Genetics of hypertrophic cardiomyopathy: established and emerging implications for clinical practice

Abstract

Pathogenic variation in genes encoding proteins of the cardiac sarcomere is responsible for 30%-40% of cases of hypertrophic cardiomyopathy. The main clinical utility of genetic testing is to provide diagnostic confirmation and facilitation of family screening. It also assists in the detection of aetiologies, which require distinct monitoring and treatment approaches. Other clinical applications, including the use of genetic information to inform risk prediction models, have been limited by the challenge of establishing robust genotype-phenotype correlations with actionable consequences, but new data on the interaction between rare and common genetic variation, as well as the emergence of therapies targeting disease-specific pathogenic mechanisms, herald a new era for genetic testing in routine practice.

Keywords: Genetic testing; Genetic therapy; Hypertrophic cardiomyopathy; Myosin inhibitors; Precision therapy.

Graphical Abstract

Established (in blue) and emerging/potential (in orange) applications of genetic testing in hypertrophic cardiomyopathy.

Figure 1

Schematic representing different modalities of nucleic acid therapies in hypertrophic cardiomyopathy. (A) Gene transfer. (B) Exon skipping. (C) Genome editing with the CRISPR/Cas9 system; gene editing can also currently be achieved with base editors. (D) Allele silencing with RNAi. AON, antisense oligonucleotide; cDNA, complementary deoxyribonucleic acid; mRNA, messenger ribonucleic acid; pre-mRNA, precursor messenger ribonucleic acid; RISC, RNA-induced silencing complex. Reproduced and modified with permission from Maltês and Lopes.