P687Arrhythmogenic right ventricular cardiomyopathy patients with desmoglein-2 variants are characterized by recessive inheritance and progressive heart failure

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited primary cardiomyopathy characterized by myocardial degeneration with fibro-fatty replacement. Clinical and genetic features of ARVC were well identified in Caucasian cohorts, but seldom examined in Chinese cohort. Aims: Our aim is to examine the genetic factor, genotype-phenotype correlations, and inheritance patterns of ARVC in a Chinese cohort. Methods: The Chinese ARVC cohort was comprised of 118 unrelated index patients of Han descent. We performed comprehensive analysis of PKP2, JUP, DSP, DSG2, DSC2, TGFb-3, RyR2, TMEM43, DES, LMNA, PLN and CTNNA by captured sequencing for all patients. Results: Among the 118 patients, 49 patients had previous heart transplantation and 45 (38%) experienced MACE. Sixty-six (56%) patients carried candidate variants and all these patients were definite cases. Single-genic variants in DSG2 and PKP2 were dominantly detected in 18 (15%) patients respectively. PKP2 variants were found to be an independent a risk factor of major arrhythmic cardiovascular event (MACE) (HR=3.275, P0.001), but a predictor of a better outcome free from heart transplantation (HR=0.125, P=0.042). Compound or oligo-genic variants was an independent risk factor of both heart transplantation (HR=3.314, P=0.003) and MACE (HR=2.949, P=0.017). Patients with non-desmosomal variants had a lower left ventricle ejection fraction (38.3±19.8% vs. 52.1±14.7%, P=0.006) than did patients with desmosomal variants. Patients with variants in DSG2 had a lower heart transplantation free survival rate than those with variants in PKP2 (P=0.034). The presence of a homozygous DSG2 variants suggests an autosomal recessive inheritance.