Age and Sex Differences in the Genetics of Cardiomyopathy

AbstractCardiomyopathy 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 moreMYH7 andMYL3 variants in hypertrophic cardiomyopathy, and fewerTTN truncating variants in dilated cardiomyopathy.MYH7 variants clustered in the myosin head and neck domains in children.OBSCN was 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 AbstractPediatric cardiomyopathy patients were more likely to be genotype-positive than adults with a higher burden of variants inMYH7, MYL3, TNNT2, VCL. Adults had a higher burden ofOBSCN andTTN variants. Females with dilated cardiomyopathy (DCM) had a higher burden of z-disc gene variants compared to males.
Source: Journal of Cardiovascular Translational Research - Category: Cardiology Source Type: research