ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel: Reappraisal of Genes associated with Hypertrophic Cardiomyopathy

作者：Sophie Hespe, Amber Waddell, Babken Asatryan, Emma Owens, Courtney Thaxton, Mhy-Lanie Adduru, Kailyn M. Anderson, Emily E. Brown, Lily Hoffman‐Andrews, Elizabeth Jordan, Katherine S. Josephs, Megan Mayers, Stacey A. Peters, Fergus Stafford, Richard D. Bagnall, Lucas Bronicki, Bert Louis Callewaert, C. Anwar A. Chahal, Cynthia A. James, Olga Jarinova, Andrew Paul Landstrom, Elizabeth M. McNally, Brittney A. Murray, Laura Muiño Mosquera, Victoria Nicole Parikh, Chloe M. Reuter, Roddy Walsh, Bess Wayburn, James S. Ware, Jodie Ingles · 发表于：medRxiv · 年份：2024 · DOI：10.1101/2024.07.29.24311195 · 被引用次数：11 · 研究领域：Cardiomyopathy and Myosin Studies、Congenital heart defects research、Genomics and Rare Diseases

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...