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Minor hypertrophic cardiomyopathy genes, major insights into the genetics of cardiomyopathies

Nature Reviews Cardiology volume 19, pages 151–167 (2022)Cite this article

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Abstract

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.

Key points

  • Cardiomyopathies are often inherited diseases, but highly variable penetrance and the lack of Mendelian genetic variants in substantial numbers of patients increasingly suggests a complex genetic aetiology.

  • Genome-wide association studies have identified large overlaps in significant loci for cardiomyopathies and left ventricular traits, with opposite effects (risk or protective alleles) observed for hypertrophic and dilated cardiomyopathy.

  • Variants in genes encoding non-sarcomeric proteins account for a small proportion of patients with Mendelian hypertrophic cardiomyopathy but are the presumed causal genes at several genome-wide association study loci, expanding their role in cardiomyopathy genetics.

  • These genes have complex genotype–phenotype correlations across different variant classes (common regulatory and rare missense, truncating and biallelic loss-of-function variants), with distinct associations often observed for hypertrophic and dilated cardiomyopathy.

  • Understanding these complex, rare variant associations is essential for variant interpretation in patients with cardiomyopathies, with hypertrophic cardiomyopathy-associated minor gene variants probably more prevalent in understudied populations.

  • The shared genes and pathways identified by these rare and common variant studies provide new insights into cardiomyopathy pathophysiology and propose novel approaches for therapeutic intervention.

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Fig. 1: Exploring the role of common genetic variants in cardiomyopathies.
Fig. 2: Associations between LV traits, cardiomyopathies and variant classes in HCM-related genes encoding non-sarcomeric proteins.
Fig. 3: Location of selected rare variants of interest in minor HCM-associated genes.
Fig. 4: Countries of origin for patients with cardiomyopathy and biallelic truncating variants.
Fig. 5: Cellular locations and functions of proteins encoded by cardiomyopathy-associated genes.

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Acknowledgements

The authors are supported by an Amsterdam Cardiovascular Sciences fellowship, Amsterdam UMC’s PhD scholarship, the Canadian Heart Rhythm Society (George Mines Award), the ESC (Research fellowship grant), the Canadian Institutes of Health Research (reference 169063), the Fonds de Recherche du Québec—Santé (reference 135055 [R.T.]), the Dutch Heart Foundation Netherlands Cardiovascular Research Initiative (CVON; PREDICT2 2018-30), the Netherlands Organization for Scientific Research (VICI fellowship, 016.150.610), the Leducq Foundation (project 17CVD02) and the Horstingstuit Foundation.

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  1. Department of Experimental Cardiology, Heart Centre, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands

    Roddy Walsh, Joost A. Offerhaus & Connie R. Bezzina

  2. Department of Medicine, Cardiovascular Genetics Center, Montreal Heart Institute and Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada

    Rafik Tadros

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R.W. and J.A.O. researched data for the article and wrote the manuscript. All the authors made substantial contributions to discussions of the content and reviewed and/or edited the manuscript before submission.

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Supplementary information

Glossary

Genetic pleiotropy

Variants in a gene can lead to two or more unrelated phenotypes or related conditions in which the direction of effect might differ.

Protein-truncating variants

Variants that disrupt the open reading frame of a transcript, often (but not always) leading to the degradation of the disrupted mRNA through nonsense-mediated decay, which causes haploinsufficiency.

Case–control association testing

Demonstration of a significant aggregated enrichment of rare variants in a gene in case cohorts compared with controls can establish a Mendelian gene–disease association.

ClinGen

ClinGen, the Clinical Genome Resource, is an NIH-funded resource that aims to define the clinical relevance of genes implicated in inherited genetic diseases through structured curation and evaluation of published evidence.

Incomplete penetrance

Only a subset of individuals with a particular pathogenic variant have the clinical phenotype, highlighting the role of other genetic and non-genetic factors.

Biallelic variants

Biallelic loss-of-function variants are homozygous or compound heterozygous variants associated with recessive disease, usually truncating variants but can also be function-altering missense variants, equivalent to ‘human knockouts’.

Haplotypes

A group of alleles that are inherited together; genome-wide association study signals usually comprise haplotypes of numerous common variants in linkage disequilibrium, any of which might be the functional variant.

Expression quantitative trait locus

(eQTL). Shows that genetic variants or loci are associated with changes in gene expression in particular tissues.

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Walsh, R., Offerhaus, J.A., Tadros, R. et al. Minor hypertrophic cardiomyopathy genes, major insights into the genetics of cardiomyopathies. Nat Rev Cardiol 19, 151–167 (2022). https://doi.org/10.1038/s41569-021-00608-2

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