Sex and age specific genetic risk across the dilated and arrhythmogenic cardiomyopathy spectrum: insights from the SHaRe registry
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Background
Dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM) are progressive cardiac muscle disorders with phenotypic and genetic overlap. Although a male predominance is noted in DCM/ACM, it remains unclear whether this extends to specific genetic subtypes or reflects variation in disease stage and whether sex influences age-dependent disease onset across pediatric and adult groups.
Objectives
The aim of this study was to define sex-based differences in genetic architecture and age at diagnosis of DCM/ACM across pediatric and adult populations.
Methods
Genetically tested adult and pediatric DCM/ACM patients and asymptomatic genotype-positive relatives enrolled in the multicenter SHaRe (Sarcomeric Human Cardiomyopathy Registry) were analyzed. Sex distribution across 27 DCM- and ACM-associated genes was evaluated using logistic regression. Age at diagnosis was compared across sex and genes using Kaplan-Meier cumulative incidence estimates.
Results
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. TTN truncating variants (TTNtv) were less common in females (OR: 0.42 [95% CI: 0.33-0.54]; P < 0.01), while DSP (OR: 3.3 [95% CI: 2.35-4.78]; P < 0.01) and grouped non-TTN sarcomeric variants (ACTC1, TNNT2, MYH7, TNNC1, TNNI3, and TPM1) were more common (OR: 1.68 [95% CI: 1.15-2.47]; P < 0.001) in females compared with males with DCM/ACM. 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). Pediatric-onset (diagnosis at <18 years) cases (n = 174) also demonstrated a male predominance (60% male) but had distinct genetic characteristics, with non-TTN sarcomeric and PKP2 variants being more prevalent compared with adult-onset disease (non-TTN sarcomeric OR: 5.5 [95% CI: 3.3-8.9; P < 0.01]; PKP2 OR: 2.8 [95% CI: 1.1-5.2; P < 0.05]) and a bimodal age at onset peaking in infancy and adolescence.
Conclusions
Gene-specific sex differences influence disease prevalence and age at onset in DCM/ACM. TTNtv are more common with earlier onset in males, whereas DSP and non-TTN sarcomeric variants predominate in females. Pediatric-onset DCM/ACM 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.
Dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM) are progressive cardiac muscle disorders with phenotypic and genetic overlap. Although a male predominance is noted in DCM/ACM, it remains unclear whether this extends to specific genetic subtypes or reflects variation in disease stage and whether sex influences age-dependent disease onset across pediatric and adult groups.
Objectives
The aim of this study was to define sex-based differences in genetic architecture and age at diagnosis of DCM/ACM across pediatric and adult populations.
Methods
Genetically tested adult and pediatric DCM/ACM patients and asymptomatic genotype-positive relatives enrolled in the multicenter SHaRe (Sarcomeric Human Cardiomyopathy Registry) were analyzed. Sex distribution across 27 DCM- and ACM-associated genes was evaluated using logistic regression. Age at diagnosis was compared across sex and genes using Kaplan-Meier cumulative incidence estimates.
Results
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. TTN truncating variants (TTNtv) were less common in females (OR: 0.42 [95% CI: 0.33-0.54]; P < 0.01), while DSP (OR: 3.3 [95% CI: 2.35-4.78]; P < 0.01) and grouped non-TTN sarcomeric variants (ACTC1, TNNT2, MYH7, TNNC1, TNNI3, and TPM1) were more common (OR: 1.68 [95% CI: 1.15-2.47]; P < 0.001) in females compared with males with DCM/ACM. 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). Pediatric-onset (diagnosis at <18 years) cases (n = 174) also demonstrated a male predominance (60% male) but had distinct genetic characteristics, with non-TTN sarcomeric and PKP2 variants being more prevalent compared with adult-onset disease (non-TTN sarcomeric OR: 5.5 [95% CI: 3.3-8.9; P < 0.01]; PKP2 OR: 2.8 [95% CI: 1.1-5.2; P < 0.05]) and a bimodal age at onset peaking in infancy and adolescence.
Conclusions
Gene-specific sex differences influence disease prevalence and age at onset in DCM/ACM. TTNtv are more common with earlier onset in males, whereas DSP and non-TTN sarcomeric variants predominate in females. Pediatric-onset DCM/ACM 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.
Date Issued
2026-06-30
Date Acceptance
2026-03-12
Citation
Journal of the American College of Cardiology, 2026, 87 (25), pp.3573-3588
ISSN
0735-1097
Publisher
Elsevier
Start Page
3573
End Page
3588
Journal / Book Title
Journal of the American College of Cardiology
Volume
87
Issue
25
Copyright Statement
Copyright © 2026 by the American College of Cardiology Foundation Published by Elsevier.
License URL
Identifier
10.1016/j.jacc.2026.03.054
Publication Status
Published
Date Publish Online
2026-05-20