Würzburg, Germany</nlm:aff></affiliation></author><author><name sortKey="Haaf, Thomas" sort="Haaf, Thomas" uniqKey="Haaf T" first="Thomas" last="Haaf">Thomas Haaf</name><affiliation><nlm:aff id="aff2">Institute of Human Genetics, University of Würzburg, Biocenter, 97047 Würzburg, Germany</nlm:aff></affiliation></author><author><name sortKey="Schellenberger, Elke" sort="Schellenberger, Elke" uniqKey="Schellenberger E" first="Elke" last="Schellenberger">Elke Schellenberger</name><affiliation><nlm:aff id="aff17">Kinderklinik am Mönchberg, Kinderfachabteilung der Missionsärztlichen Klinik Würzburg, 97067 Würzburg, Germany</nlm:aff></affiliation></author><author><name sortKey="Chelly, Jamel" sort="Chelly, Jamel" uniqKey="Chelly J" first="Jamel" last="Chelly">Jamel Chelly</name><affiliation><nlm:aff id="aff14">University Paris Descartes, 75006 Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff15">Institut National de la Santé et de la Recherche Médicale Unité 1016, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Institut Cochin, 75014 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Viot, Geraldine" sort="Viot, Geraldine" uniqKey="Viot G" first="Géraldine" last="Viot">Géraldine Viot</name><affiliation><nlm:aff id="aff18">Department of Gynecology-Obstetrics, Cochin Hospital, Assistance Publique – Hôpitaux de Paris, 75014 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Shaffer, Lisa G" sort="Shaffer, Lisa G" uniqKey="Shaffer L" first="Lisa G." last="Shaffer">Lisa G. Shaffer</name><affiliation><nlm:aff id="aff19">Signature Genomic Laboratories, PerkinElmer, Inc., Spokane, WA 99207, USA</nlm:aff></affiliation></author><author><name sortKey="Rosenfeld, Jill A" sort="Rosenfeld, Jill A" uniqKey="Rosenfeld J" first="Jill A." last="Rosenfeld">Jill A. Rosenfeld</name><affiliation><nlm:aff id="aff19">Signature Genomic Laboratories, PerkinElmer, Inc., Spokane, WA 99207, USA</nlm:aff></affiliation></author><author><name sortKey="Kramer, Nancy" sort="Kramer, Nancy" uniqKey="Kramer N" first="Nancy" last="Kramer">Nancy Kramer</name><affiliation><nlm:aff id="aff20">Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA</nlm:aff></affiliation></author><author><name sortKey="Falk, Rena" sort="Falk, Rena" uniqKey="Falk R" first="Rena" last="Falk">Rena Falk</name><affiliation><nlm:aff id="aff21">Medical Genetics Institute and Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA</nlm:aff></affiliation></author><author><name sortKey="El Khechen, Dima" sort="El Khechen, Dima" uniqKey="El Khechen D" first="Dima" last="El-Khechen">Dima El-Khechen</name><affiliation><nlm:aff id="aff22">Medical Genetics and Neurodevelopmental Center, Peyton Manning St. Vincent Children’s Hospital, Indianapolis, IN 46260, USA</nlm:aff></affiliation></author><author><name sortKey="Escobar, Luis F" sort="Escobar, Luis F" uniqKey="Escobar L" first="Luis F." last="Escobar">Luis F. Escobar</name><affiliation><nlm:aff id="aff22">Medical Genetics and Neurodevelopmental Center, Peyton Manning St. Vincent Children’s Hospital, Indianapolis, IN 46260, USA</nlm:aff></affiliation></author><author><name sortKey="Hennekam, Raoul" sort="Hennekam, Raoul" uniqKey="Hennekam R" first="Raoul" last="Hennekam">Raoul Hennekam</name><affiliation><nlm:aff id="aff23">Department of Pediatrics and Clinical Genetics, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Wieacker, Peter" sort="Wieacker, Peter" uniqKey="Wieacker P" first="Peter" last="Wieacker">Peter Wieacker</name><affiliation><nlm:aff id="aff8">Institute of Human Genetics, Westfälische Wilhelms Universität Münster, 48149 Münster, Germany</nlm:aff></affiliation></author><author><name sortKey="Hubner, Christoph" sort="Hubner, Christoph" uniqKey="Hubner C" first="Christoph" last="Hübner">Christoph Hübner</name><affiliation><nlm:aff id="aff3">Department of Neuropediatrics and NeuroCure Clinical Research Center, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Ropers, Hans Hilger" sort="Ropers, Hans Hilger" uniqKey="Ropers H" first="Hans-Hilger" last="Ropers">Hans-Hilger Ropers</name><affiliation><nlm:aff id="aff5">Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Gecz, Jozef" sort="Gecz, Jozef" uniqKey="Gecz J" first="Jozef" last="Gecz">Jozef Gecz</name><affiliation><nlm:aff id="aff11">School of Paediatrics and Reproductive Health, The University of Adelaide, Adelaide, SA 5000, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="aff13">Neurogenetics, SA Pathology, Adelaide, SA 5000, Australia</nlm:aff></affiliation></author><author><name sortKey="Schuelke, Markus" sort="Schuelke, Markus" uniqKey="Schuelke M" first="Markus" last="Schuelke">Markus Schuelke</name><affiliation><nlm:aff id="aff3">Department of Neuropediatrics and NeuroCure Clinical Research Center, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Laumonnier, Frederic" sort="Laumonnier, Frederic" uniqKey="Laumonnier F" first="Frédéric" last="Laumonnier">Frédéric Laumonnier</name><affiliation><nlm:aff id="aff6">Université François-Rabelais, 37032 Tours, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff7">Institut National de la Santé et de la Recherche Médicale Unité 930, 37032 Tours, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff24">Department of Medical Genetics, Centre Hospitalier Régional Universitaire, 37044 Tours, France</nlm:aff></affiliation></author><author><name sortKey="Kalscheuer, Vera M" sort="Kalscheuer, Vera M" uniqKey="Kalscheuer V" first="Vera M." last="Kalscheuer">Vera M. Kalscheuer</name><affiliation><nlm:aff id="aff5">Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany</nlm:aff></affiliation></author></analytic><series><title level="j">American Journal of Human Genetics</title><idno type="ISSN">0002-9297</idno><idno type="eISSN">1537-6605</idno><imprint><date when="2013">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Arthrogryposis multiplex congenita (AMC) is caused by heterogeneous pathologies leading to multiple antenatal joint contractures through fetal akinesia. Understanding the pathophysiology of this disorder is important for clinical care of the affected individuals and genetic counseling of the families. We thus aimed to establish the genetic basis of an AMC subtype that is associated with multiple dysmorphic features and intellectual disability (ID). We used haplotype analysis, next-generation sequencing, array comparative genomic hybridization, and chromosome breakpoint mapping to identify the pathogenic mutations in families and simplex cases. Suspected disease variants were verified by cosegregation analysis. We identified disease-causing mutations in the zinc-finger gene <italic>ZC4H2</italic> in four families affected by X-linked AMC plus ID and one family affected by cerebral palsy. Several heterozygous females were also affected, but to a lesser degree. Furthermore, we found two <italic>ZC4H2</italic> deletions and one rearrangement in two female and one male unrelated simplex cases, respectively. In mouse primary hippocampal neurons, transiently produced ZC4H2 localized to the postsynaptic compartment of excitatory synapses, and the altered protein influenced dendritic spine density. In zebrafish, antisense-morpholino-mediated <italic>zc4h2</italic> knockdown caused abnormal swimming and impaired α-motoneuron development. All missense mutations identified herein failed to rescue the swimming defect of zebrafish morphants. We conclude that <italic>ZC4H2</italic> point mutations, rearrangements, and small deletions cause a clinically variable broad-spectrum neurodevelopmental disorder of the central and peripheral nervous systems in both familial and simplex cases of both sexes. Our results highlight the importance of <italic>ZC4H2</italic> for genetic testing of individuals presenting with ID plus muscle weakness and minor or major forms of AMC.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Am J Hum Genet</journal-id><journal-id journal-id-type="iso-abbrev">Am. J. Hum. Genet</journal-id><journal-title-group><journal-title>American Journal of Human Genetics</journal-title></journal-title-group><issn pub-type="ppub">0002-9297</issn><issn pub-type="epub">1537-6605</issn><publisher><publisher-name>Elsevier</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">23623388</article-id><article-id pub-id-type="pmc">3644645</article-id><article-id pub-id-type="publisher-id">S0002-9297(13)00129-8</article-id><article-id pub-id-type="doi">10.1016/j.ajhg.2013.03.021</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title><italic>ZC4H2</italic> Mutations Are Associated with Arthrogryposis Multiplex Congenita and Intellectual Disability through Impairment of Central and Peripheral Synaptic Plasticity</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Hirata</surname><given-names>Hiromi</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="fn1" ref-type="fn">25</xref></contrib><contrib contrib-type="author"><name><surname>Nanda</surname><given-names>Indrajit</given-names></name><xref rid="aff2" ref-type="aff">2</xref><xref rid="fn1" ref-type="fn">25</xref></contrib><contrib contrib-type="author"><name><surname>van Riesen</surname><given-names>Anne</given-names></name><xref rid="aff3" ref-type="aff">3</xref><xref rid="fn1" ref-type="fn">25</xref></contrib><contrib contrib-type="author"><name><surname>McMichael</surname><given-names>Gai</given-names></name><xref rid="aff4" ref-type="aff">4</xref><xref rid="fn1" ref-type="fn">25</xref></contrib><contrib contrib-type="author"><name><surname>Hu</surname><given-names>Hao</given-names></name><xref rid="aff5" ref-type="aff">5</xref><xref rid="fn1" ref-type="fn">25</xref></contrib><contrib contrib-type="author"><name><surname>Hambrock</surname><given-names>Melanie</given-names></name><xref rid="aff5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>Papon</surname><given-names>Marie-Amélie</given-names></name><xref rid="aff6" ref-type="aff">6</xref><xref rid="aff7" ref-type="aff">7</xref></contrib><contrib contrib-type="author"><name><surname>Fischer</surname><given-names>Ute</given-names></name><xref rid="aff5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>Marouillat</surname><given-names>Sylviane</given-names></name><xref rid="aff6" ref-type="aff">6</xref><xref rid="aff7" ref-type="aff">7</xref></contrib><contrib contrib-type="author"><name><surname>Ding</surname><given-names>Can</given-names></name><xref rid="aff3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>Alirol</surname><given-names>Servane</given-names></name><xref rid="aff6" ref-type="aff">6</xref><xref rid="aff7" ref-type="aff">7</xref></contrib><contrib contrib-type="author"><name><surname>Bienek</surname><given-names>Melanie</given-names></name><xref rid="aff5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>Preisler-Adams</surname><given-names>Sabine</given-names></name><xref rid="aff8" ref-type="aff">8</xref></contrib><contrib contrib-type="author"><name><surname>Grimme</surname><given-names>Astrid</given-names></name><xref rid="aff5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>Seelow</surname><given-names>Dominik</given-names></name><xref rid="aff3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>Webster</surname><given-names>Richard</given-names></name><xref rid="aff9" ref-type="aff">9</xref></contrib><contrib contrib-type="author"><name><surname>Haan</surname><given-names>Eric</given-names></name><xref rid="aff10" ref-type="aff">10</xref><xref rid="aff11" ref-type="aff">11</xref></contrib><contrib contrib-type="author"><name><surname>MacLennan</surname><given-names>Alastair</given-names></name><xref rid="aff4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>Stenzel</surname><given-names>Werner</given-names></name><xref rid="aff12" ref-type="aff">12</xref></contrib><contrib contrib-type="author"><name><surname>Yap</surname><given-names>Tzu Ying</given-names></name><xref rid="aff11" ref-type="aff">11</xref></contrib><contrib contrib-type="author"><name><surname>Gardner</surname><given-names>Alison</given-names></name><xref rid="aff13" ref-type="aff">13</xref></contrib><contrib contrib-type="author"><name><surname>Nguyen</surname><given-names>Lam Son</given-names></name><xref rid="aff11" ref-type="aff">11</xref></contrib><contrib contrib-type="author"><name><surname>Shaw</surname><given-names>Marie</given-names></name><xref rid="aff11" ref-type="aff">11</xref></contrib><contrib contrib-type="author"><name><surname>Lebrun</surname><given-names>Nicolas</given-names></name><xref rid="aff14" ref-type="aff">14</xref><xref rid="aff15" ref-type="aff">15</xref></contrib><contrib contrib-type="author"><name><surname>Haas</surname><given-names>Stefan A.</given-names></name><xref rid="aff16" ref-type="aff">16</xref></contrib><contrib contrib-type="author"><name><surname>Kress</surname><given-names>Wolfram</given-names></name><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Haaf</surname><given-names>Thomas</given-names></name><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Schellenberger</surname><given-names>Elke</given-names></name><xref rid="aff17" ref-type="aff">17</xref></contrib><contrib contrib-type="author"><name><surname>Chelly</surname><given-names>Jamel</given-names></name><xref rid="aff14" ref-type="aff">14</xref><xref rid="aff15" ref-type="aff">15</xref></contrib><contrib contrib-type="author"><name><surname>Viot</surname><given-names>Géraldine</given-names></name><xref rid="aff18" ref-type="aff">18</xref></contrib><contrib contrib-type="author"><name><surname>Shaffer</surname><given-names>Lisa G.</given-names></name><xref rid="aff19" ref-type="aff">19</xref><xref rid="fn2" ref-type="fn">26</xref></contrib><contrib contrib-type="author"><name><surname>Rosenfeld</surname><given-names>Jill A.</given-names></name><xref rid="aff19" ref-type="aff">19</xref></contrib><contrib contrib-type="author"><name><surname>Kramer</surname><given-names>Nancy</given-names></name><xref rid="aff20" ref-type="aff">20</xref></contrib><contrib contrib-type="author"><name><surname>Falk</surname><given-names>Rena</given-names></name><xref rid="aff21" ref-type="aff">21</xref></contrib><contrib contrib-type="author"><name><surname>El-Khechen</surname><given-names>Dima</given-names></name><xref rid="aff22" ref-type="aff">22</xref></contrib><contrib contrib-type="author"><name><surname>Escobar</surname><given-names>Luis F.</given-names></name><xref rid="aff22" ref-type="aff">22</xref></contrib><contrib contrib-type="author"><name><surname>Hennekam</surname><given-names>Raoul</given-names></name><xref rid="aff23" ref-type="aff">23</xref></contrib><contrib contrib-type="author"><name><surname>Wieacker</surname><given-names>Peter</given-names></name><xref rid="aff8" ref-type="aff">8</xref></contrib><contrib contrib-type="author"><name><surname>Hübner</surname><given-names>Christoph</given-names></name><xref rid="aff3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>Ropers</surname><given-names>Hans-Hilger</given-names></name><xref rid="aff5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>Gecz</surname><given-names>Jozef</given-names></name><xref rid="aff11" ref-type="aff">11</xref><xref rid="aff13" ref-type="aff">13</xref></contrib><contrib contrib-type="author"><name><surname>Schuelke</surname><given-names>Markus</given-names></name><email>markus.schuelke@charite.de</email><xref rid="aff3" ref-type="aff">3</xref><xref rid="cor2" ref-type="corresp">**</xref></contrib><contrib contrib-type="author"><name><surname>Laumonnier</surname><given-names>Frédéric</given-names></name><xref rid="aff6" ref-type="aff">6</xref><xref rid="aff7" ref-type="aff">7</xref><xref rid="aff24" ref-type="aff">24</xref></contrib><contrib contrib-type="author"><name><surname>Kalscheuer</surname><given-names>Vera M.</given-names></name><email>kalscheu@molgen.mpg.de</email><xref rid="aff5" ref-type="aff">5</xref><xref rid="cor1" ref-type="corresp">*</xref></contrib></contrib-group><aff id="aff1"><label>1</label>Center for Frontier Research, National Institute of Genetics, Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Mishima 411-8540, Japan</aff><aff id="aff2"><label>2</label>Institute of Human Genetics, University of Würzburg, Biocenter, 97047 Würzburg, Germany</aff><aff id="aff3"><label>3</label>Department of Neuropediatrics and NeuroCure Clinical Research Center, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany</aff><aff id="aff4"><label>4</label>Robinson Institute, The University of Adelaide, Adelaide, SA 5000, Australia</aff><aff id="aff5"><label>5</label>Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany</aff><aff id="aff6"><label>6</label>Université François-Rabelais, 37032 Tours, France</aff><aff id="aff7"><label>7</label>Institut National de la Santé et de la Recherche Médicale Unité 930, 37032 Tours, France</aff><aff id="aff8"><label>8</label>Institute of Human Genetics, Westfälische Wilhelms Universität Münster, 48149 Münster, Germany</aff><aff id="aff9"><label>9</label>The Department of Neurology and Neurosurgery, The Children’s Hospital at Westmead, Sydney, NSW 2145, Australia</aff><aff id="aff10"><label>10</label>South Australian Clinical Genetics Service, SA Pathology, Adelaide, SA 5000, Australia</aff><aff id="aff11"><label>11</label>School of Paediatrics and Reproductive Health, The University of Adelaide, Adelaide, SA 5000, Australia</aff><aff id="aff12"><label>12</label>Institute of Neuropathology, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany</aff><aff id="aff13"><label>13</label>Neurogenetics, SA Pathology, Adelaide, SA 5000, Australia</aff><aff id="aff14"><label>14</label>University Paris Descartes, 75006 Paris, France</aff><aff id="aff15"><label>15</label>Institut National de la Santé et de la Recherche Médicale Unité 1016, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Institut Cochin, 75014 Paris, France</aff><aff id="aff16"><label>16</label>Department of Computational Biology, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany</aff><aff id="aff17"><label>17</label>Kinderklinik am Mönchberg, Kinderfachabteilung der Missionsärztlichen Klinik Würzburg, 97067 Würzburg, Germany</aff><aff id="aff18"><label>18</label>Department of Gynecology-Obstetrics, Cochin Hospital, Assistance Publique – Hôpitaux de Paris, 75014 Paris, France</aff><aff id="aff19"><label>19</label>Signature Genomic Laboratories, PerkinElmer, Inc., Spokane, WA 99207, USA</aff><aff id="aff20"><label>20</label>Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA</aff><aff id="aff21"><label>21</label>Medical Genetics Institute and Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA</aff><aff id="aff22"><label>22</label>Medical Genetics and Neurodevelopmental Center, Peyton Manning St. Vincent Children’s Hospital, Indianapolis, IN 46260, USA</aff><aff id="aff23"><label>23</label>Department of Pediatrics and Clinical Genetics, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands</aff><aff id="aff24"><label>24</label>Department of Medical Genetics, Centre Hospitalier Régional Universitaire, 37044 Tours, France</aff><author-notes><corresp id="cor1"><label>*</label>Corresponding author <email>kalscheu@molgen.mpg.de</email></corresp><corresp id="cor2"><label>**</label>Corresponding author for clinical information <email>markus.schuelke@charite.de</email></corresp><fn id="fn1"><label>25</label><p>These authors contributed equally to this work</p></fn><fn id="fn2"><label>26</label><p>Current address: Paw Print Genetics, Genetic Veterinary Sciences, Inc., Spokane, WA 99202, USA</p></fn></author-notes><pub-date pub-type="ppub"><day>02</day><month>5</month><year>2013</year></pub-date><volume>92</volume><issue>5</issue><fpage>681</fpage><lpage>695</lpage><history><date date-type="received"><day>10</day><month>2</month><year>2013</year></date><date date-type="rev-recd"><day>15</day><month>3</month><year>2013</year></date><date date-type="accepted"><day>22</day><month>3</month><year>2013</year></date></history><permissions><copyright-statement>© 2013 The American Society of Human Genetics. Published by Elsevier Ltd. All right reserved.</copyright-statement><copyright-year>2013</copyright-year><copyright-holder>The American Society of Human Genetics</copyright-holder></permissions><abstract><p>Arthrogryposis multiplex congenita (AMC) is caused by heterogeneous pathologies leading to multiple antenatal joint contractures through fetal akinesia. Understanding the pathophysiology of this disorder is important for clinical care of the affected individuals and genetic counseling of the families. We thus aimed to establish the genetic basis of an AMC subtype that is associated with multiple dysmorphic features and intellectual disability (ID). We used haplotype analysis, next-generation sequencing, array comparative genomic hybridization, and chromosome breakpoint mapping to identify the pathogenic mutations in families and simplex cases. Suspected disease variants were verified by cosegregation analysis. We identified disease-causing mutations in the zinc-finger gene <italic>ZC4H2</italic> in four families affected by X-linked AMC plus ID and one family affected by cerebral palsy. Several heterozygous females were also affected, but to a lesser degree. Furthermore, we found two <italic>ZC4H2</italic> deletions and one rearrangement in two female and one male unrelated simplex cases, respectively. In mouse primary hippocampal neurons, transiently produced ZC4H2 localized to the postsynaptic compartment of excitatory synapses, and the altered protein influenced dendritic spine density. In zebrafish, antisense-morpholino-mediated <italic>zc4h2</italic> knockdown caused abnormal swimming and impaired α-motoneuron development. All missense mutations identified herein failed to rescue the swimming defect of zebrafish morphants. We conclude that <italic>ZC4H2</italic> point mutations, rearrangements, and small deletions cause a clinically variable broad-spectrum neurodevelopmental disorder of the central and peripheral nervous systems in both familial and simplex cases of both sexes. Our results highlight the importance of <italic>ZC4H2</italic> for genetic testing of individuals presenting with ID plus muscle weakness and minor or major forms of AMC.</p></abstract></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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