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, NSW, Australia.
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
medRxiv. 2024 Jul 31:2024.07.29.24311195. doi: 10.1101/2024.07.29.24311195.
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.
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.
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 a 9th sarcomere gene with definitive HCM association. With new evidence, two genes were curated for multiple inheritance patterns ( disputed for autosomal dominant but moderate for autosomal recessive; strong for autosomal dominant and definitive for recessive). 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: and (limited), and (moderate), and (definitive).
We report 29 genes with definitive, strong or moderate evidence of causation for HCM or isolated LVH, 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，当时整理了57个与HCM相关的基因，首次对基因与疾病的关联性进行了系统评估。在此，我们报告临床基因组学遗传性心血管疾病基因整理专家小组（HCVD - 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。
采用临床基因组学系统基因整理框架，对HCM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 - 3年，则将其纳入。纳入有文献表明与HCM相关的新基因进行初步评估。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进行汇报，HCVD - GCEP由来自6个国家21个机构的29名成员组成。
重新整理了31个基因，并整理了另外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个从有限关联变为有限关联，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个从中度关联变为明确关联。其中，3个（10%）基因在临床相关性上得到了提升，包括第9个与HCM明确相关的肌节基因。基于新证据，为两个基因整理了多种遗传模式（常染色体显性遗传有争议但常染色体隐性遗传为中度关联；常染色体显性遗传为强关联且隐性遗传为明确关联）。为一种半显性遗传模式（明确关联）整理了一个基因。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中的变异进行临床报告。整理了最近报道可导致HCM的5个基因：[具体基因1]和[具体基因2]（有限关联），[具体基因3]和[具体基因4]（中度关联），以及[具体基因5]（明确关联）。
我们报告了29个基因，它们有明确、强烈或中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。
