Sex-related differences in dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM) may vary according to underlying genetic subtype, although these patterns remain incompletely characterized across pediatric and adult populations. An analysis from the Sarcomeric Human Cardiomyopathy Registry published in the Journal of the American College of Cardiology evaluated sex-based differences in genetic architecture and age at diagnosis among patients with DCM and ACM.

The study included genetically tested adult and pediatric patients with DCM or ACM, along with asymptomatic genotype-positive relatives enrolled in the multicenter SHaRe registry. Sex distribution across 27 DCM- and ACM-associated genes was evaluated using logistic regression, and age at diagnosis was compared using Kaplan-Meier cumulative incidence analyses.

Findings

• The analysis included 3,410 patients and demonstrated an overall male predominance of 61% across genotype-positive, genotype-negative, and variant-of-uncertain-significance groups (P = 0.008).
• TTN truncating variants were less common in females than males (odds ratio [OR], 0.42; 95% confidence interval [CI], 0.33-0.54; P < 0.01).
• DSP variants (OR, 3.3; 95% CI, 2.35-4.78; P < 0.01) and grouped non-TTN sarcomeric variants (OR, 1.68; 95% CI, 1.15-2.47; P < 0.001) were more common in females.
• Among TTN truncating variant carriers, males developed disease earlier than females, with a median age at diagnosis of 45 years versus 51 years, respectively (P = 0.003).
• Pediatric-onset disease accounted for 174 cases and showed a 60% male predominance.
• Pediatric-onset DCM/ACM demonstrated higher prevalence of non-TTN sarcomeric variants (OR, 5.5; 95% CI, 3.3-8.9; P < 0.01) and PKP2 variants (OR, 2.8; 95% CI, 1.1-5.2; P < 0.05) compared with adult-onset disease.

Sex-specific differences in DCM and ACM varied according to the underlying genetic subtype. TTN truncating variants were more common and presented earlier in males, whereas DSP and non-TTN sarcomeric variants were more frequently identified in females.