Hypertrophic Cardiomyopathy Gene Testing: Go Big?

Abstract

Heredity strongly influences multiple cardiovascular disorders, including arrhythmia syndromes, aortic aneurysms, dyslipidemias, cardiomyopathy, and heart failure. Genetic testing has emerged as an effective clinical tool, especially in the cardiomyopathies, because it provides information useful for diagnosis and stratification.1 Genetic testing for clinical diagnosis currently relies on gene panels, where many genes are sequenced simultaneously. With gene panel sequencing, the coding regions of specific genes are first captured and then sequenced. Most mutations detected with this method are single nucleotide polymorphisms or small insertions/deletions. It is also possible to detect larger exonic-level deletions or duplications. Most cardiomyopathy mutations are inherited in an autosomal dominant manner, and these methods can detect heterozygous variants. See Article by Cirino et al Cardiomyopathy gene panels have grown in size and scope, and it has now become commonplace to evaluate 50 to 120 genes in a single test, depending on the specific cardiomyopathy subtype and accompanying cardiac arrhythmias.2 Hypertrophic cardiomyopathy (HCM) is a more genetically restricted disease compared with dilated cardiomyopathy. The majority of HCM arises from heterozygous mutations in genes encoding sarcomere proteins with MYH7 and MYBPC3 accounting for 70% to 80% of familial HCM. The limited yield of larger panels combined with the enrichment of MYH7/MYBPC3 mutations has prompted the suggestion that genetic testing for HCM should first focus on these 2 genes.3,4 In contrast, dilated cardiomyopathy is linked to many more genes, with 1 gene, TTN , accounting for 20% of genetic dilated cardiomyopathy, and ≥80 genes explaining an additional fraction.5–7 This genetic heterogeneity has led some to suggest that >1 variant may contribute to disease onset, supporting an oligogenic pathogenesis. The sensitivity of genetic panels for cardiomyopathies ranges from 30% to 50%, depending on the subtype. The rate of variant discovery should improve as …