Sarcomere variants in arrhythmogenic cardiomyopathy: Pathogenic factor or bystander?

Arrhythmogenic cardiomyopathy (ACM) is an inherited heart muscle disease, which is mainly caused by desmosomal mutations. Sarcomere variants were the primary genetic basis of hypertrophic cardiomyopathy (HCM) and were recently detected in arrhythmogenic cardiomyopathy (ACM). Our aim is to seek potential pathogenic variants of sarcomere genes in our ACM cohort and describe their characteristics.

We performed targeted sequencing of 14 sarcomere genes in 84 patients with ACM and set strict criteria to identify potential pathogenic variants. Clinical screening was performed on all available family members of the patients carrying sarcomere variants and specific variants were tested in screened family members by Sanger sequencing.

We identified 6 sarcomere variants in 6 (7%) patients, which were all definite ACM. Sarcomere variants were detected in NEBL, MYH7, MYH6 and TNNI3, with low prevalence in controls and predicted pathogenic in silico. Among these patients, three had previous detected PKP2 variants. Patients with sarcomere variants all experienced major arrhythmic cardiac event (MACE) with the average age of the first documented MACE being 41.2 ± 11.0 years. Pedigrees analysis showed none of the sarcomere variants carriers among the family members were affected, indicating very low penetrance.

We detected some sarcomere variants in our ACM cohort. Although those patients with sarcomere variants had severe arrhythmic burden, family co-segregation analysis didn't strongly support a primary role in the pathogenesis of ACM.