Clinical features and outcome of arrhythmogenic cardiomyopathy because of a desmoglein-2 founder variant: A
Bingqi Fu1, Zhongli Chen1, Zixian Chen2
1National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Cardiac Arrhythmias Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Insights
The founder variant DSG2 c.T1592G (p.Phe531Cys) defines a unique arrhythmogenic cardiomyopathy subset in China. Homozygous and compound variants lead to more severe phenotypes and poorer outcomes than single heterozygous carriers.
Area of Science:
- Cardiology
- Genetics
- Molecular Biology
Background:
- Desmoglein-2 (DSG2) mutations are linked to arrhythmogenic cardiomyopathy (ACM).
- A specific founder variant, DSG2 c.T1592G (p.Phe531Cys), is prevalent in China.
- This variant defines a distinct ACM subset.
Purpose of the Study:
- To characterize the clinical features and outcomes associated with the DSG2 founder variant.
- To compare the phenotypes and prognoses across different variant carrier types (single heterozygous, compound heterozygous, homozygous).
Main Methods:
- Ninety-one individuals with the DSG2 c.T1592G (p.Phe531Cys) variant were recruited from 9 Chinese centers.
- Participants were classified into single heterozygous, compound heterozygous, and homozygous groups.
- Clinical data, including arrhythmias, heart failure, and composite events, were analyzed.
Main Results:
- Biventricular involvement was common (74.7% right ventricular dilatation, 49.5% biventricular).
- Compound and homozygous carriers showed earlier onset, more T-wave inversion, epsilon waves, and biventricular involvement compared to single heterozygotes.
- Homozygous and compound carriers had significantly higher rates of malignant ventricular arrhythmias, end-stage heart failure, and composite events.
Conclusions:
- The DSG2 c.T1592G founder variant is associated with a distinct ACM phenotype characterized by high rates of biventricular involvement.
- Single heterozygous carriers have a less severe phenotype and better prognosis.
- Compound and homozygous carriers exhibit advanced disease phenotypes and poorer prognoses, highlighting genotype-phenotype correlations.
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.
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