Genotypic and phenotypic analysis of 396 individuals with mutations in Sonic Hedgehog
Identifieur interne : 000517 ( France/Analysis ); précédent : 000516; suivant : 000518Genotypic and phenotypic analysis of 396 individuals with mutations in Sonic Hedgehog
Auteurs : Benjamin D. Solomon [États-Unis] ; Kelly A. Bear [États-Unis] ; Adrian Wyllie [États-Unis] ; Amelia A. Keaton [États-Unis] ; Christele Dubourg [France] ; Veronique David [France] ; Sandra Mercier [France] ; Sylvie Odent [France] ; Ute Hehr [Allemagne] ; Aimee Paulussen [Pays-Bas] ; Nancy J. Clegg [États-Unis] ; Mauricio R. Delgado [États-Unis] ; Sherri J. Bale [États-Unis] ; Felicitas Lacbawan [États-Unis] ; Holly H. Ardinger [États-Unis] ; Arthur S. Aylsworth [États-Unis] ; Ntombenhle Louisa Bhengu [Afrique du Sud] ; Stephen Braddock [États-Unis] ; Karen Brookhyser [États-Unis] ; Barbara Burton [États-Unis] ; Harald Gaspar [Allemagne] ; Art Grix [États-Unis] ; Dafne Horovitz [Brésil] ; Erin Kanetzke [États-Unis] ; Hulya Kayserili [Turquie] ; Dorit Lev [Israël] ; Sarah M. Nikkel [Canada] ; Mary Norton [États-Unis] ; Richard Roberts [États-Unis] ; Howard Saal [États-Unis] ; G B Schaefer [États-Unis] ; Adele Schneider [États-Unis] ; Erika K. Smith [Canada] ; Ellen Sowry [États-Unis] ; M Anne Spence [États-Unis] ; Stavit A. Shalev [Israël] ; Carlos E. Steiner [Brésil] ; Elizabeth M. Thompson [Australie] ; Thomas L. Winder [États-Unis] ; Joan Z. Balog [États-Unis] ; Donald W. Hadley [États-Unis] ; Nan Zhou [États-Unis] ; Daniel E. Pineda-Alvarez [États-Unis] ; Erich Roessler [États-Unis] ; Maximilian Muenke [États-Unis]Source :
- Journal of Medical Genetics [ 0022-2593 ] ; 2012-07.
Descripteurs français
- Wicri :
- topic : Génétique, Microforme.
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:
- https://api.istex.fr/document/BFFAC78ABF1C5ADDDE35769A4C10022F3A316AE5/fulltext/pdf
- http://www.hal.inserm.fr/inserm-00718148
DOI: 10.1136/jmedgenet-2012-101008
Affiliations:
- Afrique du Sud, Allemagne, Australie, Brésil, Canada, France, Israël, Pays-Bas, Turquie, États-Unis
- Arkansas, Australie-Méridionale, Bade-Wurtemberg, Californie, Caroline du Nord, District de Karlsruhe, Illinois, Maryland, Missouri (État), Ohio, Pennsylvanie, Région Bretagne, Texas, Wisconsin, État de Rio de Janeiro, État de São Paulo
- Campinas, Heidelberg, Rennes, Rio de Janeiro, São Paulo
- Université d'État de Campinas, Université de Rennes 1
Links toward previous steps (curation, corpus...)
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- to stream Main, to step Curation: 007759
- to stream Main, to step Exploration: 007759
- to stream France, to step Extraction: 000517
Links to Exploration step
ISTEX:BFFAC78ABF1C5ADDDE35769A4C10022F3A316AE5Le document en format XML
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Regensburg</wicri:regionArea><wicri:noRegion>Regensburg</wicri:noRegion><wicri:noRegion>Regensburg</wicri:noRegion></affiliation></author><author><name sortKey="Paulussen, Aimee" sort="Paulussen, Aimee" uniqKey="Paulussen A" first="Aimee" last="Paulussen">Aimee Paulussen</name><affiliation wicri:level="1"><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Clinical Genetics, Maastricht University Medical Center (MUMC+), Maastricht</wicri:regionArea><wicri:noRegion>Maastricht</wicri:noRegion></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 wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Texas Scottish Rite Hospital for Children, Dallas, Texas</wicri:regionArea><placeName><region type="state">Texas</region></placeName></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 wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Texas Scottish Rite Hospital for Children, Dallas, Texas</wicri:regionArea><placeName><region type="state">Texas</region></placeName></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 wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>GeneDx, Gaithersburg, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Lacbawan, Felicitas" sort="Lacbawan, Felicitas" uniqKey="Lacbawan F" first="Felicitas" last="Lacbawan">Felicitas Lacbawan</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Molecular Genetics Pathology, Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio</wicri:regionArea><placeName><region type="state">Ohio</region></placeName></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 wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Section of Genetics, Department of Pediatrics, Children's Mercy Hospitals and Clinics, Kansas City, Missouri</wicri:regionArea><placeName><region type="state">Missouri (État)</region></placeName></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 wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics, University of North Carolina, Chapel Hill, North Carolina</wicri:regionArea><placeName><region type="state">Caroline du Nord</region></placeName></affiliation><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Genetics, University of North Carolina, Chapel Hill, North Carolina</wicri:regionArea><placeName><region type="state">Caroline du Nord</region></placeName></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 wicri:level="1"><country xml:lang="fr">Afrique du Sud</country><wicri:regionArea>Department of Human Genetics Corner Hospital and De Korte, Johannesburg</wicri:regionArea><wicri:noRegion>Johannesburg</wicri:noRegion></affiliation></author><author><name sortKey="Braddock, Stephen" sort="Braddock, Stephen" uniqKey="Braddock S" first="Stephen" last="Braddock">Stephen Braddock</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Medical Genetics, Department of Pediatrics, Saint Louis University, St. Louis, Missouri</wicri:regionArea><placeName><region type="state">Missouri (État)</region></placeName></affiliation></author><author><name sortKey="Brookhyser, Karen" sort="Brookhyser, Karen" uniqKey="Brookhyser K" first="Karen" last="Brookhyser">Karen Brookhyser</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Genetics Department, Kaiser Permanente, Sacramento, California</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Burton, Barbara" sort="Burton, Barbara" uniqKey="Burton B" first="Barbara" last="Burton">Barbara Burton</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics, Northwestern University Feinberg School of Medicine and Division of Genetics, Birth Defects and Metabolism, Lurie Children's Hospital, Chicago, Illinois</wicri:regionArea><placeName><region type="state">Illinois</region></placeName></affiliation></author><author><name sortKey="Gaspar, Harald" sort="Gaspar, Harald" uniqKey="Gaspar H" first="Harald" last="Gaspar">Harald Gaspar</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Human Genetics, Heidelberg University, Heidelberg</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Karlsruhe</region><settlement type="city">Heidelberg</settlement></placeName></affiliation></author><author><name sortKey="Grix, Art" sort="Grix, Art" uniqKey="Grix A" first="Art" last="Grix">Art Grix</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Genetics Department, Kaiser Permanente, Sacramento, California</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Horovitz, Dafne" sort="Horovitz, Dafne" uniqKey="Horovitz D" first="Dafne" last="Horovitz">Dafne Horovitz</name><affiliation wicri:level="3"><country xml:lang="fr">Brésil</country><wicri:regionArea>Centro de Genetica Medica, Instituto Fernandes Figueira-FIOCRUZ, Rio de Janeiro</wicri:regionArea><placeName><settlement type="city">Rio de Janeiro</settlement><region type="state">État de Rio de Janeiro</region></placeName></affiliation></author><author><name sortKey="Kanetzke, Erin" sort="Kanetzke, Erin" uniqKey="Kanetzke E" first="Erin" last="Kanetzke">Erin Kanetzke</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Medical Genetics, Department of Pediatrics, Saint Louis University, St. Louis, Missouri</wicri:regionArea><placeName><region type="state">Missouri (État)</region></placeName></affiliation></author><author><name sortKey="Kayserili, Hulya" sort="Kayserili, Hulya" uniqKey="Kayserili H" first="Hulya" last="Kayserili">Hulya Kayserili</name><affiliation wicri:level="1"><country xml:lang="fr">Turquie</country><wicri:regionArea>Department of Medical Genetics, Istanbul Medical Faculty, Istanbul University, Istanbul</wicri:regionArea><wicri:noRegion>Istanbul</wicri:noRegion></affiliation></author><author><name sortKey="Lev, Dorit" sort="Lev, Dorit" uniqKey="Lev D" first="Dorit" last="Lev">Dorit Lev</name><affiliation wicri:level="1"><country xml:lang="fr">Israël</country><wicri:regionArea>Institute of Medical Genetics, Wolfson Medical Center, Holon</wicri:regionArea><wicri:noRegion>Holon</wicri:noRegion></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 wicri:level="1"><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario</wicri:regionArea><wicri:noRegion>Ontario</wicri:noRegion></affiliation></author><author><name sortKey="Norton, Mary" sort="Norton, Mary" uniqKey="Norton M" first="Mary" last="Norton">Mary Norton</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Obstetrics and Gynecology, Stanford University School of Medicine/Lucile and Packard Children's Hospital at Stanford University, Stanford, California</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Roberts, Richard" sort="Roberts, Richard" uniqKey="Roberts R" first="Richard" last="Roberts">Richard Roberts</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Genetics and Prenatal Diagnostic Center, Corpus Christi, Texas</wicri:regionArea><placeName><region type="state">Texas</region></placeName></affiliation></author><author><name sortKey="Saal, Howard" sort="Saal, Howard" uniqKey="Saal H" first="Howard" last="Saal">Howard Saal</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio</wicri:regionArea><placeName><region type="state">Ohio</region></placeName></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 wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Medical Genetics, University of Arkansas for Medical Sciences, Little Rock, Arkansas</wicri:regionArea><placeName><region type="state">Arkansas</region></placeName></affiliation></author><author><name sortKey="Schneider, Adele" sort="Schneider, Adele" uniqKey="Schneider A" first="Adele" last="Schneider">Adele Schneider</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Genetics Division, Einstein Medical Center, Philadelphia, Pennsylvania</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></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 wicri:level="1"><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario</wicri:regionArea><wicri:noRegion>Ontario</wicri:noRegion></affiliation></author><author><name sortKey="Sowry, Ellen" sort="Sowry, Ellen" uniqKey="Sowry E" first="Ellen" last="Sowry">Ellen Sowry</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Medical Genetics, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></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 wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics, University of California, Irvine, California</wicri:regionArea><placeName><region type="state">Californie</region></placeName></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 wicri:level="1"><country xml:lang="fr">Israël</country><wicri:regionArea>Genetics Institute, Emek Medical Center, Afula</wicri:regionArea><wicri:noRegion>Afula</wicri:noRegion></affiliation><affiliation wicri:level="1"><country xml:lang="fr">Israël</country><wicri:regionArea>Rappaport faculty of Medicine, Technion, Haifa</wicri:regionArea><wicri:noRegion>Haifa</wicri:noRegion></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 wicri:level="4"><country xml:lang="fr">Brésil</country><wicri:regionArea>Department of Medical Genetics, School of Medical Sciences, Universidade Estadual de Campinas (UNICAMP), Campinas, Sao Paulo</wicri:regionArea><placeName><settlement type="city">São Paulo</settlement><region type="state">État de São Paulo</region><settlement type="city">Campinas</settlement></placeName><orgName type="university">Université d'État de Campinas</orgName></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 wicri:level="2"><country>Australie</country><placeName><region type="state">Australie-Méridionale</region></placeName><wicri:cityArea>Clinical Genetics Unit, SA Pathology, Women's and Children's Hospital and University of Adelaide, Adelaide</wicri:cityArea></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 wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Prevention Genetics, Marshfield, Wisconsin</wicri:regionArea><placeName><region type="state">Wisconsin</region></placeName></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 wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></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 wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Zhou, Nan" sort="Zhou, Nan" uniqKey="Zhou N" first="Nan" last="Zhou">Nan Zhou</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></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 wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Roessler, Erich" sort="Roessler, Erich" uniqKey="Roessler E" first="Erich" last="Roessler">Erich Roessler</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Muenke, Maximilian" sort="Muenke, Maximilian" uniqKey="Muenke M" first="Maximilian" last="Muenke">Maximilian Muenke</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation><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><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Génétique</term><term>Microforme</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><affiliations><list><country><li>Afrique du Sud</li><li>Allemagne</li><li>Australie</li><li>Brésil</li><li>Canada</li><li>France</li><li>Israël</li><li>Pays-Bas</li><li>Turquie</li><li>États-Unis</li></country><region><li>Arkansas</li><li>Australie-Méridionale</li><li>Bade-Wurtemberg</li><li>Californie</li><li>Caroline du Nord</li><li>District de Karlsruhe</li><li>Illinois</li><li>Maryland</li><li>Missouri (État)</li><li>Ohio</li><li>Pennsylvanie</li><li>Région Bretagne</li><li>Texas</li><li>Wisconsin</li><li>État de Rio de Janeiro</li><li>État de São Paulo</li></region><settlement><li>Campinas</li><li>Heidelberg</li><li>Rennes</li><li>Rio de Janeiro</li><li>São Paulo</li></settlement><orgName><li>Université d'État de Campinas</li><li>Université de Rennes 1</li></orgName></list><tree><country name="États-Unis"><region name="Maryland"><name sortKey="Solomon, Benjamin D" sort="Solomon, Benjamin D" uniqKey="Solomon B" first="Benjamin D" last="Solomon">Benjamin D. Solomon</name></region><name sortKey="Ardinger, Holly H" sort="Ardinger, Holly H" uniqKey="Ardinger H" first="Holly H" last="Ardinger">Holly H. Ardinger</name><name sortKey="Aylsworth, Arthur S" sort="Aylsworth, Arthur S" uniqKey="Aylsworth A" first="Arthur S" last="Aylsworth">Arthur S. Aylsworth</name><name sortKey="Aylsworth, Arthur S" sort="Aylsworth, Arthur S" uniqKey="Aylsworth A" first="Arthur S" last="Aylsworth">Arthur S. Aylsworth</name><name sortKey="Bale, Sherri J" sort="Bale, Sherri J" uniqKey="Bale S" first="Sherri J" last="Bale">Sherri J. Bale</name><name sortKey="Balog, Joan Z" sort="Balog, Joan Z" uniqKey="Balog J" first="Joan Z" last="Balog">Joan Z. Balog</name><name sortKey="Bear, Kelly A" sort="Bear, Kelly A" uniqKey="Bear K" first="Kelly A" last="Bear">Kelly A. Bear</name><name sortKey="Bear, Kelly A" sort="Bear, Kelly A" uniqKey="Bear K" first="Kelly A" last="Bear">Kelly A. Bear</name><name sortKey="Braddock, Stephen" sort="Braddock, Stephen" uniqKey="Braddock S" first="Stephen" last="Braddock">Stephen Braddock</name><name sortKey="Brookhyser, Karen" sort="Brookhyser, Karen" uniqKey="Brookhyser K" first="Karen" last="Brookhyser">Karen Brookhyser</name><name sortKey="Burton, Barbara" sort="Burton, Barbara" uniqKey="Burton B" first="Barbara" last="Burton">Barbara Burton</name><name sortKey="Clegg, Nancy J" sort="Clegg, Nancy J" uniqKey="Clegg N" first="Nancy J" last="Clegg">Nancy J. Clegg</name><name sortKey="Delgado, Mauricio R" sort="Delgado, Mauricio R" uniqKey="Delgado M" first="Mauricio R" last="Delgado">Mauricio R. Delgado</name><name sortKey="Grix, Art" sort="Grix, Art" uniqKey="Grix A" first="Art" last="Grix">Art Grix</name><name sortKey="Hadley, Donald W" sort="Hadley, Donald W" uniqKey="Hadley D" first="Donald W" last="Hadley">Donald W. Hadley</name><name sortKey="Kanetzke, Erin" sort="Kanetzke, Erin" uniqKey="Kanetzke E" first="Erin" last="Kanetzke">Erin Kanetzke</name><name sortKey="Keaton, Amelia A" sort="Keaton, Amelia A" uniqKey="Keaton A" first="Amelia A" last="Keaton">Amelia A. Keaton</name><name sortKey="Lacbawan, Felicitas" sort="Lacbawan, Felicitas" uniqKey="Lacbawan F" first="Felicitas" last="Lacbawan">Felicitas Lacbawan</name><name sortKey="Muenke, Maximilian" sort="Muenke, Maximilian" uniqKey="Muenke M" first="Maximilian" last="Muenke">Maximilian Muenke</name><name sortKey="Norton, Mary" sort="Norton, Mary" uniqKey="Norton M" first="Mary" last="Norton">Mary Norton</name><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><name sortKey="Roberts, Richard" sort="Roberts, Richard" uniqKey="Roberts R" first="Richard" last="Roberts">Richard Roberts</name><name sortKey="Roessler, Erich" sort="Roessler, Erich" uniqKey="Roessler E" first="Erich" last="Roessler">Erich Roessler</name><name sortKey="Saal, Howard" sort="Saal, Howard" uniqKey="Saal H" first="Howard" last="Saal">Howard Saal</name><name sortKey="Schaefer, G B" sort="Schaefer, G B" uniqKey="Schaefer G" first="G B" last="Schaefer">G B Schaefer</name><name sortKey="Schneider, Adele" sort="Schneider, Adele" uniqKey="Schneider A" first="Adele" last="Schneider">Adele Schneider</name><name sortKey="Sowry, Ellen" sort="Sowry, Ellen" uniqKey="Sowry E" first="Ellen" last="Sowry">Ellen Sowry</name><name sortKey="Spence, M Anne" sort="Spence, M Anne" uniqKey="Spence M" first="M Anne" last="Spence">M Anne Spence</name><name sortKey="Winder, Thomas L" sort="Winder, Thomas L" uniqKey="Winder T" first="Thomas L" last="Winder">Thomas L. Winder</name><name sortKey="Wyllie, Adrian" sort="Wyllie, Adrian" uniqKey="Wyllie A" first="Adrian" last="Wyllie">Adrian Wyllie</name><name sortKey="Zhou, Nan" sort="Zhou, Nan" uniqKey="Zhou N" first="Nan" last="Zhou">Nan Zhou</name></country><country name="France"><region name="Région Bretagne"><name sortKey="Dubourg, Christele" sort="Dubourg, Christele" uniqKey="Dubourg C" first="Christele" last="Dubourg">Christele Dubourg</name></region><name sortKey="David, Veronique" sort="David, Veronique" uniqKey="David V" first="Veronique" last="David">Veronique David</name><name sortKey="David, Veronique" sort="David, Veronique" uniqKey="David V" first="Veronique" last="David">Veronique David</name><name sortKey="Dubourg, Christele" sort="Dubourg, Christele" uniqKey="Dubourg C" first="Christele" last="Dubourg">Christele Dubourg</name><name sortKey="Mercier, Sandra" sort="Mercier, Sandra" uniqKey="Mercier S" first="Sandra" last="Mercier">Sandra Mercier</name><name sortKey="Mercier, Sandra" sort="Mercier, Sandra" uniqKey="Mercier S" first="Sandra" last="Mercier">Sandra Mercier</name><name sortKey="Odent, Sylvie" sort="Odent, Sylvie" uniqKey="Odent S" first="Sylvie" last="Odent">Sylvie Odent</name><name sortKey="Odent, Sylvie" sort="Odent, Sylvie" uniqKey="Odent S" first="Sylvie" last="Odent">Sylvie Odent</name></country><country name="Allemagne"><noRegion><name sortKey="Hehr, Ute" sort="Hehr, Ute" uniqKey="Hehr U" first="Ute" last="Hehr">Ute Hehr</name></noRegion><name sortKey="Gaspar, Harald" sort="Gaspar, Harald" uniqKey="Gaspar H" first="Harald" last="Gaspar">Harald Gaspar</name><name sortKey="Hehr, Ute" sort="Hehr, Ute" uniqKey="Hehr U" first="Ute" last="Hehr">Ute Hehr</name></country><country name="Pays-Bas"><noRegion><name sortKey="Paulussen, Aimee" sort="Paulussen, Aimee" uniqKey="Paulussen A" first="Aimee" last="Paulussen">Aimee Paulussen</name></noRegion></country><country name="Afrique du Sud"><noRegion><name sortKey="Bhengu, Ntombenhle Louisa" sort="Bhengu, Ntombenhle Louisa" uniqKey="Bhengu N" first="Ntombenhle Louisa" last="Bhengu">Ntombenhle Louisa Bhengu</name></noRegion></country><country name="Brésil"><region name="État de Rio de Janeiro"><name sortKey="Horovitz, Dafne" sort="Horovitz, Dafne" uniqKey="Horovitz D" first="Dafne" last="Horovitz">Dafne Horovitz</name></region><name sortKey="Steiner, Carlos E" sort="Steiner, Carlos E" uniqKey="Steiner C" first="Carlos E" last="Steiner">Carlos E. Steiner</name></country><country name="Turquie"><noRegion><name sortKey="Kayserili, Hulya" sort="Kayserili, Hulya" uniqKey="Kayserili H" first="Hulya" last="Kayserili">Hulya Kayserili</name></noRegion></country><country name="Israël"><noRegion><name sortKey="Lev, Dorit" sort="Lev, Dorit" uniqKey="Lev D" first="Dorit" last="Lev">Dorit Lev</name></noRegion><name sortKey="Shalev, Stavit A" sort="Shalev, Stavit A" uniqKey="Shalev S" first="Stavit A" last="Shalev">Stavit A. Shalev</name><name sortKey="Shalev, Stavit A" sort="Shalev, Stavit A" uniqKey="Shalev S" first="Stavit A" last="Shalev">Stavit A. Shalev</name></country><country name="Canada"><noRegion><name sortKey="Nikkel, Sarah M" sort="Nikkel, Sarah M" uniqKey="Nikkel S" first="Sarah M" last="Nikkel">Sarah M. Nikkel</name></noRegion><name sortKey="Smith, Erika K" sort="Smith, Erika K" uniqKey="Smith E" first="Erika K" last="Smith">Erika K. Smith</name></country><country name="Australie"><region name="Australie-Méridionale"><name sortKey="Thompson, Elizabeth M" sort="Thompson, Elizabeth M" uniqKey="Thompson E" first="Elizabeth M" last="Thompson">Elizabeth M. Thompson</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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