Hypertrophic cardiomyopathy (HCM) was traditionally described as an autosomal dominant Mendelian disease but is now increasingly recognized as having a complex genetic aetiology. Although eight core genes encoding sarcomeric proteins account for >90% of the pathogenic variants in patients with HCM, variants in several additional genes (ACTN2, ALPK3, CSRP3, FHOD3, FLNC, JPH2, KLHL24, PLN and TRIM63), encoding non-sarcomeric proteins with diverse functions, have been shown to be disease-causing in a small number of patients. Genome-wide association studies (GWAS) have identified numerous loci in cardiomyopathy case–control studies and biobank investigations of left ventricular functional traits. Genes associated with Mendelian cardiomyopathy are enriched in the putative causal gene lists at these loci. Intriguingly, many loci are associated with both HCM and dilated cardiomyopathy but with opposite directions of effect on left ventricular traits, highlighting a genetic basis underlying the contrasting pathophysiological effects observed in each condition. This overlap extends to rare Mendelian variants with distinct variant classes in several genes associated with HCM and dilated cardiomyopathy. In this Review, we appraise the complex contribution of the non-sarcomeric, HCM-associated genes to cardiomyopathies across a range of variant classes (from common non-coding variants of individually low effect size to complete gene knockouts), which provides insights into the genetic basis of cardiomyopathies, causal genes at GWAS loci and the application of clinical genetic testing.

肥厚型心肌病 (HCM) 传统上被描述为常染色体显性遗传的孟德尔疾病，但现在越来越多地被认为具有复杂的遗传病因。虽然编码肌节蛋白的八个核心基因占 HCM 患者致病变异的 90% 以上，但几个其他基因的变异（ACTN2、ALPK3、CSRP3、FHOD3、FLNC、JPH2、KLHL24、PLN和TRIM63), 编码具有不同功能的非肌节蛋白，已被证明在少数患者中引起疾病​​。全基因组关联研究 (GWAS) 已经在心肌病病例对照研究和左心室功能特征的生物库调查中确定了许多位点。与孟德尔心肌病相关的基因在这些位点的假定致病基因列表中得到丰富。有趣的是，许多位点与 HCM 和扩张型心肌病相关，但对左心室特征的影响方向相反，突出了在每种情况下观察到的不同病理生理效应背后的遗传基础。这种重叠扩展到罕见的孟德尔变异，在与 HCM 和扩张型心肌病相关的几个基因中具有不同的变异类别。在这篇评论中，