Genotypic and phenotypic analysis of 396 individuals with mutations in Sonic Hedgehog
Identifieur interne : 002372 ( Istex/Corpus ); précédent : 002371; suivant : 002373Genotypic and phenotypic analysis of 396 individuals with mutations in Sonic Hedgehog
Auteurs : Benjamin D. Solomon ; Kelly A. Bear ; Adrian Wyllie ; Amelia A. Keaton ; Christele Dubourg ; Veronique David ; Sandra Mercier ; Sylvie Odent ; Ute Hehr ; Aimee Paulussen ; Nancy J. Clegg ; Mauricio R. Delgado ; Sherri J. Bale ; Felicitas Lacbawan ; Holly H. Ardinger ; Arthur S. Aylsworth ; Ntombenhle Louisa Bhengu ; Stephen Braddock ; Karen Brookhyser ; Barbara Burton ; Harald Gaspar ; Art Grix ; Dafne Horovitz ; Erin Kanetzke ; Hulya Kayserili ; Dorit Lev ; Sarah M. Nikkel ; Mary Norton ; Richard Roberts ; Howard Saal ; G B Schaefer ; Adele Schneider ; Erika K. Smith ; Ellen Sowry ; M Anne Spence ; Stavit A. Shalev ; Carlos E. Steiner ; Elizabeth M. Thompson ; Thomas L. Winder ; Joan Z. Balog ; Donald W. Hadley ; Nan Zhou ; Daniel E. Pineda-Alvarez ; Erich Roessler ; Maximilian MuenkeSource :
- Journal of Medical Genetics [ 0022-2593 ] ; 2012-07.
English descriptors
- KwdEn :
- Additional variant, Alobar, Anomaly, Birth defects, Cohort, Exact test, Genet, Genetics, Genome research institute, Hedgehog, Holoprosencephaly, Human genetics, Human holoprosencephaly, Large number, Medical genetics, Microform, Missense, Missense mutations, Muenke, Mutation, Mutation location, National institutes, Pathogenicity, Pediatrics, Phenotype, Phenotypic, Phenotypic severity, Probands, Roessler, Semilobar, Six3, Sonic, Sonic hedgehog, Sonic hedgehog mutations, Truncating, Truncating mutations, Unknown gender, Unrelated kindreds, Variant, Zic2.
- Teeft :
- Additional variant, Alobar, Anomaly, Birth defects, Cohort, Exact test, Genet, Genetics, Genome research institute, Hedgehog, Holoprosencephaly, Human genetics, Human holoprosencephaly, Large number, Medical genetics, Microform, Missense, Missense mutations, Muenke, Mutation, Mutation location, National institutes, Pathogenicity, Pediatrics, Phenotype, Phenotypic, Phenotypic severity, Probands, Roessler, Semilobar, Six3, Sonic, Sonic hedgehog, Sonic hedgehog mutations, Truncating, Truncating mutations, Unknown gender, Unrelated kindreds, Variant, Zic2.
Abstract
Background Holoprosencephaly (HPE), the most common malformation of the human forebrain, may result from mutations in over 12 genes. Sonic Hedgehog (SHH) was the first such gene discovered; mutations in SHH remain the most common cause of non-chromosomal HPE. The severity spectrum is wide, ranging from incompatibility with extrauterine life to isolated midline facial differences. Objective To characterise genetic and clinical findings in individuals with SHH mutations. Methods Through the National Institutes of Health and collaborating centres, DNA from approximately 2000 individuals with HPE spectrum disorders were analysed for SHH variations. Clinical details were examined and combined with published cases. Results This study describes 396 individuals, representing 157 unrelated kindreds, with SHH mutations; 141 (36%) have not been previously reported. SHH mutations more commonly resulted in non-HPE (64%) than frank HPE (36%), and non-HPE was significantly more common in patients with SHH than in those with mutations in the other common HPE related genes (p<0.0001 compared to ZIC2 or SIX3). Individuals with truncating mutations were significantly more likely to have frank HPE than those with non-truncating mutations (49% vs 35%, respectively; p=0.012). While mutations were significantly more common in the N-terminus than in the C-terminus (including accounting for the relative size of the coding regions, p=0.00010), no specific genotype―phenotype correlations could be established regarding mutation location. Conclusions SHH mutations overall result in milder disease than mutations in other common HPE related genes. HPE is more frequent in individuals with truncating mutations, but clinical predictions at the individual level remain elusive.
Url:
DOI: 10.1136/jmedgenet-2012-101008
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Bear</name><affiliation><mods:affiliation>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Pediatrics, Walter Reed National Military Medical Center, Bethesda, Maryland, USA</mods:affiliation></affiliation></author><author><name sortKey="Wyllie, Adrian" sort="Wyllie, Adrian" uniqKey="Wyllie A" first="Adrian" last="Wyllie">Adrian Wyllie</name><affiliation><mods:affiliation>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</mods:affiliation></affiliation></author><author><name sortKey="Keaton, Amelia A" sort="Keaton, Amelia A" uniqKey="Keaton A" first="Amelia A" last="Keaton">Amelia A. 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Clegg</name><affiliation><mods:affiliation>Texas Scottish Rite Hospital for Children, Dallas, Texas, USA</mods:affiliation></affiliation></author><author><name sortKey="Delgado, Mauricio R" sort="Delgado, Mauricio R" uniqKey="Delgado M" first="Mauricio R" last="Delgado">Mauricio R. Delgado</name><affiliation><mods:affiliation>Texas Scottish Rite Hospital for Children, Dallas, Texas, USA</mods:affiliation></affiliation></author><author><name sortKey="Bale, Sherri J" sort="Bale, Sherri J" uniqKey="Bale S" first="Sherri J" last="Bale">Sherri J. Bale</name><affiliation><mods:affiliation>GeneDx, Gaithersburg, Maryland, USA</mods:affiliation></affiliation></author><author><name sortKey="Lacbawan, Felicitas" sort="Lacbawan, Felicitas" uniqKey="Lacbawan F" first="Felicitas" last="Lacbawan">Felicitas Lacbawan</name><affiliation><mods:affiliation>Molecular Genetics Pathology, Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio, USA</mods:affiliation></affiliation></author><author><name sortKey="Ardinger, Holly H" sort="Ardinger, Holly H" uniqKey="Ardinger H" first="Holly H" last="Ardinger">Holly H. Ardinger</name><affiliation><mods:affiliation>Section of Genetics, Department of Pediatrics, Children's Mercy Hospitals and Clinics, Kansas City, Missouri, USA</mods:affiliation></affiliation></author><author><name sortKey="Aylsworth, Arthur S" sort="Aylsworth, Arthur S" uniqKey="Aylsworth A" first="Arthur S" last="Aylsworth">Arthur S. Aylsworth</name><affiliation><mods:affiliation>Department of Pediatrics, University of North Carolina, Chapel Hill, North Carolina, USA</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA</mods:affiliation></affiliation></author><author><name sortKey="Bhengu, Ntombenhle Louisa" sort="Bhengu, Ntombenhle Louisa" uniqKey="Bhengu N" first="Ntombenhle Louisa" last="Bhengu">Ntombenhle Louisa Bhengu</name><affiliation><mods:affiliation>Department of Human Genetics Corner Hospital and De Korte, Johannesburg, South Africa</mods:affiliation></affiliation></author><author><name sortKey="Braddock, Stephen" sort="Braddock, Stephen" uniqKey="Braddock S" first="Stephen" last="Braddock">Stephen Braddock</name><affiliation><mods:affiliation>Division of Medical Genetics, Department of Pediatrics, Saint Louis University, St. Louis, Missouri, USA</mods:affiliation></affiliation></author><author><name sortKey="Brookhyser, Karen" sort="Brookhyser, Karen" uniqKey="Brookhyser K" first="Karen" last="Brookhyser">Karen Brookhyser</name><affiliation><mods:affiliation>Genetics Department, Kaiser Permanente, Sacramento, California, USA</mods:affiliation></affiliation></author><author><name sortKey="Burton, Barbara" sort="Burton, Barbara" uniqKey="Burton B" first="Barbara" last="Burton">Barbara Burton</name><affiliation><mods:affiliation>Department of Pediatrics, Northwestern University Feinberg School of Medicine and Division of Genetics, Birth Defects and Metabolism, Lurie Children's Hospital, Chicago, Illinois, USA</mods:affiliation></affiliation></author><author><name sortKey="Gaspar, Harald" sort="Gaspar, Harald" uniqKey="Gaspar H" first="Harald" last="Gaspar">Harald Gaspar</name><affiliation><mods:affiliation>Institute of Human Genetics, Heidelberg University, Heidelberg, Germany</mods:affiliation></affiliation></author><author><name sortKey="Grix, Art" sort="Grix, Art" uniqKey="Grix A" first="Art" last="Grix">Art Grix</name><affiliation><mods:affiliation>Genetics Department, Kaiser Permanente, Sacramento, California, USA</mods:affiliation></affiliation></author><author><name sortKey="Horovitz, Dafne" sort="Horovitz, Dafne" uniqKey="Horovitz D" first="Dafne" last="Horovitz">Dafne Horovitz</name><affiliation><mods:affiliation>Centro de Genetica Medica, Instituto Fernandes Figueira-FIOCRUZ, Rio de Janeiro, Brazil</mods:affiliation></affiliation></author><author><name sortKey="Kanetzke, Erin" sort="Kanetzke, Erin" uniqKey="Kanetzke E" first="Erin" last="Kanetzke">Erin Kanetzke</name><affiliation><mods:affiliation>Division of Medical Genetics, Department of Pediatrics, Saint Louis University, St. Louis, Missouri, USA</mods:affiliation></affiliation></author><author><name sortKey="Kayserili, Hulya" sort="Kayserili, Hulya" uniqKey="Kayserili H" first="Hulya" last="Kayserili">Hulya Kayserili</name><affiliation><mods:affiliation>Department of Medical Genetics, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey</mods:affiliation></affiliation></author><author><name sortKey="Lev, Dorit" sort="Lev, Dorit" uniqKey="Lev D" first="Dorit" last="Lev">Dorit Lev</name><affiliation><mods:affiliation>Institute of Medical Genetics, Wolfson Medical Center, Holon, Israel</mods:affiliation></affiliation></author><author><name sortKey="Nikkel, Sarah M" sort="Nikkel, Sarah M" uniqKey="Nikkel S" first="Sarah M" last="Nikkel">Sarah M. Nikkel</name><affiliation><mods:affiliation>Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada</mods:affiliation></affiliation></author><author><name sortKey="Norton, Mary" sort="Norton, Mary" uniqKey="Norton M" first="Mary" last="Norton">Mary Norton</name><affiliation><mods:affiliation>Department of Obstetrics and Gynecology, Stanford University School of Medicine/Lucile and Packard Children's Hospital at Stanford University, Stanford, California, USA</mods:affiliation></affiliation></author><author><name sortKey="Roberts, Richard" sort="Roberts, Richard" uniqKey="Roberts R" first="Richard" last="Roberts">Richard Roberts</name><affiliation><mods:affiliation>Genetics and Prenatal Diagnostic Center, Corpus Christi, Texas, USA</mods:affiliation></affiliation></author><author><name sortKey="Saal, Howard" sort="Saal, Howard" uniqKey="Saal H" first="Howard" last="Saal">Howard Saal</name><affiliation><mods:affiliation>Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA</mods:affiliation></affiliation></author><author><name sortKey="Schaefer, G B" sort="Schaefer, G B" uniqKey="Schaefer G" first="G B" last="Schaefer">G B Schaefer</name><affiliation><mods:affiliation>Division of Medical Genetics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA</mods:affiliation></affiliation></author><author><name sortKey="Schneider, Adele" sort="Schneider, Adele" uniqKey="Schneider A" first="Adele" last="Schneider">Adele Schneider</name><affiliation><mods:affiliation>Genetics Division, Einstein Medical Center, Philadelphia, Pennsylvania, USA</mods:affiliation></affiliation></author><author><name sortKey="Smith, Erika K" sort="Smith, Erika K" uniqKey="Smith E" first="Erika K" last="Smith">Erika K. Smith</name><affiliation><mods:affiliation>Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada</mods:affiliation></affiliation></author><author><name sortKey="Sowry, Ellen" sort="Sowry, Ellen" uniqKey="Sowry E" first="Ellen" last="Sowry">Ellen Sowry</name><affiliation><mods:affiliation>Division of Medical Genetics, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA</mods:affiliation></affiliation></author><author><name sortKey="Spence, M Anne" sort="Spence, M Anne" uniqKey="Spence M" first="M Anne" last="Spence">M Anne Spence</name><affiliation><mods:affiliation>Department of Pediatrics, University of California, Irvine, California, USA</mods:affiliation></affiliation></author><author><name sortKey="Shalev, Stavit A" sort="Shalev, Stavit A" uniqKey="Shalev S" first="Stavit A" last="Shalev">Stavit A. Shalev</name><affiliation><mods:affiliation>Genetics Institute, Emek Medical Center, Afula, Israel</mods:affiliation></affiliation><affiliation><mods:affiliation>Rappaport faculty of Medicine, Technion, Haifa, Israel</mods:affiliation></affiliation></author><author><name sortKey="Steiner, Carlos E" sort="Steiner, Carlos E" uniqKey="Steiner C" first="Carlos E" last="Steiner">Carlos E. Steiner</name><affiliation><mods:affiliation>Department of Medical Genetics, School of Medical Sciences, Universidade Estadual de Campinas (UNICAMP), Campinas, Sao Paulo, Brazil</mods:affiliation></affiliation></author><author><name sortKey="Thompson, Elizabeth M" sort="Thompson, Elizabeth M" uniqKey="Thompson E" first="Elizabeth M" last="Thompson">Elizabeth M. Thompson</name><affiliation><mods:affiliation>Clinical Genetics Unit, SA Pathology, Women's and Children's Hospital and University of Adelaide, Adelaide, South Australia</mods:affiliation></affiliation></author><author><name sortKey="Winder, Thomas L" sort="Winder, Thomas L" uniqKey="Winder T" first="Thomas L" last="Winder">Thomas L. Winder</name><affiliation><mods:affiliation>Prevention Genetics, Marshfield, Wisconsin, USA</mods:affiliation></affiliation></author><author><name sortKey="Balog, Joan Z" sort="Balog, Joan Z" uniqKey="Balog J" first="Joan Z" last="Balog">Joan Z. Balog</name><affiliation><mods:affiliation>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</mods:affiliation></affiliation></author><author><name sortKey="Hadley, Donald W" sort="Hadley, Donald W" uniqKey="Hadley D" first="Donald W" last="Hadley">Donald W. Hadley</name><affiliation><mods:affiliation>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</mods:affiliation></affiliation></author><author><name sortKey="Zhou, Nan" sort="Zhou, Nan" uniqKey="Zhou N" first="Nan" last="Zhou">Nan Zhou</name><affiliation><mods:affiliation>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</mods:affiliation></affiliation></author><author><name sortKey="Pineda Alvarez, Daniel E" sort="Pineda Alvarez, Daniel E" uniqKey="Pineda Alvarez D" first="Daniel E" last="Pineda-Alvarez">Daniel E. Pineda-Alvarez</name><affiliation><mods:affiliation>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</mods:affiliation></affiliation></author><author><name sortKey="Roessler, Erich" sort="Roessler, Erich" uniqKey="Roessler E" first="Erich" last="Roessler">Erich Roessler</name><affiliation><mods:affiliation>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</mods:affiliation></affiliation></author><author><name sortKey="Muenke, Maximilian" sort="Muenke, Maximilian" uniqKey="Muenke M" first="Maximilian" last="Muenke">Maximilian Muenke</name><affiliation><mods:affiliation>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: mamuenke@mail.nih.gov</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:BFFAC78ABF1C5ADDDE35769A4C10022F3A316AE5</idno><date when="2012" year="2012">2012</date><idno type="doi">10.1136/jmedgenet-2012-101008</idno><idno type="url">https://api.istex.fr/document/BFFAC78ABF1C5ADDDE35769A4C10022F3A316AE5/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">002372</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">002372</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a">Genotypic and phenotypic analysis of 396 individuals with mutations in Sonic Hedgehog</title><author><name sortKey="Solomon, Benjamin D" sort="Solomon, Benjamin D" uniqKey="Solomon B" first="Benjamin D" last="Solomon">Benjamin D. Solomon</name><affiliation><mods:affiliation>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</mods:affiliation></affiliation></author><author><name sortKey="Bear, Kelly A" sort="Bear, Kelly A" uniqKey="Bear K" first="Kelly A" last="Bear">Kelly A. Bear</name><affiliation><mods:affiliation>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Pediatrics, Walter Reed National Military Medical Center, Bethesda, Maryland, USA</mods:affiliation></affiliation></author><author><name sortKey="Wyllie, Adrian" sort="Wyllie, Adrian" uniqKey="Wyllie A" first="Adrian" last="Wyllie">Adrian Wyllie</name><affiliation><mods:affiliation>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</mods:affiliation></affiliation></author><author><name sortKey="Keaton, Amelia A" sort="Keaton, Amelia A" uniqKey="Keaton A" first="Amelia A" last="Keaton">Amelia A. Keaton</name><affiliation><mods:affiliation>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</mods:affiliation></affiliation></author><author><name sortKey="Dubourg, Christele" sort="Dubourg, Christele" uniqKey="Dubourg C" first="Christele" last="Dubourg">Christele Dubourg</name><affiliation><mods:affiliation>CHU Rennes, Laboratoire de Génétique Moléculaire, Rennes, France</mods:affiliation></affiliation><affiliation><mods:affiliation>CNRS, UMR 6290, Institut Génétique et Développement de Rennes, Université de Rennes 1, UEB, IFR 140, Faculté, de Médecine, Rennes, France</mods:affiliation></affiliation></author><author><name sortKey="David, Veronique" sort="David, Veronique" uniqKey="David V" first="Veronique" last="David">Veronique David</name><affiliation><mods:affiliation>CHU Rennes, Laboratoire de Génétique Moléculaire, Rennes, France</mods:affiliation></affiliation><affiliation><mods:affiliation>CNRS, UMR 6290, Institut Génétique et Développement de Rennes, Université de Rennes 1, UEB, IFR 140, Faculté, de Médecine, Rennes, France</mods:affiliation></affiliation></author><author><name sortKey="Mercier, Sandra" sort="Mercier, Sandra" uniqKey="Mercier S" first="Sandra" last="Mercier">Sandra Mercier</name><affiliation><mods:affiliation>CNRS, UMR 6290, Institut Génétique et Développement de Rennes, Université de Rennes 1, UEB, IFR 140, Faculté, de Médecine, Rennes, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Service de genetique Clinique, CHU Hopital Sud, Rennes, France</mods:affiliation></affiliation></author><author><name sortKey="Odent, Sylvie" sort="Odent, Sylvie" uniqKey="Odent S" first="Sylvie" last="Odent">Sylvie Odent</name><affiliation><mods:affiliation>CNRS, UMR 6290, Institut Génétique et Développement de Rennes, Université de Rennes 1, UEB, IFR 140, Faculté, de Médecine, Rennes, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Service de genetique Clinique, CHU Hopital Sud, Rennes, France</mods:affiliation></affiliation></author><author><name sortKey="Hehr, Ute" sort="Hehr, Ute" uniqKey="Hehr U" first="Ute" last="Hehr">Ute Hehr</name><affiliation><mods:affiliation>Center for Human Genetics, University of Regensburg, Regensburg, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Human Genetics, University of Regensburg, Regensburg, Germany</mods:affiliation></affiliation></author><author><name sortKey="Paulussen, Aimee" sort="Paulussen, Aimee" uniqKey="Paulussen A" first="Aimee" last="Paulussen">Aimee Paulussen</name><affiliation><mods:affiliation>Department of Clinical Genetics, Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Clegg, Nancy J" sort="Clegg, Nancy J" uniqKey="Clegg N" first="Nancy J" last="Clegg">Nancy J. Clegg</name><affiliation><mods:affiliation>Texas Scottish Rite Hospital for Children, Dallas, Texas, USA</mods:affiliation></affiliation></author><author><name sortKey="Delgado, Mauricio R" sort="Delgado, Mauricio R" uniqKey="Delgado M" first="Mauricio R" last="Delgado">Mauricio R. Delgado</name><affiliation><mods:affiliation>Texas Scottish Rite Hospital for Children, Dallas, Texas, USA</mods:affiliation></affiliation></author><author><name sortKey="Bale, Sherri J" sort="Bale, Sherri J" uniqKey="Bale S" first="Sherri J" last="Bale">Sherri J. Bale</name><affiliation><mods:affiliation>GeneDx, Gaithersburg, Maryland, USA</mods:affiliation></affiliation></author><author><name sortKey="Lacbawan, Felicitas" sort="Lacbawan, Felicitas" uniqKey="Lacbawan F" first="Felicitas" last="Lacbawan">Felicitas Lacbawan</name><affiliation><mods:affiliation>Molecular Genetics Pathology, Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio, USA</mods:affiliation></affiliation></author><author><name sortKey="Ardinger, Holly H" sort="Ardinger, Holly H" uniqKey="Ardinger H" first="Holly H" last="Ardinger">Holly H. Ardinger</name><affiliation><mods:affiliation>Section of Genetics, Department of Pediatrics, Children's Mercy Hospitals and Clinics, Kansas City, Missouri, USA</mods:affiliation></affiliation></author><author><name sortKey="Aylsworth, Arthur S" sort="Aylsworth, Arthur S" uniqKey="Aylsworth A" first="Arthur S" last="Aylsworth">Arthur S. Aylsworth</name><affiliation><mods:affiliation>Department of Pediatrics, University of North Carolina, Chapel Hill, North Carolina, USA</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA</mods:affiliation></affiliation></author><author><name sortKey="Bhengu, Ntombenhle Louisa" sort="Bhengu, Ntombenhle Louisa" uniqKey="Bhengu N" first="Ntombenhle Louisa" last="Bhengu">Ntombenhle Louisa Bhengu</name><affiliation><mods:affiliation>Department of Human Genetics Corner Hospital and De Korte, Johannesburg, South Africa</mods:affiliation></affiliation></author><author><name sortKey="Braddock, Stephen" sort="Braddock, Stephen" uniqKey="Braddock S" first="Stephen" last="Braddock">Stephen Braddock</name><affiliation><mods:affiliation>Division of Medical Genetics, Department of Pediatrics, Saint Louis University, St. Louis, Missouri, USA</mods:affiliation></affiliation></author><author><name sortKey="Brookhyser, Karen" sort="Brookhyser, Karen" uniqKey="Brookhyser K" first="Karen" last="Brookhyser">Karen Brookhyser</name><affiliation><mods:affiliation>Genetics Department, Kaiser Permanente, Sacramento, California, USA</mods:affiliation></affiliation></author><author><name sortKey="Burton, Barbara" sort="Burton, Barbara" uniqKey="Burton B" first="Barbara" last="Burton">Barbara Burton</name><affiliation><mods:affiliation>Department of Pediatrics, Northwestern University Feinberg School of Medicine and Division of Genetics, Birth Defects and Metabolism, Lurie Children's Hospital, Chicago, Illinois, USA</mods:affiliation></affiliation></author><author><name sortKey="Gaspar, Harald" sort="Gaspar, Harald" uniqKey="Gaspar H" first="Harald" last="Gaspar">Harald Gaspar</name><affiliation><mods:affiliation>Institute of Human Genetics, Heidelberg University, Heidelberg, Germany</mods:affiliation></affiliation></author><author><name sortKey="Grix, Art" sort="Grix, Art" uniqKey="Grix A" first="Art" last="Grix">Art Grix</name><affiliation><mods:affiliation>Genetics Department, Kaiser Permanente, Sacramento, California, USA</mods:affiliation></affiliation></author><author><name sortKey="Horovitz, Dafne" sort="Horovitz, Dafne" uniqKey="Horovitz D" first="Dafne" last="Horovitz">Dafne Horovitz</name><affiliation><mods:affiliation>Centro de Genetica Medica, Instituto Fernandes Figueira-FIOCRUZ, Rio de Janeiro, Brazil</mods:affiliation></affiliation></author><author><name sortKey="Kanetzke, Erin" sort="Kanetzke, Erin" uniqKey="Kanetzke E" first="Erin" last="Kanetzke">Erin Kanetzke</name><affiliation><mods:affiliation>Division of Medical Genetics, Department of Pediatrics, Saint Louis University, St. Louis, Missouri, USA</mods:affiliation></affiliation></author><author><name sortKey="Kayserili, Hulya" sort="Kayserili, Hulya" uniqKey="Kayserili H" first="Hulya" last="Kayserili">Hulya Kayserili</name><affiliation><mods:affiliation>Department of Medical Genetics, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey</mods:affiliation></affiliation></author><author><name sortKey="Lev, Dorit" sort="Lev, Dorit" uniqKey="Lev D" first="Dorit" last="Lev">Dorit Lev</name><affiliation><mods:affiliation>Institute of Medical Genetics, Wolfson Medical Center, Holon, Israel</mods:affiliation></affiliation></author><author><name sortKey="Nikkel, Sarah M" sort="Nikkel, Sarah M" uniqKey="Nikkel S" first="Sarah M" last="Nikkel">Sarah M. Nikkel</name><affiliation><mods:affiliation>Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada</mods:affiliation></affiliation></author><author><name sortKey="Norton, Mary" sort="Norton, Mary" uniqKey="Norton M" first="Mary" last="Norton">Mary Norton</name><affiliation><mods:affiliation>Department of Obstetrics and Gynecology, Stanford University School of Medicine/Lucile and Packard Children's Hospital at Stanford University, Stanford, California, USA</mods:affiliation></affiliation></author><author><name sortKey="Roberts, Richard" sort="Roberts, Richard" uniqKey="Roberts R" first="Richard" last="Roberts">Richard Roberts</name><affiliation><mods:affiliation>Genetics and Prenatal Diagnostic Center, Corpus Christi, Texas, USA</mods:affiliation></affiliation></author><author><name sortKey="Saal, Howard" sort="Saal, Howard" uniqKey="Saal H" first="Howard" last="Saal">Howard Saal</name><affiliation><mods:affiliation>Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA</mods:affiliation></affiliation></author><author><name sortKey="Schaefer, G B" sort="Schaefer, G B" uniqKey="Schaefer G" first="G B" last="Schaefer">G B Schaefer</name><affiliation><mods:affiliation>Division of Medical Genetics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA</mods:affiliation></affiliation></author><author><name sortKey="Schneider, Adele" sort="Schneider, Adele" uniqKey="Schneider A" first="Adele" last="Schneider">Adele Schneider</name><affiliation><mods:affiliation>Genetics Division, Einstein Medical Center, Philadelphia, Pennsylvania, USA</mods:affiliation></affiliation></author><author><name sortKey="Smith, Erika K" sort="Smith, Erika K" uniqKey="Smith E" first="Erika K" last="Smith">Erika K. Smith</name><affiliation><mods:affiliation>Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada</mods:affiliation></affiliation></author><author><name sortKey="Sowry, Ellen" sort="Sowry, Ellen" uniqKey="Sowry E" first="Ellen" last="Sowry">Ellen Sowry</name><affiliation><mods:affiliation>Division of Medical Genetics, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA</mods:affiliation></affiliation></author><author><name sortKey="Spence, M Anne" sort="Spence, M Anne" uniqKey="Spence M" first="M Anne" last="Spence">M Anne Spence</name><affiliation><mods:affiliation>Department of Pediatrics, University of California, Irvine, California, USA</mods:affiliation></affiliation></author><author><name sortKey="Shalev, Stavit A" sort="Shalev, Stavit A" uniqKey="Shalev S" first="Stavit A" last="Shalev">Stavit A. Shalev</name><affiliation><mods:affiliation>Genetics Institute, Emek Medical Center, Afula, Israel</mods:affiliation></affiliation><affiliation><mods:affiliation>Rappaport faculty of Medicine, Technion, Haifa, Israel</mods:affiliation></affiliation></author><author><name sortKey="Steiner, Carlos E" sort="Steiner, Carlos E" uniqKey="Steiner C" first="Carlos E" last="Steiner">Carlos E. Steiner</name><affiliation><mods:affiliation>Department of Medical Genetics, School of Medical Sciences, Universidade Estadual de Campinas (UNICAMP), Campinas, Sao Paulo, Brazil</mods:affiliation></affiliation></author><author><name sortKey="Thompson, Elizabeth M" sort="Thompson, Elizabeth M" uniqKey="Thompson E" first="Elizabeth M" last="Thompson">Elizabeth M. Thompson</name><affiliation><mods:affiliation>Clinical Genetics Unit, SA Pathology, Women's and Children's Hospital and University of Adelaide, Adelaide, South Australia</mods:affiliation></affiliation></author><author><name sortKey="Winder, Thomas L" sort="Winder, Thomas L" uniqKey="Winder T" first="Thomas L" last="Winder">Thomas L. Winder</name><affiliation><mods:affiliation>Prevention Genetics, Marshfield, Wisconsin, USA</mods:affiliation></affiliation></author><author><name sortKey="Balog, Joan Z" sort="Balog, Joan Z" uniqKey="Balog J" first="Joan Z" last="Balog">Joan Z. Balog</name><affiliation><mods:affiliation>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</mods:affiliation></affiliation></author><author><name sortKey="Hadley, Donald W" sort="Hadley, Donald W" uniqKey="Hadley D" first="Donald W" last="Hadley">Donald W. Hadley</name><affiliation><mods:affiliation>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</mods:affiliation></affiliation></author><author><name sortKey="Zhou, Nan" sort="Zhou, Nan" uniqKey="Zhou N" first="Nan" last="Zhou">Nan Zhou</name><affiliation><mods:affiliation>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</mods:affiliation></affiliation></author><author><name sortKey="Pineda Alvarez, Daniel E" sort="Pineda Alvarez, Daniel E" uniqKey="Pineda Alvarez D" first="Daniel E" last="Pineda-Alvarez">Daniel E. Pineda-Alvarez</name><affiliation><mods:affiliation>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</mods:affiliation></affiliation></author><author><name sortKey="Roessler, Erich" sort="Roessler, Erich" uniqKey="Roessler E" first="Erich" last="Roessler">Erich Roessler</name><affiliation><mods:affiliation>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</mods:affiliation></affiliation></author><author><name sortKey="Muenke, Maximilian" sort="Muenke, Maximilian" uniqKey="Muenke M" first="Maximilian" last="Muenke">Maximilian Muenke</name><affiliation><mods:affiliation>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: mamuenke@mail.nih.gov</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Journal of Medical Genetics</title><title level="j" type="abbrev">J Med Genet</title><idno type="ISSN">0022-2593</idno><idno type="eISSN">1468-6244</idno><imprint><publisher>BMJ Publishing Group Ltd</publisher><date type="published" when="2012-07">2012-07</date><biblScope unit="volume">49</biblScope><biblScope unit="issue">7</biblScope><biblScope unit="page" from="473">473</biblScope></imprint><idno type="ISSN">0022-2593</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0022-2593</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Additional variant</term><term>Alobar</term><term>Anomaly</term><term>Birth defects</term><term>Cohort</term><term>Exact test</term><term>Genet</term><term>Genetics</term><term>Genome research institute</term><term>Hedgehog</term><term>Holoprosencephaly</term><term>Human genetics</term><term>Human holoprosencephaly</term><term>Large number</term><term>Medical genetics</term><term>Microform</term><term>Missense</term><term>Missense mutations</term><term>Muenke</term><term>Mutation</term><term>Mutation location</term><term>National institutes</term><term>Pathogenicity</term><term>Pediatrics</term><term>Phenotype</term><term>Phenotypic</term><term>Phenotypic severity</term><term>Probands</term><term>Roessler</term><term>Semilobar</term><term>Six3</term><term>Sonic</term><term>Sonic hedgehog</term><term>Sonic hedgehog mutations</term><term>Truncating</term><term>Truncating mutations</term><term>Unknown gender</term><term>Unrelated kindreds</term><term>Variant</term><term>Zic2</term></keywords><keywords scheme="Teeft" xml:lang="en"><term>Additional variant</term><term>Alobar</term><term>Anomaly</term><term>Birth defects</term><term>Cohort</term><term>Exact test</term><term>Genet</term><term>Genetics</term><term>Genome research institute</term><term>Hedgehog</term><term>Holoprosencephaly</term><term>Human genetics</term><term>Human holoprosencephaly</term><term>Large number</term><term>Medical genetics</term><term>Microform</term><term>Missense</term><term>Missense mutations</term><term>Muenke</term><term>Mutation</term><term>Mutation location</term><term>National institutes</term><term>Pathogenicity</term><term>Pediatrics</term><term>Phenotype</term><term>Phenotypic</term><term>Phenotypic severity</term><term>Probands</term><term>Roessler</term><term>Semilobar</term><term>Six3</term><term>Sonic</term><term>Sonic hedgehog</term><term>Sonic hedgehog mutations</term><term>Truncating</term><term>Truncating mutations</term><term>Unknown gender</term><term>Unrelated kindreds</term><term>Variant</term><term>Zic2</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract">Background Holoprosencephaly (HPE), the most common malformation of the human forebrain, may result from mutations in over 12 genes. Sonic Hedgehog (SHH) was the first such gene discovered; mutations in SHH remain the most common cause of non-chromosomal HPE. The severity spectrum is wide, ranging from incompatibility with extrauterine life to isolated midline facial differences. Objective To characterise genetic and clinical findings in individuals with SHH mutations. Methods Through the National Institutes of Health and collaborating centres, DNA from approximately 2000 individuals with HPE spectrum disorders were analysed for SHH variations. Clinical details were examined and combined with published cases. Results This study describes 396 individuals, representing 157 unrelated kindreds, with SHH mutations; 141 (36%) have not been previously reported. SHH mutations more commonly resulted in non-HPE (64%) than frank HPE (36%), and non-HPE was significantly more common in patients with SHH than in those with mutations in the other common HPE related genes (p<0.0001 compared to ZIC2 or SIX3). Individuals with truncating mutations were significantly more likely to have frank HPE than those with non-truncating mutations (49% vs 35%, respectively; p=0.012). While mutations were significantly more common in the N-terminus than in the C-terminus (including accounting for the relative size of the coding regions, p=0.00010), no specific genotype―phenotype correlations could be established regarding mutation location. Conclusions SHH mutations overall result in milder disease than mutations in other common HPE related genes. HPE is more frequent in individuals with truncating mutations, but clinical predictions at the individual level remain elusive.</div></front></TEI><istex><corpusName>bmj</corpusName><keywords><teeft><json:string>mutation</json:string><json:string>holoprosencephaly</json:string><json:string>genetics</json:string><json:string>genet</json:string><json:string>microform</json:string><json:string>muenke</json:string><json:string>missense</json:string><json:string>probands</json:string><json:string>roessler</json:string><json:string>phenotype</json:string><json:string>truncating</json:string><json:string>hedgehog</json:string><json:string>cohort</json:string><json:string>zic2</json:string><json:string>semilobar</json:string><json:string>alobar</json:string><json:string>truncating mutations</json:string><json:string>phenotypic</json:string><json:string>six3</json:string><json:string>pathogenicity</json:string><json:string>pediatrics</json:string><json:string>anomaly</json:string><json:string>medical genetics</json:string><json:string>exact test</json:string><json:string>sonic hedgehog</json:string><json:string>human holoprosencephaly</json:string><json:string>unrelated kindreds</json:string><json:string>national institutes</json:string><json:string>genome research institute</json:string><json:string>mutation location</json:string><json:string>human genetics</json:string><json:string>variant</json:string><json:string>additional variant</json:string><json:string>large number</json:string><json:string>phenotypic severity</json:string><json:string>sonic hedgehog mutations</json:string><json:string>missense mutations</json:string><json:string>birth defects</json:string><json:string>unknown gender</json:string><json:string>sonic</json:string><json:string>gender</json:string></teeft></keywords><author><json:item><name>Benjamin D Solomon</name><affiliations><json:string>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</json:string></affiliations></json:item><json:item><name>Kelly A Bear</name><affiliations><json:string>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</json:string><json:string>Department of Pediatrics, Walter Reed National Military Medical Center, Bethesda, Maryland, USA</json:string></affiliations></json:item><json:item><name>Adrian Wyllie</name><affiliations><json:string>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</json:string></affiliations></json:item><json:item><name>Amelia A Keaton</name><affiliations><json:string>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</json:string></affiliations></json:item><json:item><name>Christele Dubourg</name><affiliations><json:string>CHU Rennes, Laboratoire de Génétique Moléculaire, Rennes, France</json:string><json:string>CNRS, UMR 6290, Institut Génétique et Développement de Rennes, Université de Rennes 1, UEB, IFR 140, Faculté, de Médecine, Rennes, France</json:string></affiliations></json:item><json:item><name>Veronique David</name><affiliations><json:string>CHU Rennes, Laboratoire de Génétique Moléculaire, Rennes, France</json:string><json:string>CNRS, UMR 6290, Institut Génétique et Développement de Rennes, Université de Rennes 1, UEB, IFR 140, Faculté, de Médecine, Rennes, France</json:string></affiliations></json:item><json:item><name>Sandra Mercier</name><affiliations><json:string>CNRS, UMR 6290, Institut Génétique et Développement de Rennes, Université de Rennes 1, UEB, IFR 140, Faculté, de Médecine, Rennes, France</json:string><json:string>Service de genetique Clinique, CHU Hopital Sud, Rennes, France</json:string></affiliations></json:item><json:item><name>Sylvie Odent</name><affiliations><json:string>CNRS, UMR 6290, Institut Génétique et Développement de Rennes, Université de Rennes 1, UEB, IFR 140, Faculté, de Médecine, Rennes, France</json:string><json:string>Service de genetique Clinique, CHU Hopital Sud, Rennes, France</json:string></affiliations></json:item><json:item><name>Ute Hehr</name><affiliations><json:string>Center for Human Genetics, University of Regensburg, Regensburg, Germany</json:string><json:string>Department of Human Genetics, University of Regensburg, Regensburg, Germany</json:string></affiliations></json:item><json:item><name>Aimee Paulussen</name><affiliations><json:string>Department of Clinical Genetics, Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands</json:string></affiliations></json:item><json:item><name>Nancy J Clegg</name><affiliations><json:string>Texas Scottish Rite Hospital for Children, Dallas, Texas, USA</json:string></affiliations></json:item><json:item><name>Mauricio R Delgado</name><affiliations><json:string>Texas Scottish Rite Hospital for Children, Dallas, Texas, USA</json:string></affiliations></json:item><json:item><name>Sherri J Bale</name><affiliations><json:string>GeneDx, Gaithersburg, Maryland, USA</json:string></affiliations></json:item><json:item><name>Felicitas Lacbawan</name><affiliations><json:string>Molecular Genetics Pathology, Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio, USA</json:string></affiliations></json:item><json:item><name>Holly H Ardinger</name><affiliations><json:string>Section of Genetics, Department of Pediatrics, Children's Mercy Hospitals and Clinics, Kansas City, Missouri, USA</json:string></affiliations></json:item><json:item><name>Arthur S Aylsworth</name><affiliations><json:string>Department of Pediatrics, University of North Carolina, Chapel Hill, North Carolina, USA</json:string><json:string>Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA</json:string></affiliations></json:item><json:item><name>Ntombenhle Louisa Bhengu</name><affiliations><json:string>Department of Human Genetics Corner Hospital and De Korte, Johannesburg, South Africa</json:string></affiliations></json:item><json:item><name>Stephen Braddock</name><affiliations><json:string>Division of Medical Genetics, Department of Pediatrics, Saint Louis University, St. Louis, Missouri, USA</json:string></affiliations></json:item><json:item><name>Karen Brookhyser</name><affiliations><json:string>Genetics Department, Kaiser Permanente, Sacramento, California, USA</json:string></affiliations></json:item><json:item><name>Barbara Burton</name><affiliations><json:string>Department of Pediatrics, Northwestern University Feinberg School of Medicine and Division of Genetics, Birth Defects and Metabolism, Lurie Children's Hospital, Chicago, Illinois, USA</json:string></affiliations></json:item><json:item><name>Harald Gaspar</name><affiliations><json:string>Institute of Human Genetics, Heidelberg University, Heidelberg, Germany</json:string></affiliations></json:item><json:item><name>Art Grix</name><affiliations><json:string>Genetics Department, Kaiser Permanente, Sacramento, California, USA</json:string></affiliations></json:item><json:item><name>Dafne Horovitz</name><affiliations><json:string>Centro de Genetica Medica, Instituto Fernandes Figueira-FIOCRUZ, Rio de Janeiro, Brazil</json:string></affiliations></json:item><json:item><name>Erin Kanetzke</name><affiliations><json:string>Division of Medical Genetics, Department of Pediatrics, Saint Louis University, St. Louis, Missouri, USA</json:string></affiliations></json:item><json:item><name>Hulya Kayserili</name><affiliations><json:string>Department of Medical Genetics, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey</json:string></affiliations></json:item><json:item><name>Dorit Lev</name><affiliations><json:string>Institute of Medical Genetics, Wolfson Medical Center, Holon, Israel</json:string></affiliations></json:item><json:item><name>Sarah M Nikkel</name><affiliations><json:string>Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada</json:string></affiliations></json:item><json:item><name>Mary Norton</name><affiliations><json:string>Department of Obstetrics and Gynecology, Stanford University School of Medicine/Lucile and Packard Children's Hospital at Stanford University, Stanford, California, USA</json:string></affiliations></json:item><json:item><name>Richard Roberts</name><affiliations><json:string>Genetics and Prenatal Diagnostic Center, Corpus Christi, Texas, USA</json:string></affiliations></json:item><json:item><name>Howard Saal</name><affiliations><json:string>Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA</json:string></affiliations></json:item><json:item><name>G B Schaefer</name><affiliations><json:string>Division of Medical Genetics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA</json:string></affiliations></json:item><json:item><name>Adele Schneider</name><affiliations><json:string>Genetics Division, Einstein Medical Center, Philadelphia, Pennsylvania, USA</json:string></affiliations></json:item><json:item><name>Erika K Smith</name><affiliations><json:string>Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada</json:string></affiliations></json:item><json:item><name>Ellen Sowry</name><affiliations><json:string>Division of Medical Genetics, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA</json:string></affiliations></json:item><json:item><name>M Anne Spence</name><affiliations><json:string>Department of Pediatrics, University of California, Irvine, California, USA</json:string></affiliations></json:item><json:item><name>Stavit A Shalev</name><affiliations><json:string>Genetics Institute, Emek Medical Center, Afula, Israel</json:string><json:string>Rappaport faculty of Medicine, Technion, Haifa, Israel</json:string></affiliations></json:item><json:item><name>Carlos E Steiner</name><affiliations><json:string>Department of Medical Genetics, School of Medical Sciences, Universidade Estadual de Campinas (UNICAMP), Campinas, Sao Paulo, Brazil</json:string></affiliations></json:item><json:item><name>Elizabeth M Thompson</name><affiliations><json:string>Clinical Genetics Unit, SA Pathology, Women's and Children's Hospital and University of Adelaide, Adelaide, South Australia</json:string></affiliations></json:item><json:item><name>Thomas L Winder</name><affiliations><json:string>Prevention Genetics, Marshfield, Wisconsin, USA</json:string></affiliations></json:item><json:item><name>Joan Z Balog</name><affiliations><json:string>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</json:string></affiliations></json:item><json:item><name>Donald W Hadley</name><affiliations><json:string>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</json:string></affiliations></json:item><json:item><name>Nan Zhou</name><affiliations><json:string>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</json:string></affiliations></json:item><json:item><name>Daniel E Pineda-Alvarez</name><affiliations><json:string>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</json:string></affiliations></json:item><json:item><name>Erich Roessler</name><affiliations><json:string>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</json:string></affiliations></json:item><json:item><name>Maximilian Muenke</name><affiliations><json:string>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</json:string><json:string>E-mail: mamuenke@mail.nih.gov</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>Holoprosencephaly</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Sonic Hedgehog</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>SHH</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>genetics</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>genome-wide</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>academic medicine</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>adrenal disorders</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>anterior segment disease</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>cancer: breast</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>cancer: CNS</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>cytogenetics</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>molecular genetics</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>clinical genetics</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>developmental</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>diagnosis</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>guidelines</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>congenital heart disease</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>epigenetics</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>genetic screening/counselling</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>aneuploidy</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>chromosomal</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>ethics</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>complex traits</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>neurosciences</value></json:item></subject><articleId><json:string>jmedgenet-2012-101008</json:string></articleId><arkIstex>ark:/67375/NVC-4ZG5RTLZ-T</arkIstex><language><json:string>eng</json:string></language><originalGenre><json:string>research-article</json:string></originalGenre><abstract>Background Holoprosencephaly (HPE), the most common malformation of the human forebrain, may result from mutations in over 12 genes. Sonic Hedgehog (SHH) was the first such gene discovered; mutations in SHH remain the most common cause of non-chromosomal HPE. The severity spectrum is wide, ranging from incompatibility with extrauterine life to isolated midline facial differences. Objective To characterise genetic and clinical findings in individuals with SHH mutations. Methods Through the National Institutes of Health and collaborating centres, DNA from approximately 2000 individuals with HPE spectrum disorders were analysed for SHH variations. Clinical details were examined and combined with published cases. Results This study describes 396 individuals, representing 157 unrelated kindreds, with SHH mutations; 141 (36%) have not been previously reported. SHH mutations more commonly resulted in non-HPE (64%) than frank HPE (36%), and non-HPE was significantly more common in patients with SHH than in those with mutations in the other common HPE related genes (p>0.0001 compared to ZIC2 or SIX3). Individuals with truncating mutations were significantly more likely to have frank HPE than those with non-truncating mutations (49% vs 35%, respectively; p=0.012). While mutations were significantly more common in the N-terminus than in the C-terminus (including accounting for the relative size of the coding regions, p=0.00010), no specific genotype―phenotype correlations could be established regarding mutation location. Conclusions SHH mutations overall result in milder disease than mutations in other common HPE related genes. HPE is more frequent in individuals with truncating mutations, but clinical predictions at the individual level remain elusive.</abstract><qualityIndicators><score>9.834</score><pdfWordCount>4834</pdfWordCount><pdfCharCount>33865</pdfCharCount><pdfVersion>1.4</pdfVersion><pdfPageCount>7</pdfPageCount><pdfPageSize>595.276 x 793.701 pts</pdfPageSize><refBibsNative>true</refBibsNative><abstractWordCount>250</abstractWordCount><abstractCharCount>1772</abstractCharCount><keywordCount>24</keywordCount></qualityIndicators><title>Genotypic and phenotypic analysis of 396 individuals with mutations in Sonic Hedgehog</title><pmid><json:string>22791840</json:string></pmid><genre><json:string>research-article</json:string></genre><host><title>Journal of Medical Genetics</title><language><json:string>unknown</json:string></language><issn><json:string>0022-2593</json:string></issn><eissn><json:string>1468-6244</json:string></eissn><publisherId><json:string>jmg</json:string></publisherId><volume>49</volume><issue>7</issue><pages><first>473</first></pages><genre><json:string>journal</json:string></genre></host><namedEntities><unitex><date><json:string>2012</json:string><json:string>1988</json:string></date><geogName></geogName><orgName><json:string>Department of Pediatrics, University of North Carolina, Chapel Hill, North Carolina, USA</json:string><json:string>Department of Obstetrics and Gynecology</json:string><json:string>Stanford University</json:string><json:string>Department of Human Genetics, University of Regensburg, Regensburg, Germany</json:string><json:string>Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA</json:string><json:string>Department of Medical Genetics, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey</json:string><json:string>Division of Medical Genetics</json:string><json:string>Division of Human Genetics</json:string><json:string>Department of Clinical Genetics, Maastricht University Medical Center</json:string><json:string>Department of the Army</json:string><json:string>Texas Scottish Rite Hospital for Children, Dallas, Texas, USA</json:string><json:string>Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio, USA</json:string><json:string>Department of Pediatrics, University of California, Irvine, California, USA</json:string><json:string>Department of Pediatrics, Cincinnati Children</json:string><json:string>Prenatal Diagnostic Center, Corpus Christi</json:string><json:string>Institute of Human Genetics, Heidelberg University, Heidelberg, Germany</json:string><json:string>Hospital Medical Center, Cincinnati</json:string><json:string>Children’s Hospital and University of Adelaide, South Australia</json:string><json:string>Department of Genetics, Children</json:string><json:string>Department of Pediatrics, Walter Reed National Military Medical Center, Bethesda, Maryland, USA</json:string><json:string>National Institutes of Health</json:string><json:string>Department of Pediatrics, Northwestern University Feinberg School of Medicine and Division</json:string><json:string>Children’s Hospital and University of Adelaide, Adelaide, South Australia</json:string><json:string>Department of Pediatrics, Children</json:string><json:string>Department of Human Genetics Corner Hospital and De</json:string><json:string>Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA</json:string><json:string>Einstein Medical Center, Philadelphia</json:string><json:string>Genetics Institute, Emek Medical Center, Afula, Israel</json:string><json:string>National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</json:string><json:string>University of Regensburg</json:string><json:string>Genetics Department, Kaiser Permanente, Sacramento, California, USA</json:string><json:string>Department of Medical Genetics, School of Medical Sciences, Universidade Estadual</json:string><json:string>Institute of Medical Genetics, Wolfson Medical Center, Holon, Israel</json:string><json:string>Department of Pediatrics, Saint Louis University, St</json:string><json:string>Lurie Children’s Hospital, Chicago, Illinois, USA</json:string><json:string>University of Arkansas</json:string><json:string>Human Services</json:string><json:string>National Human Genome Research Institute</json:string><json:string>Department of Health</json:string><json:string>Division of Intramural Research</json:string><json:string>National Institutes of Health</json:string><json:string>USA</json:string></orgName><orgName_funder><json:string>Human Services</json:string><json:string>National Human Genome Research Institute</json:string><json:string>Department of Health</json:string><json:string>Division of Intramural Research</json:string><json:string>National Institutes of Health</json:string><json:string>USA</json:string></orgName_funder><orgName_provider></orgName_provider><persName><json:string>Dafne Horovitz</json:string><json:string>Karen Brookhyser</json:string><json:string>Veronique David</json:string><json:string>Richard Roberts</json:string><json:string>Stephen Braddock</json:string><json:string>Louisa Bhengu</json:string><json:string>Barbara Burton</json:string><json:string>Ellen Sowry</json:string><json:string>Thomas L Winder</json:string><json:string>Nan Zhou</json:string><json:string>Harald Gaspar</json:string><json:string>Mary Norton</json:string><json:string>Alexia Pena</json:string><json:string>Hospital</json:string><json:string>Darryl Leja</json:string><json:string>Sandra Mercier</json:string><json:string>Aimee Paulussen</json:string><json:string>Sylvie Odent</json:string><json:string>Howard Saal</json:string><json:string>Adele Schneider</json:string><json:string>Erin Kanetzke</json:string><json:string>Anne Spence</json:string><json:string>Maximilian Muenke</json:string><json:string>CHU Hopital</json:string></persName><placeName><json:string>Maastricht</json:string><json:string>Stanford</json:string><json:string>Germany</json:string><json:string>Brazil</json:string><json:string>Regensburg</json:string><json:string>Rennes</json:string><json:string>Canada</json:string><json:string>Rio de Janeiro</json:string><json:string>Haifa</json:string><json:string>South Africa</json:string><json:string>Israel</json:string><json:string>Ottawa</json:string><json:string>Kansas City</json:string><json:string>France</json:string><json:string>Sao Paulo</json:string><json:string>Campinas</json:string><json:string>Johannesburg</json:string><json:string>Netherlands</json:string></placeName><ref_url><json:string>http://jmg.bmj.com/</json:string></ref_url><ref_bibl><json:string>Wannasilp et al</json:string><json:string>Solomon et al</json:string><json:string>Pineda-Alvarez et al</json:string></ref_bibl><bibl></bibl></unitex></namedEntities><ark><json:string>ark:/67375/NVC-4ZG5RTLZ-T</json:string></ark><categories><wos><json:string>1 - science</json:string><json:string>2 - genetics & heredity</json:string></wos><scienceMetrix><json:string>1 - health sciences</json:string><json:string>2 - biomedical research</json:string><json:string>3 - genetics & heredity</json:string></scienceMetrix><scopus><json:string>1 - Health Sciences</json:string><json:string>2 - Medicine</json:string><json:string>3 - Genetics(clinical)</json:string><json:string>1 - Life Sciences</json:string><json:string>2 - Biochemistry, Genetics and Molecular Biology</json:string><json:string>3 - Genetics</json:string></scopus><inist><json:string>1 - sciences appliquees, technologies et medecines</json:string><json:string>2 - sciences biologiques et medicales</json:string><json:string>3 - sciences medicales</json:string></inist></categories><publicationDate>2012</publicationDate><copyrightDate>2012</copyrightDate><doi><json:string>10.1136/jmedgenet-2012-101008</json:string></doi><id>BFFAC78ABF1C5ADDDE35769A4C10022F3A316AE5</id><score>1</score><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/document/BFFAC78ABF1C5ADDDE35769A4C10022F3A316AE5/fulltext/pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api.istex.fr/document/BFFAC78ABF1C5ADDDE35769A4C10022F3A316AE5/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/BFFAC78ABF1C5ADDDE35769A4C10022F3A316AE5/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a">Genotypic and phenotypic analysis of 396 individuals with mutations in Sonic Hedgehog</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher scheme="https://publisher-list.data.istex.fr">BMJ Publishing Group Ltd</publisher><availability><licence><p>© 2012, Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.</p></licence><p scheme="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-7M42M2QJ-2">bmj</p></availability><date>2012</date></publicationStmt><notesStmt><note type="research-article" scheme="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</note><note type="journal" scheme="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</note><note>BDS and KAB contributed equally to this work. The views expressed by KAB in this article are those of the author and do not necessarily reflect the official policy or position of the Department of the Army, nor the US government.</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a">Genotypic and phenotypic analysis of 396 individuals with mutations in Sonic Hedgehog</title><author xml:id="author-0000"><persName><forename type="first">Benjamin D</forename><surname>Solomon</surname></persName><affiliation>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</affiliation></author><author xml:id="author-0001"><persName><forename type="first">Kelly A</forename><surname>Bear</surname></persName><affiliation>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</affiliation><affiliation>Department of Pediatrics, Walter Reed National Military Medical Center, Bethesda, Maryland, USA</affiliation></author><author xml:id="author-0002"><persName><forename type="first">Adrian</forename><surname>Wyllie</surname></persName><affiliation>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</affiliation></author><author xml:id="author-0003"><persName><forename type="first">Amelia A</forename><surname>Keaton</surname></persName><affiliation>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</affiliation></author><author xml:id="author-0004"><persName><forename type="first">Christele</forename><surname>Dubourg</surname></persName><affiliation>CHU Rennes, Laboratoire de Génétique Moléculaire, Rennes, France</affiliation><affiliation>CNRS, UMR 6290, Institut Génétique et Développement de Rennes, Université de Rennes 1, UEB, IFR 140, Faculté, de Médecine, Rennes, France</affiliation></author><author xml:id="author-0005"><persName><forename type="first">Veronique</forename><surname>David</surname></persName><affiliation>CHU Rennes, Laboratoire de Génétique Moléculaire, Rennes, France</affiliation><affiliation>CNRS, UMR 6290, Institut Génétique et Développement de Rennes, Université de Rennes 1, UEB, IFR 140, Faculté, de Médecine, Rennes, France</affiliation></author><author xml:id="author-0006"><persName><forename type="first">Sandra</forename><surname>Mercier</surname></persName><affiliation>CNRS, UMR 6290, Institut Génétique et Développement de Rennes, Université de Rennes 1, UEB, IFR 140, Faculté, de Médecine, Rennes, France</affiliation><affiliation>Service de genetique Clinique, CHU Hopital Sud, Rennes, France</affiliation></author><author xml:id="author-0007"><persName><forename type="first">Sylvie</forename><surname>Odent</surname></persName><affiliation>CNRS, UMR 6290, Institut Génétique et Développement de Rennes, Université de Rennes 1, UEB, IFR 140, Faculté, de Médecine, Rennes, France</affiliation><affiliation>Service de genetique Clinique, CHU Hopital Sud, Rennes, France</affiliation></author><author xml:id="author-0008"><persName><forename type="first">Ute</forename><surname>Hehr</surname></persName><affiliation>Center for Human Genetics, University of Regensburg, Regensburg, Germany</affiliation><affiliation>Department of Human Genetics, University of Regensburg, Regensburg, Germany</affiliation></author><author xml:id="author-0009"><persName><forename type="first">Aimee</forename><surname>Paulussen</surname></persName><affiliation>Department of Clinical Genetics, Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands</affiliation></author><author xml:id="author-0010"><persName><forename type="first">Nancy J</forename><surname>Clegg</surname></persName><affiliation>Texas Scottish Rite Hospital for Children, Dallas, Texas, USA</affiliation></author><author xml:id="author-0011"><persName><forename type="first">Mauricio R</forename><surname>Delgado</surname></persName><affiliation>Texas Scottish Rite Hospital for Children, Dallas, Texas, USA</affiliation></author><author xml:id="author-0012"><persName><forename type="first">Sherri J</forename><surname>Bale</surname></persName><affiliation>GeneDx, Gaithersburg, Maryland, USA</affiliation></author><author xml:id="author-0013"><persName><forename type="first">Felicitas</forename><surname>Lacbawan</surname></persName><affiliation>Molecular Genetics Pathology, Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio, USA</affiliation></author><author xml:id="author-0014"><persName><forename type="first">Holly H</forename><surname>Ardinger</surname></persName><affiliation>Section of Genetics, Department of Pediatrics, Children's Mercy Hospitals and Clinics, Kansas City, Missouri, USA</affiliation></author><author xml:id="author-0015"><persName><forename type="first">Arthur S</forename><surname>Aylsworth</surname></persName><affiliation>Department of Pediatrics, University of North Carolina, Chapel Hill, North Carolina, USA</affiliation><affiliation>Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA</affiliation></author><author xml:id="author-0016"><persName><forename type="first">Ntombenhle Louisa</forename><surname>Bhengu</surname></persName><affiliation>Department of Human Genetics Corner Hospital and De Korte, Johannesburg, South Africa</affiliation></author><author xml:id="author-0017"><persName><forename type="first">Stephen</forename><surname>Braddock</surname></persName><affiliation>Division of Medical Genetics, Department of Pediatrics, Saint Louis University, St. Louis, Missouri, USA</affiliation></author><author xml:id="author-0018"><persName><forename type="first">Karen</forename><surname>Brookhyser</surname></persName><affiliation>Genetics Department, Kaiser Permanente, Sacramento, California, USA</affiliation></author><author xml:id="author-0019"><persName><forename type="first">Barbara</forename><surname>Burton</surname></persName><affiliation>Department of Pediatrics, Northwestern University Feinberg School of Medicine and Division of Genetics, Birth Defects and Metabolism, Lurie Children's Hospital, Chicago, Illinois, USA</affiliation></author><author xml:id="author-0020"><persName><forename type="first">Harald</forename><surname>Gaspar</surname></persName><affiliation>Institute of Human Genetics, Heidelberg University, Heidelberg, Germany</affiliation></author><author xml:id="author-0021"><persName><forename type="first">Art</forename><surname>Grix</surname></persName><affiliation>Genetics Department, Kaiser Permanente, Sacramento, California, USA</affiliation></author><author xml:id="author-0022"><persName><forename type="first">Dafne</forename><surname>Horovitz</surname></persName><affiliation>Centro de Genetica Medica, Instituto Fernandes Figueira-FIOCRUZ, Rio de Janeiro, Brazil</affiliation></author><author xml:id="author-0023"><persName><forename type="first">Erin</forename><surname>Kanetzke</surname></persName><affiliation>Division of Medical Genetics, Department of Pediatrics, Saint Louis University, St. Louis, Missouri, USA</affiliation></author><author xml:id="author-0024"><persName><forename type="first">Hulya</forename><surname>Kayserili</surname></persName><affiliation>Department of Medical Genetics, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey</affiliation></author><author xml:id="author-0025"><persName><forename type="first">Dorit</forename><surname>Lev</surname></persName><affiliation>Institute of Medical Genetics, Wolfson Medical Center, Holon, Israel</affiliation></author><author xml:id="author-0026"><persName><forename type="first">Sarah M</forename><surname>Nikkel</surname></persName><affiliation>Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada</affiliation></author><author xml:id="author-0027"><persName><forename type="first">Mary</forename><surname>Norton</surname></persName><affiliation>Department of Obstetrics and Gynecology, Stanford University School of Medicine/Lucile and Packard Children's Hospital at Stanford University, Stanford, California, USA</affiliation></author><author xml:id="author-0028"><persName><forename type="first">Richard</forename><surname>Roberts</surname></persName><affiliation>Genetics and Prenatal Diagnostic Center, Corpus Christi, Texas, USA</affiliation></author><author xml:id="author-0029"><persName><forename type="first">Howard</forename><surname>Saal</surname></persName><affiliation>Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA</affiliation></author><author xml:id="author-0030"><persName><forename type="first">G B</forename><surname>Schaefer</surname></persName><affiliation>Division of Medical Genetics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA</affiliation></author><author xml:id="author-0031"><persName><forename type="first">Adele</forename><surname>Schneider</surname></persName><affiliation>Genetics Division, Einstein Medical Center, Philadelphia, Pennsylvania, USA</affiliation></author><author xml:id="author-0032"><persName><forename type="first">Erika K</forename><surname>Smith</surname></persName><affiliation>Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada</affiliation></author><author xml:id="author-0033"><persName><forename type="first">Ellen</forename><surname>Sowry</surname></persName><affiliation>Division of Medical Genetics, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA</affiliation></author><author xml:id="author-0034"><persName><forename type="first">M Anne</forename><surname>Spence</surname></persName><affiliation>Department of Pediatrics, University of California, Irvine, California, USA</affiliation></author><author xml:id="author-0035"><persName><forename type="first">Stavit A</forename><surname>Shalev</surname></persName><affiliation>Genetics Institute, Emek Medical Center, Afula, Israel</affiliation><affiliation>Rappaport faculty of Medicine, Technion, Haifa, Israel</affiliation></author><author xml:id="author-0036"><persName><forename type="first">Carlos E</forename><surname>Steiner</surname></persName><affiliation>Department of Medical Genetics, School of Medical Sciences, Universidade Estadual de Campinas (UNICAMP), Campinas, Sao Paulo, Brazil</affiliation></author><author xml:id="author-0037"><persName><forename type="first">Elizabeth M</forename><surname>Thompson</surname></persName><affiliation>Clinical Genetics Unit, SA Pathology, Women's and Children's Hospital and University of Adelaide, Adelaide, South Australia</affiliation></author><author xml:id="author-0038"><persName><forename type="first">Thomas L</forename><surname>Winder</surname></persName><affiliation>Prevention Genetics, Marshfield, Wisconsin, USA</affiliation></author><author xml:id="author-0039"><persName><forename type="first">Joan Z</forename><surname>Balog</surname></persName><affiliation>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</affiliation></author><author xml:id="author-0040"><persName><forename type="first">Donald W</forename><surname>Hadley</surname></persName><affiliation>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</affiliation></author><author xml:id="author-0041"><persName><forename type="first">Nan</forename><surname>Zhou</surname></persName><affiliation>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</affiliation></author><author xml:id="author-0042"><persName><forename type="first">Daniel E</forename><surname>Pineda-Alvarez</surname></persName><affiliation>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</affiliation></author><author xml:id="author-0043"><persName><forename type="first">Erich</forename><surname>Roessler</surname></persName><affiliation>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</affiliation></author><author xml:id="author-0044" corresp="yes"><persName><forename type="first">Maximilian</forename><surname>Muenke</surname></persName><email>mamuenke@mail.nih.gov</email><affiliation>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</affiliation></author><idno type="istex">BFFAC78ABF1C5ADDDE35769A4C10022F3A316AE5</idno><idno type="ark">ark:/67375/NVC-4ZG5RTLZ-T</idno><idno type="DOI">10.1136/jmedgenet-2012-101008</idno><idno type="href">jmedgenet-49-473.pdf</idno><idno type="article-id">jmedgenet-2012-101008</idno><idno type="local">jmedgenet;49/7/473</idno></analytic><monogr><title level="j">Journal of Medical Genetics</title><title level="j" type="abbrev">J Med Genet</title><idno type="pISSN">0022-2593</idno><idno type="eISSN">1468-6244</idno><idno type="publisher-id">jmg</idno><idno type="PublisherID-hwp">jmedgenet</idno><idno type="PublisherID-nlm-ta">J Med Genet</idno><imprint><publisher>BMJ Publishing Group Ltd</publisher><date type="published" when="2012-07"></date><biblScope unit="volume">49</biblScope><biblScope unit="issue">7</biblScope><biblScope unit="page" from="473">473</biblScope></imprint></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2012</date></creation><langUsage><language ident="en">en</language></langUsage><abstract><p>Background Holoprosencephaly (HPE), the most common malformation of the human forebrain, may result from mutations in over 12 genes. Sonic Hedgehog (SHH) was the first such gene discovered; mutations in SHH remain the most common cause of non-chromosomal HPE. The severity spectrum is wide, ranging from incompatibility with extrauterine life to isolated midline facial differences. Objective To characterise genetic and clinical findings in individuals with SHH mutations. Methods Through the National Institutes of Health and collaborating centres, DNA from approximately 2000 individuals with HPE spectrum disorders were analysed for SHH variations. Clinical details were examined and combined with published cases. Results This study describes 396 individuals, representing 157 unrelated kindreds, with SHH mutations; 141 (36%) have not been previously reported. SHH mutations more commonly resulted in non-HPE (64%) than frank HPE (36%), and non-HPE was significantly more common in patients with SHH than in those with mutations in the other common HPE related genes (p<0.0001 compared to ZIC2 or SIX3). Individuals with truncating mutations were significantly more likely to have frank HPE than those with non-truncating mutations (49% vs 35%, respectively; p=0.012). While mutations were significantly more common in the N-terminus than in the C-terminus (including accounting for the relative size of the coding regions, p=0.00010), no specific genotype―phenotype correlations could be established regarding mutation location. Conclusions SHH mutations overall result in milder disease than mutations in other common HPE related genes. HPE is more frequent in individuals with truncating mutations, but clinical predictions at the individual level remain elusive.</p></abstract><textClass><keywords scheme="keyword"><list><head>keywords</head><item><term>Holoprosencephaly</term></item><item><term>Sonic Hedgehog</term></item><item><term>SHH</term></item><item><term>genetics</term></item><item><term>genome-wide</term></item><item><term>academic medicine</term></item><item><term>adrenal disorders</term></item><item><term>anterior segment disease</term></item><item><term>cancer: breast</term></item><item><term>cancer: CNS</term></item><item><term>cytogenetics</term></item><item><term>molecular genetics</term></item><item><term>clinical genetics</term></item><item><term>developmental</term></item><item><term>diagnosis</term></item><item><term>guidelines</term></item><item><term>congenital heart disease</term></item><item><term>epigenetics</term></item><item><term>genetic screening/counselling</term></item><item><term>aneuploidy</term></item><item><term>chromosomal</term></item><item><term>ethics</term></item><item><term>complex traits</term></item><item><term>neurosciences</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2012-07">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/document/BFFAC78ABF1C5ADDDE35769A4C10022F3A316AE5/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus bmj" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="no"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Archiving and Interchange DTD v2.3 20070202//EN" URI="archivearticle.dtd" name="istex:docType"></istex:docType><istex:document><article article-type="research-article"><front><journal-meta><journal-id journal-id-type="hwp">jmedgenet</journal-id><journal-id journal-id-type="nlm-ta">J Med Genet</journal-id><journal-id journal-id-type="publisher-id">jmg</journal-id><journal-title>Journal of Medical Genetics</journal-title><abbrev-journal-title abbrev-type="publisher">J Med Genet</abbrev-journal-title><abbrev-journal-title>J Med Genet</abbrev-journal-title><issn pub-type="ppub">0022-2593</issn><issn pub-type="epub">1468-6244</issn><publisher><publisher-name>BMJ Publishing Group Ltd</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="publisher-id">jmedgenet-2012-101008</article-id><article-id pub-id-type="doi">10.1136/jmedgenet-2012-101008</article-id><article-id pub-id-type="other">jmedgenet;49/7/473</article-id><article-id pub-id-type="other">jmedgenet;jmedgenet-2012-101008</article-id><article-id pub-id-type="other">473</article-id><article-id pub-id-type="other">jmedgenet-2012-101008</article-id><article-categories><subj-group subj-group-type="heading"><subject>Genotype-phenotype correlations</subject></subj-group><series-title>Original article</series-title></article-categories><title-group><article-title>Genotypic and phenotypic analysis of 396 individuals with mutations in <italic>Sonic Hedgehog</italic></article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Solomon</surname><given-names>Benjamin D</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Bear</surname><given-names>Kelly A</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Wyllie</surname><given-names>Adrian</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Keaton</surname><given-names>Amelia A</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Dubourg</surname><given-names>Christele</given-names></name><xref ref-type="aff" rid="aff3">3</xref><xref ref-type="aff" rid="aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>David</surname><given-names>Veronique</given-names></name><xref ref-type="aff" rid="aff3">3</xref><xref ref-type="aff" rid="aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Mercier</surname><given-names>Sandra</given-names></name><xref ref-type="aff" rid="aff4">4</xref><xref ref-type="aff" rid="aff5">5</xref></contrib><contrib contrib-type="author"><name><surname>Odent</surname><given-names>Sylvie</given-names></name><xref ref-type="aff" rid="aff4">4</xref><xref ref-type="aff" rid="aff5">5</xref></contrib><contrib contrib-type="author"><name><surname>Hehr</surname><given-names>Ute</given-names></name><xref ref-type="aff" rid="aff6">6</xref><xref ref-type="aff" rid="aff7">7</xref></contrib><contrib contrib-type="author"><name><surname>Paulussen</surname><given-names>Aimee</given-names></name><xref ref-type="aff" rid="aff8">8</xref></contrib><contrib contrib-type="author"><name><surname>Clegg</surname><given-names>Nancy J</given-names></name><xref ref-type="aff" rid="aff9">9</xref></contrib><contrib contrib-type="author"><name><surname>Delgado</surname><given-names>Mauricio R</given-names></name><xref ref-type="aff" rid="aff9">9</xref></contrib><contrib contrib-type="author"><name><surname>Bale</surname><given-names>Sherri J</given-names></name><xref ref-type="aff" rid="aff10">10</xref></contrib><contrib contrib-type="author"><name><surname>Lacbawan</surname><given-names>Felicitas</given-names></name><xref ref-type="aff" rid="aff11">11</xref></contrib><contrib contrib-type="author"><name><surname>Ardinger</surname><given-names>Holly H</given-names></name><xref ref-type="aff" rid="aff12">12</xref></contrib><contrib contrib-type="author"><name><surname>Aylsworth</surname><given-names>Arthur S</given-names></name><xref ref-type="aff" rid="aff13">13</xref><xref ref-type="aff" rid="aff14">14</xref></contrib><contrib contrib-type="author"><name><surname>Bhengu</surname><given-names>Ntombenhle Louisa</given-names></name><xref ref-type="aff" rid="aff15">15</xref></contrib><contrib contrib-type="author"><name><surname>Braddock</surname><given-names>Stephen</given-names></name><xref ref-type="aff" rid="aff16">16</xref></contrib><contrib contrib-type="author"><name><surname>Brookhyser</surname><given-names>Karen</given-names></name><xref ref-type="aff" rid="aff17">17</xref></contrib><contrib contrib-type="author"><name><surname>Burton</surname><given-names>Barbara</given-names></name><xref ref-type="aff" rid="aff18">18</xref></contrib><contrib contrib-type="author"><name><surname>Gaspar</surname><given-names>Harald</given-names></name><xref ref-type="aff" rid="aff19">19</xref></contrib><contrib contrib-type="author"><name><surname>Grix</surname><given-names>Art</given-names></name><xref ref-type="aff" rid="aff17">17</xref></contrib><contrib contrib-type="author"><name><surname>Horovitz</surname><given-names>Dafne</given-names></name><xref ref-type="aff" rid="aff20">20</xref></contrib><contrib contrib-type="author"><name><surname>Kanetzke</surname><given-names>Erin</given-names></name><xref ref-type="aff" rid="aff16">16</xref></contrib><contrib contrib-type="author"><name><surname>Kayserili</surname><given-names>Hulya</given-names></name><xref ref-type="aff" rid="aff21">21</xref></contrib><contrib contrib-type="author"><name><surname>Lev</surname><given-names>Dorit</given-names></name><xref ref-type="aff" rid="aff22">22</xref></contrib><contrib contrib-type="author"><name><surname>Nikkel</surname><given-names>Sarah M</given-names></name><xref ref-type="aff" rid="aff23">23</xref></contrib><contrib contrib-type="author"><name><surname>Norton</surname><given-names>Mary</given-names></name><xref ref-type="aff" rid="aff24">24</xref></contrib><contrib contrib-type="author"><name><surname>Roberts</surname><given-names>Richard</given-names></name><xref ref-type="aff" rid="aff25">25</xref></contrib><contrib contrib-type="author"><name><surname>Saal</surname><given-names>Howard</given-names></name><xref ref-type="aff" rid="aff26">26</xref></contrib><contrib contrib-type="author"><name><surname>Schaefer</surname><given-names>G B</given-names></name><xref ref-type="aff" rid="aff27">27</xref></contrib><contrib contrib-type="author"><name><surname>Schneider</surname><given-names>Adele</given-names></name><xref ref-type="aff" rid="aff28">28</xref></contrib><contrib contrib-type="author"><name><surname>Smith</surname><given-names>Erika K</given-names></name><xref ref-type="aff" rid="aff23">23</xref></contrib><contrib contrib-type="author"><name><surname>Sowry</surname><given-names>Ellen</given-names></name><xref ref-type="aff" rid="aff29">29</xref></contrib><contrib contrib-type="author"><name><surname>Spence</surname><given-names>M Anne</given-names></name><xref ref-type="aff" rid="aff30">30</xref></contrib><contrib contrib-type="author"><name><surname>Shalev</surname><given-names>Stavit A</given-names></name><xref ref-type="aff" rid="aff31">31</xref><xref ref-type="aff" rid="aff32">32</xref></contrib><contrib contrib-type="author"><name><surname>Steiner</surname><given-names>Carlos E</given-names></name><xref ref-type="aff" rid="aff33">33</xref></contrib><contrib contrib-type="author"><name><surname>Thompson</surname><given-names>Elizabeth M</given-names></name><xref ref-type="aff" rid="aff34">34</xref></contrib><contrib contrib-type="author"><name><surname>Winder</surname><given-names>Thomas L</given-names></name><xref ref-type="aff" rid="aff35">35</xref></contrib><contrib contrib-type="author"><name><surname>Balog</surname><given-names>Joan Z</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Hadley</surname><given-names>Donald W</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Zhou</surname><given-names>Nan</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Pineda-Alvarez</surname><given-names>Daniel E</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Roessler</surname><given-names>Erich</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Muenke</surname><given-names>Maximilian</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib></contrib-group><aff id="aff1"><label>1</label>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</aff><aff id="aff2"><label>2</label>Department of Pediatrics, Walter Reed National Military Medical Center, Bethesda, Maryland, USA</aff><aff id="aff3"><label>3</label>CHU Rennes, Laboratoire de Génétique Moléculaire, Rennes, France</aff><aff id="aff4"><label>4</label>CNRS, UMR 6290, Institut Génétique et Développement de Rennes, Université de Rennes 1, UEB, IFR 140, Faculté, de Médecine, Rennes, France</aff><aff id="aff5"><label>5</label>Service de genetique Clinique, CHU Hopital Sud, Rennes, France</aff><aff id="aff6"><label>6</label>Center for Human Genetics, University of Regensburg, Regensburg, Germany</aff><aff id="aff7"><label>7</label>Department of Human Genetics, University of Regensburg, Regensburg, Germany</aff><aff id="aff8"><label>8</label>Department of Clinical Genetics, Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands</aff><aff id="aff9"><label>9</label>Texas Scottish Rite Hospital for Children, Dallas, Texas, USA</aff><aff id="aff10"><label>10</label>GeneDx, Gaithersburg, Maryland, USA</aff><aff id="aff11"><label>11</label>Molecular Genetics Pathology, Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio, USA</aff><aff id="aff12"><label>12</label>Section of Genetics, Department of Pediatrics, Children's Mercy Hospitals and Clinics, Kansas City, Missouri, USA</aff><aff id="aff13"><label>13</label>Department of Pediatrics, University of North Carolina, Chapel Hill, North Carolina, USA</aff><aff id="aff14"><label>14</label>Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA</aff><aff id="aff15"><label>15</label>Department of Human Genetics Corner Hospital and De Korte, Johannesburg, South Africa</aff><aff id="aff16"><label>16</label>Division of Medical Genetics, Department of Pediatrics, Saint Louis University, St. Louis, Missouri, USA</aff><aff id="aff17"><label>17</label>Genetics Department, Kaiser Permanente, Sacramento, California, USA</aff><aff id="aff18"><label>18</label>Department of Pediatrics, Northwestern University Feinberg School of Medicine and Division of Genetics, Birth Defects and Metabolism, Lurie Children's Hospital, Chicago, Illinois, USA</aff><aff id="aff19"><label>19</label>Institute of Human Genetics, Heidelberg University, Heidelberg, Germany</aff><aff id="aff20"><label>20</label>Centro de Genetica Medica, Instituto Fernandes Figueira-FIOCRUZ, Rio de Janeiro, Brazil</aff><aff id="aff21"><label>21</label>Department of Medical Genetics, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey</aff><aff id="aff22"><label>22</label>Institute of Medical Genetics, Wolfson Medical Center, Holon, Israel</aff><aff id="aff23"><label>23</label>Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada</aff><aff id="aff24"><label>24</label>Department of Obstetrics and Gynecology, Stanford University School of Medicine/Lucile and Packard Children's Hospital at Stanford University, Stanford, California, USA</aff><aff id="aff25"><label>25</label>Genetics and Prenatal Diagnostic Center, Corpus Christi, Texas, USA</aff><aff id="aff26"><label>26</label>Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA</aff><aff id="aff27"><label>27</label>Division of Medical Genetics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA</aff><aff id="aff28"><label>28</label>Genetics Division, Einstein Medical Center, Philadelphia, Pennsylvania, USA</aff><aff id="aff29"><label>29</label>Division of Medical Genetics, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA</aff><aff id="aff30"><label>30</label>Department of Pediatrics, University of California, Irvine, California, USA</aff><aff id="aff31"><label>31</label>Genetics Institute, Emek Medical Center, Afula, Israel</aff><aff id="aff32"><label>32</label>Rappaport faculty of Medicine, Technion, Haifa, Israel</aff><aff id="aff33"><label>33</label>Department of Medical Genetics, School of Medical Sciences, Universidade Estadual de Campinas (UNICAMP), Campinas, Sao Paulo, Brazil</aff><aff id="aff34"><label>34</label>Clinical Genetics Unit, SA Pathology, Women's and Children's Hospital and University of Adelaide, Adelaide, South Australia</aff><aff id="aff35"><label>35</label>Prevention Genetics, Marshfield, Wisconsin, USA</aff><author-notes><corresp><label>Correspondence to</label> Dr Maximilian Muenke, Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USA 20892; <email>mamuenke@mail.nih.gov</email></corresp><fn fn-type="other"><p>BDS and KAB contributed equally to this work. The views expressed by KAB in this article are those of the author and do not necessarily reflect the official policy or position of the Department of the Army, nor the US government.</p></fn></author-notes><pub-date pub-type="ppub"><month>7</month><year>2012</year></pub-date><volume>49</volume><volume-id pub-id-type="other">49</volume-id><volume-id pub-id-type="other">49</volume-id><issue>7</issue><issue-id pub-id-type="other">jmedgenet;49/7</issue-id><issue-id pub-id-type="other">7</issue-id><issue-id pub-id-type="other">49/7</issue-id><fpage>473</fpage><history><date date-type="received"><day>26</day><month>4</month><year>2012</year></date><date date-type="rev-recd"><day>17</day><month>5</month><year>2012</year></date><date date-type="accepted"><day>29</day><month>5</month><year>2012</year></date></history><permissions><copyright-statement>© 2012, Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.</copyright-statement><copyright-year>2012</copyright-year></permissions><self-uri content-type="pdf" xlink:role="full-text" xlink:href="jmedgenet-49-473.pdf"></self-uri><abstract><sec><title>Background</title><p>Holoprosencephaly (HPE), the most common malformation of the human forebrain, may result from mutations in over 12 genes. <italic>Sonic Hedgehog</italic> (<italic>SHH</italic>) was the first such gene discovered; mutations in <italic>SHH</italic> remain the most common cause of non-chromosomal HPE. The severity spectrum is wide, ranging from incompatibility with extrauterine life to isolated midline facial differences.</p></sec><sec><title>Objective</title><p>To characterise genetic and clinical findings in individuals with <italic>SHH</italic> mutations.</p></sec><sec><title>Methods</title><p>Through the National Institutes of Health and collaborating centres, DNA from approximately 2000 individuals with HPE spectrum disorders were analysed for <italic>SHH</italic> variations. Clinical details were examined and combined with published cases.</p></sec><sec><title>Results</title><p>This study describes 396 individuals, representing 157 unrelated kindreds, with <italic>SHH</italic> mutations; 141 (36%) have not been previously reported. <italic>SHH</italic> mutations more commonly resulted in non-HPE (64%) than frank HPE (36%), and non-HPE was significantly more common in patients with <italic>SHH</italic> than in those with mutations in the other common HPE related genes (p<0.0001 compared to <italic>ZIC2</italic> or <italic>SIX3</italic>). Individuals with truncating mutations were significantly more likely to have frank HPE than those with non-truncating mutations (49% vs 35%, respectively; p=0.012). While mutations were significantly more common in the N-terminus than in the C-terminus (including accounting for the relative size of the coding regions, p=0.00010), no specific genotype―phenotype correlations could be established regarding mutation location.</p></sec><sec><title>Conclusions</title><p><italic>SHH</italic> mutations overall result in milder disease than mutations in other common HPE related genes. HPE is more frequent in individuals with truncating mutations, but clinical predictions at the individual level remain elusive.</p></sec></abstract><kwd-group><kwd>Holoprosencephaly</kwd><kwd><italic>Sonic Hedgehog</italic></kwd><kwd>SHH</kwd><kwd>genetics</kwd><kwd>genome-wide</kwd><kwd>academic medicine</kwd><kwd>adrenal disorders</kwd><kwd>anterior segment disease</kwd><kwd>cancer: breast</kwd><kwd>cancer: CNS</kwd><kwd>cytogenetics</kwd><kwd>molecular genetics</kwd><kwd>clinical genetics</kwd><kwd>developmental</kwd><kwd>diagnosis</kwd><kwd>guidelines</kwd><kwd>congenital heart disease</kwd><kwd>epigenetics</kwd><kwd>genetic screening/counselling</kwd><kwd>aneuploidy</kwd><kwd>chromosomal</kwd><kwd>ethics</kwd><kwd>complex traits</kwd><kwd>neurosciences</kwd></kwd-group></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Genotypic and phenotypic analysis of 396 individuals with mutations in Sonic Hedgehog</title><partName>Original article</partName></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Genotypic and phenotypic analysis of 396 individuals with mutations in Sonic Hedgehog</title><partName>Original article</partName></titleInfo><name type="personal"><namePart type="given">Benjamin D</namePart><namePart type="family">Solomon</namePart><affiliation>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Kelly A</namePart><namePart type="family">Bear</namePart><affiliation>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</affiliation><affiliation>Department of Pediatrics, Walter Reed National Military Medical Center, Bethesda, Maryland, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Adrian</namePart><namePart type="family">Wyllie</namePart><affiliation>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Amelia A</namePart><namePart type="family">Keaton</namePart><affiliation>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Christele</namePart><namePart type="family">Dubourg</namePart><affiliation>CHU Rennes, Laboratoire de Génétique Moléculaire, Rennes, France</affiliation><affiliation>CNRS, UMR 6290, Institut Génétique et Développement de Rennes, Université de Rennes 1, UEB, IFR 140, Faculté, de Médecine, Rennes, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Veronique</namePart><namePart type="family">David</namePart><affiliation>CHU Rennes, Laboratoire de Génétique Moléculaire, Rennes, France</affiliation><affiliation>CNRS, UMR 6290, Institut Génétique et Développement de Rennes, Université de Rennes 1, UEB, IFR 140, Faculté, de Médecine, Rennes, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Sandra</namePart><namePart type="family">Mercier</namePart><affiliation>CNRS, UMR 6290, Institut Génétique et Développement de Rennes, Université de Rennes 1, UEB, IFR 140, Faculté, de Médecine, Rennes, France</affiliation><affiliation>Service de genetique Clinique, CHU Hopital Sud, Rennes, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Sylvie</namePart><namePart type="family">Odent</namePart><affiliation>CNRS, UMR 6290, Institut Génétique et Développement de Rennes, Université de Rennes 1, UEB, IFR 140, Faculté, de Médecine, Rennes, France</affiliation><affiliation>Service de genetique Clinique, CHU Hopital Sud, Rennes, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ute</namePart><namePart type="family">Hehr</namePart><affiliation>Center for Human Genetics, University of Regensburg, Regensburg, Germany</affiliation><affiliation>Department of Human Genetics, University of Regensburg, Regensburg, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Aimee</namePart><namePart type="family">Paulussen</namePart><affiliation>Department of Clinical Genetics, Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Nancy J</namePart><namePart type="family">Clegg</namePart><affiliation>Texas Scottish Rite Hospital for Children, Dallas, Texas, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Mauricio R</namePart><namePart type="family">Delgado</namePart><affiliation>Texas Scottish Rite Hospital for Children, Dallas, Texas, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Sherri J</namePart><namePart type="family">Bale</namePart><affiliation>GeneDx, Gaithersburg, Maryland, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Felicitas</namePart><namePart type="family">Lacbawan</namePart><affiliation>Molecular Genetics Pathology, Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Holly H</namePart><namePart type="family">Ardinger</namePart><affiliation>Section of Genetics, Department of Pediatrics, Children's Mercy Hospitals and Clinics, Kansas City, Missouri, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Arthur S</namePart><namePart type="family">Aylsworth</namePart><affiliation>Department of Pediatrics, University of North Carolina, Chapel Hill, North Carolina, USA</affiliation><affiliation>Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ntombenhle Louisa</namePart><namePart type="family">Bhengu</namePart><affiliation>Department of Human Genetics Corner Hospital and De Korte, Johannesburg, South Africa</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Stephen</namePart><namePart type="family">Braddock</namePart><affiliation>Division of Medical Genetics, Department of Pediatrics, Saint Louis University, St. Louis, Missouri, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Karen</namePart><namePart type="family">Brookhyser</namePart><affiliation>Genetics Department, Kaiser Permanente, Sacramento, California, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Barbara</namePart><namePart type="family">Burton</namePart><affiliation>Department of Pediatrics, Northwestern University Feinberg School of Medicine and Division of Genetics, Birth Defects and Metabolism, Lurie Children's Hospital, Chicago, Illinois, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Harald</namePart><namePart type="family">Gaspar</namePart><affiliation>Institute of Human Genetics, Heidelberg University, Heidelberg, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Art</namePart><namePart type="family">Grix</namePart><affiliation>Genetics Department, Kaiser Permanente, Sacramento, California, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Dafne</namePart><namePart type="family">Horovitz</namePart><affiliation>Centro de Genetica Medica, Instituto Fernandes Figueira-FIOCRUZ, Rio de Janeiro, Brazil</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Erin</namePart><namePart type="family">Kanetzke</namePart><affiliation>Division of Medical Genetics, Department of Pediatrics, Saint Louis University, St. Louis, Missouri, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Hulya</namePart><namePart type="family">Kayserili</namePart><affiliation>Department of Medical Genetics, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Dorit</namePart><namePart type="family">Lev</namePart><affiliation>Institute of Medical Genetics, Wolfson Medical Center, Holon, Israel</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Sarah M</namePart><namePart type="family">Nikkel</namePart><affiliation>Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Mary</namePart><namePart type="family">Norton</namePart><affiliation>Department of Obstetrics and Gynecology, Stanford University School of Medicine/Lucile and Packard Children's Hospital at Stanford University, Stanford, California, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Richard</namePart><namePart type="family">Roberts</namePart><affiliation>Genetics and Prenatal Diagnostic Center, Corpus Christi, Texas, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Howard</namePart><namePart type="family">Saal</namePart><affiliation>Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">G B</namePart><namePart type="family">Schaefer</namePart><affiliation>Division of Medical Genetics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Adele</namePart><namePart type="family">Schneider</namePart><affiliation>Genetics Division, Einstein Medical Center, Philadelphia, Pennsylvania, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Erika K</namePart><namePart type="family">Smith</namePart><affiliation>Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ellen</namePart><namePart type="family">Sowry</namePart><affiliation>Division of Medical Genetics, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">M Anne</namePart><namePart type="family">Spence</namePart><affiliation>Department of Pediatrics, University of California, Irvine, California, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Stavit A</namePart><namePart type="family">Shalev</namePart><affiliation>Genetics Institute, Emek Medical Center, Afula, Israel</affiliation><affiliation>Rappaport faculty of Medicine, Technion, Haifa, Israel</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Carlos E</namePart><namePart type="family">Steiner</namePart><affiliation>Department of Medical Genetics, School of Medical Sciences, Universidade Estadual de Campinas (UNICAMP), Campinas, Sao Paulo, Brazil</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Elizabeth M</namePart><namePart type="family">Thompson</namePart><affiliation>Clinical Genetics Unit, SA Pathology, Women's and Children's Hospital and University of Adelaide, Adelaide, South Australia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Thomas L</namePart><namePart type="family">Winder</namePart><affiliation>Prevention Genetics, Marshfield, Wisconsin, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Joan Z</namePart><namePart type="family">Balog</namePart><affiliation>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Donald W</namePart><namePart type="family">Hadley</namePart><affiliation>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Nan</namePart><namePart type="family">Zhou</namePart><affiliation>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Daniel E</namePart><namePart type="family">Pineda-Alvarez</namePart><affiliation>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Erich</namePart><namePart type="family">Roessler</namePart><affiliation>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal" displayLabel="corresp"><namePart type="given">Maximilian</namePart><namePart type="family">Muenke</namePart><affiliation>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA</affiliation><affiliation>E-mail: mamuenke@mail.nih.gov</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</genre><originInfo><publisher>BMJ Publishing Group Ltd</publisher><dateIssued encoding="w3cdtf">2012-07</dateIssued><copyrightDate encoding="w3cdtf">2012</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><abstract>Background Holoprosencephaly (HPE), the most common malformation of the human forebrain, may result from mutations in over 12 genes. Sonic Hedgehog (SHH) was the first such gene discovered; mutations in SHH remain the most common cause of non-chromosomal HPE. The severity spectrum is wide, ranging from incompatibility with extrauterine life to isolated midline facial differences. Objective To characterise genetic and clinical findings in individuals with SHH mutations. Methods Through the National Institutes of Health and collaborating centres, DNA from approximately 2000 individuals with HPE spectrum disorders were analysed for SHH variations. Clinical details were examined and combined with published cases. Results This study describes 396 individuals, representing 157 unrelated kindreds, with SHH mutations; 141 (36%) have not been previously reported. SHH mutations more commonly resulted in non-HPE (64%) than frank HPE (36%), and non-HPE was significantly more common in patients with SHH than in those with mutations in the other common HPE related genes (p<0.0001 compared to ZIC2 or SIX3). Individuals with truncating mutations were significantly more likely to have frank HPE than those with non-truncating mutations (49% vs 35%, respectively; p=0.012). While mutations were significantly more common in the N-terminus than in the C-terminus (including accounting for the relative size of the coding regions, p=0.00010), no specific genotype―phenotype correlations could be established regarding mutation location. Conclusions SHH mutations overall result in milder disease than mutations in other common HPE related genes. HPE is more frequent in individuals with truncating mutations, but clinical predictions at the individual level remain elusive.</abstract><note type="footnotes">BDS and KAB contributed equally to this work. The views expressed by KAB in this article are those of the author and do not necessarily reflect the official policy or position of the Department of the Army, nor the US government.</note><subject><genre>keywords</genre><topic>Holoprosencephaly</topic><topic>Sonic Hedgehog</topic><topic>SHH</topic><topic>genetics</topic><topic>genome-wide</topic><topic>academic medicine</topic><topic>adrenal disorders</topic><topic>anterior segment disease</topic><topic>cancer: breast</topic><topic>cancer: CNS</topic><topic>cytogenetics</topic><topic>molecular genetics</topic><topic>clinical genetics</topic><topic>developmental</topic><topic>diagnosis</topic><topic>guidelines</topic><topic>congenital heart disease</topic><topic>epigenetics</topic><topic>genetic screening/counselling</topic><topic>aneuploidy</topic><topic>chromosomal</topic><topic>ethics</topic><topic>complex traits</topic><topic>neurosciences</topic></subject><relatedItem type="host"><titleInfo><title>Journal of Medical Genetics</title></titleInfo><titleInfo type="abbreviated"><title>J Med Genet</title></titleInfo><genre type="journal" authority="ISTEX" authorityURI="https://publication-type.data.istex.fr" valueURI="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</genre><identifier type="ISSN">0022-2593</identifier><identifier type="eISSN">1468-6244</identifier><identifier type="PublisherID">jmg</identifier><identifier type="PublisherID-hwp">jmedgenet</identifier><identifier type="PublisherID-nlm-ta">J Med Genet</identifier><part><date>2012</date><detail type="volume"><caption>vol.</caption><number>49</number></detail><detail type="issue"><caption>no.</caption><number>7</number></detail><extent unit="pages"><start>473</start></extent></part></relatedItem><identifier type="istex">BFFAC78ABF1C5ADDDE35769A4C10022F3A316AE5</identifier><identifier type="ark">ark:/67375/NVC-4ZG5RTLZ-T</identifier><identifier type="DOI">10.1136/jmedgenet-2012-101008</identifier><identifier type="href">jmedgenet-49-473.pdf</identifier><identifier type="ArticleID">jmedgenet-2012-101008</identifier><identifier type="local">jmedgenet;49/7/473</identifier><accessCondition type="use and reproduction" contentType="copyright">© 2012, Published by the BMJ Publishing Group Limited. 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