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Journal of Cardiovascular Translational Research

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Open Access 21-07-2023 | Cardiomyopathy | Original Article

Age and Sex Differences in the Genetics of Cardiomyopathy

Authors: Oyediran Akinrinade, Robert Lesurf, Jane Lougheed, Tapas Mondal, John Smythe, Luis Altamirano-Diaz, Erwin Oechslin, Seema Mital, Genomics England Research Consortium

Published in: Journal of Cardiovascular Translational Research | Issue 6/2023

Abstract

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.

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Title: Age and Sex Differences in the Genetics of Cardiomyopathy
Authors: Oyediran Akinrinade
Robert Lesurf
Jane Lougheed
Tapas Mondal
John Smythe
Luis Altamirano-Diaz
Erwin Oechslin
Seema Mital
Genomics England Research Consortium
Publication date: 21-07-2023
Publisher: Springer US
Keyword: Cardiomyopathy
Published in: Journal of Cardiovascular Translational Research / Issue 6/2023
Print ISSN: 1937-5387
Electronic ISSN: 1937-5395
DOI: https://doi.org/10.1007/s12265-023-10411-8

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Age and Sex Differences in the Genetics of Cardiomyopathy

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