Case report: Severe arrhythmogenic cardiomyopathy in a young girl with compound heterozygous DSG2 and MYBPC3 variants with a 6-year follow-up.

Abstract

Introduction: Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disorder characterized by progressive fibrofatty replacement of the myocardium. In the Japanese population, variants of the desmoglein-2 (DSG2) gene are a major cause of ACM, typically following an autosomal recessive inheritance pattern. Myosin-binding protein C (MYBPC3) variants are primarily associated with hypertrophic cardiomyopathy (HCM). Here, we report a severe pediatric case of ACM associated with compound heterozygous DSG2 and MYBPC3 variants.

Case presentation: A 6-year-old asymptomatic girl was diagnosed with ACM based on abnormal electrocardiogram findings, including epsilon waves, and T-wave inversions in leads V_1-6 and III. Echocardiography revealed right ventricular (RV) dilatation (RV outflow tract diameter/body surface area: 22.9 mm/m²) and reduced RV function (fractional area change: 18.0%). Cardiac magnetic resonance imaging confirmed RV dysfunction (ejection fraction [EF]: 9.7%) and left ventricular (LV) involvement (EF: 48.9%). Genetic testing identified compound heterozygous DSG2 variants (p.Arg119* and p. Arg292Cys) and an MYBPC3 variant (p.Arg820Gln). The patient remained asymptomatic until age 10.5 years, when she developed heart failure requiring hospitalization. Imaging revealed severe biventricular dilatation (LV end-diastolic volume index: 149.5 mL/m²; RV end-diastolic volume index: 255.9 mL/m²) and biventricular dysfunction (LVEF: 9.5%; RVEF: 9.7%). Despite medical management, the patient's condition progressively worsened, and she was deemed eligible for heart transplantation.

Discussion: This case illustrates the potential for severe pediatric ACM associated with compound heterozygous DSG2 variants and a MYBPC3 variant. The DSG2 variants likely played a primary role disease pathogenesis, while the MYBPC3 variant may have exacerbated the phenotype. The coexistence of desmosomal and sarcomeric gene variants is rare in cardiomyopathies, making genotype-phenotype correlations complex. Further research is needed to elucidate the interplay between these genetic factors.

Conclusion: This case underscores the genetic heterogeneity and phenotypic variability in inherited cardiomyopathies. It emphasizes the importance of comprehensive genetic testing and close monitoring of affected individuals and their families.