Jeanne Jury, Thomas Besnard, Wallid Deb, Annick Toutain, Paul Gueguen, Ange-Line Bruel, Arjan Bouman, Danielle Veenma, Tahsin Stefan Barakat, Laura Do Souto Ferreira, Petra J G Zwijnenburg, Sarah Schuhmann, Georgia Vasileiou, Matthieu Egloff, Frédéric Bilan, Anne Mercier, Pascaline Letard, Elsa Leitão, Christopher Schroeder, Christel Depienne, Pierre Blanc, Stéphane Bézieau, Benjamin Cogné, Bertrand Isidor
{"title":"<b>Heterozygous alterations of</b> <i>GTF2I</i> <b>at the Williams-Beuren syndrome's locus cause a neurodevelopmental disorder</b>.","authors":"Jeanne Jury, Thomas Besnard, Wallid Deb, Annick Toutain, Paul Gueguen, Ange-Line Bruel, Arjan Bouman, Danielle Veenma, Tahsin Stefan Barakat, Laura Do Souto Ferreira, Petra J G Zwijnenburg, Sarah Schuhmann, Georgia Vasileiou, Matthieu Egloff, Frédéric Bilan, Anne Mercier, Pascaline Letard, Elsa Leitão, Christopher Schroeder, Christel Depienne, Pierre Blanc, Stéphane Bézieau, Benjamin Cogné, Bertrand Isidor","doi":"10.1136/jmg-2024-110471","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>Williams-Beuren syndrome (WBS) is a well-known neurodevelopmental disorder caused by a copy-number loss at the 7q11.23 locus. Although the 1.5-1.8 Mb recurrent deletion carries several genes of interest, no single gene has been identified in which pathogenic variants cause a neurodevelopmental phenotype. At this locus, <i>GTF2I,</i> encoding the general transcription factor II-I, has been considered as the main candidate gene for the cognitive and behavioural phenotype of WBS, based on clinical observations of cases with atypical 7q.11.23 deletions and functional studies in humans and mice.</p><p><strong>Methods: </strong>Individuals with a neurodevelopmental disorder were identified through a multicentre collaboration using GeneMatcher and the ERN-ITHACA network. They remained undiagnosed following genome/exome sequencing. Clinical evaluations were performed in each participating centre.</p><p><strong>Results: </strong>We identified seven unrelated individuals with <i>de novo</i> variants in <i>GTF2I</i> (two non-sense, two splice-site, one missense, one indel and one intragenic deletion). We also identified one individual with a WBS phenotype and low <i>GTF2I</i> expression identified by RNA sequencing. All eight individuals presented with global developmental delay and facial dysmorphic features, with speech delay and/or autistic features in seven cases. The effect of the two splice-site variants was confirmed by RNA sequencing.</p><p><strong>Conclusion: </strong>Pathogenic heterozygous <i>GTF2I</i> variants cause a neurodevelopmental disorder characterised by global developmental delay with facial dysmorphic features, partly resembling the phenotype observed in individuals affected with WBS.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7000,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medical Genetics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1136/jmg-2024-110471","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
引用次数: 0
Abstract
Purpose: Williams-Beuren syndrome (WBS) is a well-known neurodevelopmental disorder caused by a copy-number loss at the 7q11.23 locus. Although the 1.5-1.8 Mb recurrent deletion carries several genes of interest, no single gene has been identified in which pathogenic variants cause a neurodevelopmental phenotype. At this locus, GTF2I, encoding the general transcription factor II-I, has been considered as the main candidate gene for the cognitive and behavioural phenotype of WBS, based on clinical observations of cases with atypical 7q.11.23 deletions and functional studies in humans and mice.
Methods: Individuals with a neurodevelopmental disorder were identified through a multicentre collaboration using GeneMatcher and the ERN-ITHACA network. They remained undiagnosed following genome/exome sequencing. Clinical evaluations were performed in each participating centre.
Results: We identified seven unrelated individuals with de novo variants in GTF2I (two non-sense, two splice-site, one missense, one indel and one intragenic deletion). We also identified one individual with a WBS phenotype and low GTF2I expression identified by RNA sequencing. All eight individuals presented with global developmental delay and facial dysmorphic features, with speech delay and/or autistic features in seven cases. The effect of the two splice-site variants was confirmed by RNA sequencing.
Conclusion: Pathogenic heterozygous GTF2I variants cause a neurodevelopmental disorder characterised by global developmental delay with facial dysmorphic features, partly resembling the phenotype observed in individuals affected with WBS.
期刊介绍:
Journal of Medical Genetics is a leading international peer-reviewed journal covering original research in human genetics, including reviews of and opinion on the latest developments. Articles cover the molecular basis of human disease including germline cancer genetics, clinical manifestations of genetic disorders, applications of molecular genetics to medical practice and the systematic evaluation of such applications worldwide.