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Heterozygous loss-of-function SMC3 variants are associated with variable growth and developmental features.
Ansari, Morad; Faour, Kamli N W; Shimamura, Akiko; Grimes, Graeme; Kao, Emeline M; Denhoff, Erica R; Blatnik, Ana; Ben-Isvy, Daniel; Wang, Lily; Helm, Benjamin M; Firth, Helen; Breman, Amy M; Bijlsma, Emilia K; Iwata-Otsubo, Aiko; de Ravel, Thomy J L; Fusaro, Vincent; Fryer, Alan; Nykamp, Keith; Stühn, Lara G; Haack, Tobias B; Korenke, G Christoph; Constantinou, Panayiotis; Bujakowska, Kinga M; Low, Karen J; Place, Emily; Humberson, Jennifer; Napier, Melanie P; Hoffman, Jessica; Juusola, Jane; Deardorff, Matthew A; Shao, Wanqing; Rockowitz, Shira; Krantz, Ian; Kaur, Maninder; Raible, Sarah; Dortenzio, Victoria; Kliesch, Sabine; Singer-Berk, Moriel; Groopman, Emily; DiTroia, Stephanie; Ballal, Sonia; Srivastava, Siddharth; Rothfelder, Kathrin; Biskup, Saskia; Rzasa, Jessica; Kerkhof, Jennifer; McConkey, Haley; Sadikovic, Bekim; Hilton, Sarah; Banka, Siddharth.
Afiliação
  • Ansari M; South East Scotland Genetic Service, Western General Hospital, Edinburgh, UK; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
  • Faour KNW; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA; Cornelia de Lange Syndrome and Related Disorders Clinic, Boston Children's Hospital, Boston, MA, USA.
  • Shimamura A; Division of Hematology and Oncology, Boston Children's Hospital, Boston, MA, USA.
  • Grimes G; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
  • Kao EM; Institutional Centers for Clinical and Translational Research, Boston Children's Hospital, Boston, MA, USA.
  • Denhoff ER; Institutional Centers for Clinical and Translational Research, Boston Children's Hospital, Boston, MA, USA.
  • Blatnik A; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK; Department of Clinical Cancer Genetics, Institute of Oncology Ljubljana, Ljubljana, Slovenia.
  • Ben-Isvy D; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Medical Sciences, Harvard Medical School, Boston, MA, USA.
  • Wang L; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Medical Sciences, Harvard Medical School, Boston, MA, USA.
  • Helm BM; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
  • Firth H; Clinical Genetics, Addenbrooke's Hospital, Cambridge University Hospitals, Cambridge, UK.
  • Breman AM; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
  • Bijlsma EK; Department of Clinical Genetics, Leiden University Medical Centre, Leiden, the Netherlands.
  • Iwata-Otsubo A; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
  • de Ravel TJL; Centre for Human Genetics, UZ Leuven/Leuven University Hospitals, Leuven, Belgium.
  • Fusaro V; Invitae, San Francisco, CA, USA.
  • Fryer A; Department of Clinical Genetics, Alder Hey Children's Hospital Liverpool, Liverpool, UK.
  • Nykamp K; Invitae, San Francisco, CA, USA.
  • Stühn LG; Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
  • Haack TB; Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
  • Korenke GC; Department of Neuropaediatric and Metabolic Diseases, University Children's Hospital Oldenburg, Oldenburg, Germany.
  • Constantinou P; West of Scotland Centre for Genomic Medicine, Queen Elizabeth University Hospital, Glasgow, UK.
  • Bujakowska KM; Massachusetts Eye and Ear Infirmary, Boston, MA, USA.
  • Low KJ; University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK; University of Bristol, Bristol, UK.
  • Place E; Massachusetts Eye and Ear Infirmary, Boston, MA, USA.
  • Humberson J; University of Virginia Health System, Charlottesville, VA, USA.
  • Napier MP; GeneDx, Gaithersburg, MD, USA.
  • Hoffman J; GeneDx, Gaithersburg, MD, USA.
  • Juusola J; GeneDx, Gaithersburg, MD, USA.
  • Deardorff MA; Departments of Pathology and Pediatrics, Children's Hospital Los Angeles and University of Southern California, Los Angeles, CA, USA.
  • Shao W; Research Computing, Information Technology, Boston Children's Hospital, Boston, MA, USA.
  • Rockowitz S; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA; Research Computing, Information Technology, Boston Children's Hospital, Boston, MA, USA; The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA.
  • Krantz I; Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • Kaur M; Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • Raible S; Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • Dortenzio V; Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • Kliesch S; Department of Clinical and Surgical Andrology, Centre of Reproductive Medicine and Andrology, University Hospital Münster, Münster, Germany.
  • Singer-Berk M; Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Groopman E; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA; Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • DiTroia S; Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Ballal S; Cornelia de Lange Syndrome and Related Disorders Clinic, Boston Children's Hospital, Boston, MA, USA; Division of Gastroenterology, Boston Children's Hospital, Boston, MA, USA.
  • Srivastava S; Cornelia de Lange Syndrome and Related Disorders Clinic, Boston Children's Hospital, Boston, MA, USA; Divison of Neurology, Boston Children's Hospital, Boston, MA, USA.
  • Rothfelder K; Zentrum für Humangenetik, Tübingen, Germany.
  • Biskup S; Zentrum für Humangenetik, Tübingen, Germany; Center for Genomics and Transcriptomics (CeGaT), Tübingen, Germany.
  • Rzasa J; Molecular Diagnostics Program and Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON, Canada.
  • Kerkhof J; Molecular Diagnostics Program and Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON, Canada.
  • McConkey H; Molecular Diagnostics Program and Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON, Canada.
  • Sadikovic B; Molecular Diagnostics Program and Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON, Canada.
  • Hilton S; Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK.
  • Banka S; Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK; Division of Evolution, Infection, and Genomics, School of Biological Sciences, Faculty of Biology, Medicine, and Health, University of Manchester, Manchester, UK.
HGG Adv ; 5(2): 100273, 2024 Apr 11.
Article em En | MEDLINE | ID: mdl-38297832
ABSTRACT
Heterozygous missense variants and in-frame indels in SMC3 are a cause of Cornelia de Lange syndrome (CdLS), marked by intellectual disability, growth deficiency, and dysmorphism, via an apparent dominant-negative mechanism. However, the spectrum of manifestations associated with SMC3 loss-of-function variants has not been reported, leading to hypotheses of alternative phenotypes or even developmental lethality. We used matchmaking servers, patient registries, and other resources to identify individuals with heterozygous, predicted loss-of-function (pLoF) variants in SMC3, and analyzed population databases to characterize mutational intolerance in this gene. Here, we show that SMC3 behaves as an archetypal haploinsufficient gene it is highly constrained against pLoF variants, strongly depleted for missense variants, and pLoF variants are associated with a range of developmental phenotypes. Among 14 individuals with SMC3 pLoF variants, phenotypes were variable but coalesced on low growth parameters, developmental delay/intellectual disability, and dysmorphism, reminiscent of atypical CdLS. Comparisons to individuals with SMC3 missense/in-frame indel variants demonstrated an overall milder presentation in pLoF carriers. Furthermore, several individuals harboring pLoF variants in SMC3 were nonpenetrant for growth, developmental, and/or dysmorphic features, and some had alternative symptomatologies with rational biological links to SMC3. Analyses of tumor and model system transcriptomic data and epigenetic data in a subset of cases suggest that SMC3 pLoF variants reduce SMC3 expression but do not strongly support clustering with functional genomic signatures of typical CdLS. Our finding of substantial population-scale LoF intolerance in concert with variable growth and developmental features in subjects with SMC3 pLoF variants expands the scope of cohesinopathies, informs on their allelic architecture, and suggests the existence of additional clearly LoF-constrained genes whose disease links will be confirmed only by multilayered genomic data paired with careful phenotyping.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Síndrome de Cornélia de Lange / Deficiência Intelectual Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Síndrome de Cornélia de Lange / Deficiência Intelectual Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article