Journal of the American College of Cardiology · 2025
Genes Associated With Hypertrophic Cardiomyopathy: A Reappraisal by the ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel.
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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
Аннотация
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.
OBJECTIVES: The authors report work by the Clinical Genome Resource Hereditary Cardiovascular Disease (HCVD) Gene Curation Expert Panel (GCEP) to reappraise the clinical validity of previously curated and new putative HCM genes.
METHODS: The Clinical Genome Resource systematic gene curation framework was used to reclassify 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 to 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 recurated and an additional 5 new potential HCM-associated genes were curated. Among the recurated 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, 2 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 semidominant 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 left ventricular hypertrophy, including sarcomere, sarcomere-associated, and syndromic conditions.
OBJECTIVES: The authors report work by the Clinical Genome Resource Hereditary Cardiovascular Disease (HCVD) Gene Curation Expert Panel (GCEP) to reappraise the clinical validity of previously curated and new putative HCM genes.
METHODS: The Clinical Genome Resource systematic gene curation framework was used to reclassify 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 to 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 recurated and an additional 5 new potential HCM-associated genes were curated. Among the recurated 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, 2 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 semidominant 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 left ventricular hypertrophy, including sarcomere, sarcomere-associated, and syndromic conditions.