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
Genomics and Inherited Disease Program, Garvan Institute of Medical Research, and UNSW Sydney, Sydney, New South Wales, Australia.
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
J Am Coll Cardiol. 2025 Feb 25;85(7):727-740. doi: 10.1016/j.jacc.2024.12.010.
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.
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.
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.
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).
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.
肥厚型心肌病（HCM）是一种遗传性心脏疾病，发病率约为1/500，具有显著的遗传异质性。2019年曾发表过相关研究，当时整理出57个与HCM相关的基因，这是对基因与疾病关联性的首次系统评估。
作者报告临床基因组资源遗传性心血管疾病（HCVD）基因整理专家小组（GCEP）的工作，以重新评估先前整理的以及新发现的可能与HCM相关的基因的临床有效性。
采用临床基因组资源系统基因整理框架，对HCM以及涉及左心室肥厚的相关综合征实体的基因与疾病关系进行重新分类。如果先前整理的基因分类不明确，且自整理以来的时间超过2至3年，则将其纳入。有文献表明与HCM相关的新基因也纳入初始评估。对于存在证据的新遗传模式，对现有基因进行整理。整理结果在每月两次的会议上展示，HCVD GCEP由来自6个国家21个机构的29名成员组成。
对31个基因进行了重新整理，并整理出另外5个新的可能与HCM相关的基因。在重新整理的基因中，17个（55%）基因的分类发生了变化：1个从有限关联变为无已知疾病关联，4个从无已知疾病关联变为有争议关联，9个从有限关联变为有争议关联，3个从中等关联变为明确关联。其中，3个（10%）基因在临床上有相关的升级，包括TNNC1，这是第9个与HCM有明确关联的肌节基因。有了新证据后，2个基因被整理为具有多种遗传模式（TRIM63，常染色体显性遗传有争议但常染色体隐性遗传为中等关联；ALPK3，常染色体显性遗传关联强，隐性遗传关联明确）。CSRP3被整理为半显性遗传模式（明确）。9个（29%）基因被降级为有争议关联，进一步不鼓励对这些基因的变异进行临床报告。最近报道的5个导致HCM的基因也被整理：RPS6KB1和RBM20（有限关联），KLHL24和MT-TI（中等关联），以及FHOD3（明确关联）。
我们报告了29个基因，它们有明确、强烈或中等程度的证据表明可导致HCM或孤立性左心室肥厚，包括肌节、肌节相关和综合征性疾病。
