Cardiomyopathy has variable penetrance. We analyzed age and sex-related genetic differences in 1,397 cardiomyopathy patients (Ontario, UK) with whole genome sequencing. Pediatric cases (n = 471) harbored more deleterious protein-coding variants in Tier 1 cardiomyopathy genes compared to adults (n = 926) (34.6% vs 25.9% respectively, p = 0.0015), with variant enrichment in constrained coding regions. Pediatric patients had a higher burden of sarcomere and lower burden of channelopathy gene variants compared to adults. Specifically, pediatric patients had more
MYH7and MYL3variants in hypertrophic cardiomyopathy, and fewer TTNtruncating variants in dilated cardiomyopathy. MYH7variants clustered in the myosin head and neck domains in children. OBSCNwas a top mutated gene in adults, enriched for protein-truncating variants. In dilated cardiomyopathy, female patients had a higher burden of z-disc gene variants compared to males. Genetic differences may explain age and sex-related variability in cardiomyopathy penetrance. Genotype-guided predictions of age of onset can inform pre-test genetic counseling. Graphical Abstract
Pediatric cardiomyopathy patients were more likely to be genotype-positive than adults with a higher burden of variants in
MYH7, MYL3, TNNT2, VCL. Adults had a higher burden of OBSCNand TTNvariants. Females with dilated cardiomyopathy (DCM) had a higher burden of z-disc gene variants compared to males.