Deleterious Rare Desmosomal Variants Contribute to Hypertrophic Cardiomyopathy and Are Associated With Distinctive Clinical Features

Abstract

Background: Deleterious rare variants in genes encoding desmosome proteins have been identified as the essential basis of arrhythmogenic cardiomyopathy (ACM) and detected in dilated cardiomyopathy, but the relationship between deleterious rare desmosomal variants and hypertrophic cardiomyopathy (HCM) remains unknown.

Methods: Whole exome sequencing was performed in 1000 patients with HCM and 761 non-HCM controls to search for deleterious rare variants in genes encoding desmosomal proteins including PKP2, JUP, DSC2, DSG2, and DSP. Clinical phenotypes were assessed in patients with HCM, and patients with deleterious rare desmosomal variants underwent evaluation of ACM revised Task Force Criteria.

Results: A total of 27 deleterious rare desmosomal variants were present in 24 (2.4%) patients with HCM and 5 (0.66%) controls. The variants were more prevalent in the patients with HCM than in the controls (P = 0.004). The majority of patients possessing deleterious rare desmosomal variants could not be diagnosed as ACM. Moreover, the patients with deleterious rare desmosomal variants possessed several distinctive clinical features compared with patients without such variants, including a higher incidence of nonsustained ventricular tachycardia (29.2% vs 4.5%, P < 0.001), left bundle branch block (33.3% vs 1.6%, P < 0.001), and right ventricular involvement for an HCM phenotype (29.2% vs 0.30%, P < 0.001).

Conclusions: We screened deleterious rare desmosomal variants in a large HCM case-control cohort and found deleterious rare desmosomal variants can be relevant to HCM. Moreover, our data indicated deleterious rare desmosomal variants were associated with distinctive clinical features of HCM. These findings require validation in other HCM cohorts.