Heart Rhythm. 2026 Feb 7:S1547-5271(26)00120-7. doi: 10.1016/j.hrthm.2026.01.053. Online ahead of print.
ABSTRACT
BACKGROUND: Desmoglein-2 (DSG2)-associated cardiomyopathy represents a distinct subset of arrhythmogenic cardiomyopathy (ACM). 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 (MVA), end-stage heart failure (ESHF), and composite events of heart transplantation or cardiac death were analyzed.
RESULTS: Ninety-one subjects were included: 21 (23.1%) single heterozygous, 21 (23.1%) compound, and 49 (53.8%) homozygous. Most of 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, compound and homozygous had younger age at onset, more T wave inversion, epsilon waves, and biventricular involvement (all pairwise P<0.05). Homozygous experienced significantly earlier MVA than compound (P=0.013), and single heterozygous (P<0.001), with a trend toward earlier MVA in compound compared with single heterozygous (P=0.089). Compound and homozygous exhibited significantly higher incidences of ESHF and composite events while single heterozygous remains event-free (all P<0.05).
CONCLUSION: DSG2 c.T1592G (p.Phe531Cys) founder variant defines a distinct ACM subset with high prevalence of biventricular involvement. Single heterozygous variant carriers held less severe phenotype and relatively favorable prognosis, while compound and homozygous held advanced phenotype and poorer prognosis.
PMID:41662985 | DOI:10.1016/j.hrthm.2026.01.053