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Trans. Res."],"published-print":{"date-parts":[[2023,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    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\u2009=\u2009471) harbored more deleterious protein-coding variants in Tier 1 cardiomyopathy genes compared to adults (n\u2009=\u2009926) (34.6% vs 25.9% respectively, p\u2009=\u20090.0015), 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\n                    <jats:italic>MYH7<\/jats:italic>\n                    and\n                    <jats:italic>MYL3<\/jats:italic>\n                    variants in hypertrophic cardiomyopathy, and fewer\n                    <jats:italic>TTN<\/jats:italic>\n                    truncating variants in dilated cardiomyopathy.\n                    <jats:italic>MYH7<\/jats:italic>\n                    variants clustered in the myosin head and neck domains in children.\n                    <jats:italic>OBSCN<\/jats:italic>\n                    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.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>\n                  <jats:p>\n                    Pediatric cardiomyopathy patients were more likely to be genotype-positive than adults with a higher burden of variants in\n                    <jats:italic>MYH7, MYL3, TNNT2, VCL<\/jats:italic>\n                    . Adults had a higher burden of\n                    <jats:italic>OBSCN<\/jats:italic>\n                    and\n                    <jats:italic>TTN<\/jats:italic>\n                    variants. Females with dilated cardiomyopathy (DCM) had a higher burden of z-disc gene variants compared to males.\n                  <\/jats:p>","DOI":"10.1007\/s12265-023-10411-8","type":"journal-article","created":{"date-parts":[[2023,7,21]],"date-time":"2023-07-21T11:02:05Z","timestamp":1689937325000},"page":"1287-1302","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Age and Sex Differences in the Genetics of Cardiomyopathy"],"prefix":"10.1007","volume":"16","author":[{"given":"Oyediran","family":"Akinrinade","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Lesurf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Genomics England Research Consortium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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The remaining authors have nothing to disclose.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflicts of Interest"}},{"value":"All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for being included in the study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Human Subjects Statement"}},{"value":"No animal studies were carried out by the authors for this article.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Animal Studies"}},{"value":"Sequencing data from the Ontario Registry are deposited in the European Genome-Phenome Archive (EGA) under accession EGAS00001004929, and are available for download upon approval by the Data Access Committee. The 100,000 Genomes Project data are available to researchers and trainees using the Genomics England Research Environment upon institutional approval through their Participation Agreement process. Additional data generated or analyzed during this study are included in the supplementary information files, and additional raw data used for figures and results are available from the corresponding author on reasonable request.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data Statement"}},{"value":"All authors contributed to the study conception and design, and to data collection. Data analysis was performed by [Oyediran Akinrinade] [Robert Lesurf]. The first draft of the manuscript was written by [Oyediran Akinrinade]. Funding was acquired by [Seema Mital]. All authors commented on manuscript versions and read and approved the final manuscript.","order":6,"name":"Ethics","group":{"name":"EthicsHeading","label":"Author Statement"}}]}}