Sex and Age Specific Genetic Risk Across the Dilated and Arrhythmogenic Cardiomyopathy Spectrum: Insights From the SHaRe Registry.
DSP variants are more common in females with dilated or arrhythmogenic cardiomyopathy.
Sex and Age Specific Genetic Risk Across the Dilated and Arrhythmogenic Cardiomyopathy Spectrum: Insights From the SHaRe Registry.
Dilated cardiomyopathy (dilated cardiomyopathy) and arrhythmogenic cardiomyopathy (arrhythmogenic cardiomyopathy) are progressive cardiac muscle disorders with phenotypic and genetic overlap.
The aim of this study was to define sex-based differences in genetic architecture and age at diagnosis of dilated cardiomyopathy/arrhythmogenic cardiomyopathy across pediatric and adult populations.
Genetically tested adult and pediatric dilated cardiomyopathy/arrhythmogenic cardiomyopathy patients and asymptomatic genotype-positive relatives enrolled in the multicenter SHaRe (Sarcomeric Human Cardiomyopathy Registry) were analyzed.
DSP variants are more common in females with dilated or arrhythmogenic cardiomyopathy
Among 3,410 patients, a 61% male predominance was present across subgroups of genotype positive, genotype negative, and variants of uncertain significance (P = 0.008), with significant gene-specific variation.
Age at diagnosis was comparable between sexes, except in TTNtv carriers, among whom males exhibited earlier disease onset compared with females (median age 45 years [Q1-Q3: 33-55 years] vs 51 years [Q1-Q3: 38-60 years]; P = 0.003).
Gene-specific sex differences influence disease prevalence and age at onset in dilated cardiomyopathy/arrhythmogenic cardiomyopathy.
TTNtv are more common with earlier onset in males, whereas DSP and non-TTN sarcomeric variants predominate in females.
Pediatric-onset dilated cardiomyopathy/arrhythmogenic cardiomyopathy is genetically distinct and caused predominantly by non-TTN sarcomeric variants, especially during infancy.
These findings support age- and sex-informed surveillance strategies and prioritize future research into the mechanisms of observed sex-based differences.