Age and Sex Differences in the Genetics of Cardiomyopathy

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 = ...

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Bibliographic Details
Published in:Journal of cardiovascular translational research 2023-12, Vol.16 (6), p.1287-1302
Main Authors: Akinrinade, Oyediran, Lesurf, Robert, Lougheed, Jane, Mondal, Tapas, Smythe, John, Altamirano-Diaz, Luis, Oechslin, Erwin, Mital, Seema
Format: Article
Language:English
Subjects:
Adult
Biomedical Engineering and Bioengineering
Biomedicine
Cardiology
Cardiomyopathies - genetics
Cardiomyopathy, Dilated - diagnosis
Cardiomyopathy, Dilated - genetics
Cardiomyopathy, Hypertrophic
Child
Female
Genotype
Human Genetics
Humans
Male
Medicine
Medicine & Public Health
Mutation
Original Article
Sex Characteristics
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Summary: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 MYH7 and MYL3 variants in hypertrophic cardiomyopathy, and fewer TTN 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 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 OBSCN and TTN variants. Females with dilated cardiomyopathy (DCM) had a higher burden of z-disc gene variants compared to males.
ISSN:1937-5387
1937-5395
DOI:10.1007/s12265-023-10411-8