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ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel: Reappraisal of Genes associated with Hypertrophic Cardiomyopathy.
Hespe, Sophie; Waddell, Amber; Asatryan, Babken; Owens, Emma; Thaxton, Courtney; Adduru, Mhy-Lanie; Anderson, Kailyn; Brown, Emily E; Hoffman-Andrews, Lily; Jordan, Elizabeth; Josephs, Katherine; Mayers, Megan; Peters, Stacey; Stafford, Fergus; Bagnall, Richard D; Bronicki, Lucas; Callewaert, Bert; Chahal, C Anwar A; James, Cynthia A; Jarinova, Olga; Landstrom, Andrew P; McNally, Elizabeth M; Murray, Brittney; Muiño-Mosquera, Laura; Parikh, Victoria; Reuter, Chloe; Walsh, Roddy; Wayburn, Bess; Ware, James S; Ingles, Jodie.
Afiliação
  • Hespe S; Genomics and Inherited Disease Program, Garvan Institute of Medical Research, and UNSW Sydney, Sydney, NSW, Australia.
  • Waddell A; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Asatryan B; Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Owens E; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Thaxton C; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Adduru ML; Predictiv Care, San Francisco, CA, USA.
  • Anderson K; Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA.
  • Brown EE; Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
  • Hoffman-Andrews L; Division of Cardiovascular Medicine, Department of Medicine, Center for Inherited Cardiovascular Disease, Perelman School of Medicine at the University of Pennsylvania, Perelman Center for Advanced Medicine, Philadelphia, PA, USA.
  • Jordan E; Division of Human Genetics, Department of Internal Medicine, Ohio State University, Columbus, OH, USA.
  • Josephs K; National Heart and Lung Institute and MRC Laboratory of Medical Science, Imperial College London, London, UK.
  • Mayers M; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Peters S; Department of Cardiology and Genomic Medicine, Royal Melbourne Hospital, Melbourne, Australia.
  • Stafford F; Genomics and Inherited Disease Program, Garvan Institute of Medical Research, and UNSW Sydney, Sydney, NSW, Australia.
  • Bagnall RD; Bioinformatics and Molecular Genetics at Centenary Institute, University of Sydney, Sydney, Australia.
  • Bronicki L; Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.
  • Callewaert B; Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Ontario, Canada.
  • Chahal CAA; Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
  • James CA; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
  • Jarinova O; Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
  • Landstrom AP; Center for Inherited Cardiovascular Diseases, WellSpan Health, Lancaster, Pennsylvania, USA; Mayo Clinic, Rochester, MN, USA; Barts Heart Centre, London, UK, William Harvey Research Institute, Queen Mary University of London, London, UK.
  • McNally EM; Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
  • Murray B; Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
  • Muiño-Mosquera L; Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
  • Parikh V; Department of Pediatrics and Cell Biology, Duke University School of Medicine, Durham, NC, USA.
  • Reuter C; Center for Genetic Medicine, Dept of Medicine (Cardiology), Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
  • Walsh R; Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
  • Wayburn B; Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
  • Ware JS; Division of Pediatric Cardiology, Department of Pediatrics, Ghent University Hospital, Ghent, Belgium.
  • Ingles J; Stanford Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
medRxiv ; 2024 Jul 31.
Article em En | MEDLINE | ID: mdl-39132495
ABSTRACT

Background:

Hypertrophic cardiomyopathy (HCM) is an inherited cardiac condition affecting ~1 in 500 and exhibits marked genetic heterogeneity. Previously published in 2019, 57 HCM-associated genes were curated providing the first systematic evaluation of gene-disease validity. Here we report work by the ClinGen Hereditary Cardiovascular Disorders Gene Curation Expert Panel (HCVD-GCEP) to reappraise the clinical validity of previously curated and new putative HCM genes.

Methods:

The ClinGen systematic gene curation framework was used to re-classify the gene-disease relationships for HCM and related syndromic entities involving left ventricular hypertrophy. Genes previously curated were included if their classification was not definitive, and if the time since curation was >2-3 years. New genes with literature assertions for HCM were included for initial evaluation. Existing genes were curated for new inheritance patterns where evidence existed. Curations were presented on twice monthly calls, with the HCVD-GCEP composed of 29 individuals from 21 institutions across 6 countries.

Results:

Thirty-one genes were re-curated and an additional 5 new potential HCM-associated genes were curated. Among the re-curated genes, 17 (55%) genes changed classification 1 limited and 4 disputed (from no known disease relationship), 9 disputed (from limited), and 3 definitive (from moderate). Among these, 3 (10%) genes had a clinically relevant upgrade, including TNNC1, a 9th sarcomere gene with definitive HCM association. With new evidence, two genes were curated for multiple inheritance patterns (TRIM63, disputed for autosomal dominant but moderate for autosomal recessive; ALPK3, strong for autosomal dominant and definitive for recessive). CSRP3 was curated for a semi-dominant mode of inheritance (definitive). Nine (29%) genes were downgraded to disputed, further discouraging clinical reporting of variants in these genes. Five genes recently reported to cause HCM were curated RPS6KB1 and RBM20 (limited), KLHL24 and MT-TI (moderate), and FHOD3 (definitive).

Conclusions:

We report 29 genes with definitive, strong or moderate evidence of causation for HCM or isolated LVH, including sarcomere, sarcomere-associated and syndromic conditions.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: MedRxiv Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Austrália
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: MedRxiv Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Austrália