Identification of sarcomeric variants in probands with a clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC)

Abstract

AimsArrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by ventricular arrhythmias and sudden death. Currently 60% of patients meeting Task Force Criteria (TFC) have an identifiable mutation in one of the desmosomal genes. As much overlap is described between other cardiomyopathies and ARVC, we examined the prevalence of rare, possibly pathogenic sarcomere variants in the ARVC population.MethodsOne hundred and thirty‐seven (137) individuals meeting 2010 TFC for a diagnosis of ARVC, negative for pathogenic desmosomal variants, TMEM43, SCN5A, and PLN were screened for variants in the sarcomere genes (ACTC1, MYBPC3, MYH7, MYL2, MYL3, TNNC1, TNNI3, TNNT2, and TPM1) through either clinical or research genetic testing.ResultsSix probands (6/137, 4%) were found to carry rare variants in the sarcomere genes. These variants have low prevalence in controls, are predicted damaging by Polyphen‐2, and some of the variants are known pathogenic hypertrophic cardiomyopathy mutations. Sarcomere variant carriers had a phenotype that did not differ significantly from desmosomal mutation carriers. As most of these probands were the only affected individuals in their families, however, segregation data are noninformative.ConclusionThese data show variants in the sarcomere can be identified in individuals with an ARVC phenotype. Although rare and predicted damaging, proven functional and segregational evidence that these variants can cause ARVC is lacking. Therefore, caution is warranted in interpreting these variants when identified on large next‐generation sequencing panels for cardiomyopathies.

2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy

“…Sanger sequencing is a reliable method with good coverage of the nucleotides that need to be studied, *Genes with significant excess in cases over ExAc reference samples. 100 Other genes that have been identified in ACM with insufficient or conflicting evidence are ABCC9, 112 TGFB3, 113 TTN, 114 CTNNA3, 115 sarcomeric genes (MYH7, MYBPC3), 116,117 particularly for evaluating a single or a small number of genes. Sanger sequencing is also appropriate for cascade testing in at-risk family members, clinical confirmation of research genetic results, and cosegregation studies.…”

Arrhythmogenic cardiomyopathy: what blood can reveal?

“…Genetic and phenotypic overlap between ACM and other types of cardiomyopathy have been reported, particularly with dilated cardiomyopathy, Brugada syndrome, and hypertrophic cardiomyopathy (Supplemental Table S1). 24 In these cases, differential diagnosis is challenging even with the help of blood genetic tests.…”

Distinct molecular signature of phospholamban p.Arg14del arrhythmogenic cardiomyopathy

“…The pathogenic variant in MYBPC3 (case 5), a sarcomeric gene, had been observed previously in another ARVC case but this may be a chance finding. 24 In case 1, where we observed an overall diminished synapse-associated protein 97 signal intensity and junctional redistribution of glycogen synthase kinase-3 beta, a VUS in the EMD-gene encoding emerin was detected in addition to the pathogenic PLN p.Arg14del variant ( Table 1). Emerin is a nuclear envelope protein implicated in regulating muscle-and heart-specific gene expression and nuclear architecture.…”