Clinical features and outcome of arrhythmogenic cardiomyopathy because of a desmoglein-2 founder variant: A multicenter study.

BACKGROUND

Desmoglein 2 (DSG2)-associated cardiomyopathy represents a distinct subset of arrhythmogenic cardiomyopathy. A founder variant, NM_001943.5 (DSG2): c.T1592G (p.Phe531Cys), was identified with high frequency in China.

OBJECTIVE

The study aimed to describe clinical features and outcomes of this founder variant.

METHODS

Individuals with DSG2 c.T1592G (p.Phe531Cys) variants were recruited from 9 centers across China and categorized as single heterozygous, compound heterozygous (single variant plus rare variants of uncertain significance; abbreviated as compound), and homozygous. Clinical features and risk factors for malignant ventricular arrhythmias (MVAs), end-stage heart failure, and composite events of heart transplantation or cardiac death were analyzed.

RESULTS

91 subjects were included: 21 (23.1%) single heterozygous, 21 (23.1%) compound, and 49 (53.8%) homozygous. Most subjects (74.7%) showed right ventricular dilatation, and nearly half (49.5%) had biventricular involvement. In patients with contrast-enhanced magnetic resonance imaging, 75.9% exhibited biventricular involvement. Compared with single heterozygous variant carriers, compound and homozygous variant carriers had a younger age at onset, more T-wave inversion, epsilon waves, and biventricular involvement (all pairwise P < .05). Homozygous variant carriers experienced significantly earlier MVA than compound (P = .013) and single heterozygous variant carriers (P < .001), with a trend toward earlier MVA in compound than single heterozygous variant carriers (P = .089). Compound and homozygous variant carriers exhibited significantly higher incidences of end-stage heart failure and composite events, whereas single heterozygous variant carriers remained event-free (all P < .05).

CONCLUSION

DSG2 c.T1592G (p.Phe531Cys) founder variant defines a distinct arrhythmogenic cardiomyopathy subset with a high prevalence of biventricular involvement. Single heterozygous variant carriers held a less severe phenotype and relatively favorable prognosis, whereas compound and homozygous variant carriers held an advanced phenotype and poorer prognosis.