TY - JOUR
T1 - Minor hypertrophic cardiomyopathy genes, major insights into the genetics of cardiomyopathies
AU - Walsh, Roddy
AU - Offerhaus, Joost A.
AU - Tadros, Rafik
AU - Bezzina, Connie R.
N1 - Funding Information: 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. Publisher Copyright: © 2021, Springer Nature Limited.
PY - 2022/3
Y1 - 2022/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85115128996&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41569-021-00608-2
DO - https://doi.org/10.1038/s41569-021-00608-2
M3 - Review article
C2 - 34526680
SN - 1759-5002
VL - 19
SP - 151
EP - 167
JO - Nature Reviews. Cardiology
JF - Nature Reviews. Cardiology
IS - 3
ER -