Genetic variants associated with inherited cardiovascular disorders among 13,131 asymptomatic older adults of European descent

Abstract Genetic testing is used to optimise the management of inherited cardiovascular disorders that can cause sudden cardiac death. Yet more genotype–phenotype correlation studies from populations not ascertained on clinical symptoms or family history of disease are required to improve understand...

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Autores principales:	Paul Lacaze, Robert Sebra, Moeen Riaz, Jodie Ingles, Jane Tiller, Bryony A. Thompson, Paul A. James, Diane Fatkin, Christopher Semsarian, Christopher M. Reid, Andrew M. Tonkin, Ingrid Winship, Eric Schadt, John J. McNeil
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Genetics QH426-470
Acceso en línea:	https://doaj.org/article/3e5b23d8d40846fe86c233e0dbe01b83
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spelling	oai:doaj.org-article:3e5b23d8d40846fe86c233e0dbe01b832021-12-02T16:04:14ZGenetic variants associated with inherited cardiovascular disorders among 13,131 asymptomatic older adults of European descent10.1038/s41525-021-00211-x2056-7944https://doaj.org/article/3e5b23d8d40846fe86c233e0dbe01b832021-06-01T00:00:00Zhttps://doi.org/10.1038/s41525-021-00211-xhttps://doaj.org/toc/2056-7944Abstract Genetic testing is used to optimise the management of inherited cardiovascular disorders that can cause sudden cardiac death. Yet more genotype–phenotype correlation studies from populations not ascertained on clinical symptoms or family history of disease are required to improve understanding of gene penetrance. We performed targeted sequencing of 25 genes used routinely in clinical genetic testing for inherited cardiovascular disorders in a population of 13,131 asymptomatic older individuals (mean age 75 years) enrolled in the ASPREE trial. Participants had no prior history of cardiovascular disease events, dementia or physical disability at enrolment. Variants were classified following ACMG/AMP standards. Sudden and rapid cardiac deaths were clinically adjudicated as ASPREE trial endpoints, and assessed during mean 4.7 years of follow-up. In total, 119 participants had pathogenic/deleterious variants in one of the 25 genes analysed (carrier rate of 1 in 110 or 0.9%). Participants carried variants associated with hypertrophic cardiomyopathy (N = 24), dilated cardiomyopathy (N = 29), arrhythmogenic right-ventricular cardiomyopathy (N = 22), catecholaminergic polymorphic ventricular tachycardia (N = 4), aortopathies (N = 1), and long-QT syndrome (N = 39). Among 119 carriers, two died from presumed sudden/rapid cardiac deaths during follow-up (1.7%); both with pathogenic variants in long-QT syndrome genes (KCNQ1, SCN5A). Among non-carriers, the rate of sudden/rapid cardiac deaths was significantly lower (0.08%, 11/12936, p < 0.001). Variants associated with inherited cardiovascular disorders are found in asymptomatic individuals aged 70 years and older without a history of cardiovascular disease.Paul LacazeRobert SebraMoeen RiazJodie InglesJane TillerBryony A. ThompsonPaul A. JamesDiane FatkinChristopher SemsarianChristopher M. ReidAndrew M. TonkinIngrid WinshipEric SchadtJohn J. McNeilNature PortfolioarticleMedicineRGeneticsQH426-470ENnpj Genomic Medicine, Vol 6, Iss 1, Pp 1-8 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Genetics QH426-470
spellingShingle	Medicine R Genetics QH426-470 Paul Lacaze Robert Sebra Moeen Riaz Jodie Ingles Jane Tiller Bryony A. Thompson Paul A. James Diane Fatkin Christopher Semsarian Christopher M. Reid Andrew M. Tonkin Ingrid Winship Eric Schadt John J. McNeil Genetic variants associated with inherited cardiovascular disorders among 13,131 asymptomatic older adults of European descent
description	Abstract Genetic testing is used to optimise the management of inherited cardiovascular disorders that can cause sudden cardiac death. Yet more genotype–phenotype correlation studies from populations not ascertained on clinical symptoms or family history of disease are required to improve understanding of gene penetrance. We performed targeted sequencing of 25 genes used routinely in clinical genetic testing for inherited cardiovascular disorders in a population of 13,131 asymptomatic older individuals (mean age 75 years) enrolled in the ASPREE trial. Participants had no prior history of cardiovascular disease events, dementia or physical disability at enrolment. Variants were classified following ACMG/AMP standards. Sudden and rapid cardiac deaths were clinically adjudicated as ASPREE trial endpoints, and assessed during mean 4.7 years of follow-up. In total, 119 participants had pathogenic/deleterious variants in one of the 25 genes analysed (carrier rate of 1 in 110 or 0.9%). Participants carried variants associated with hypertrophic cardiomyopathy (N = 24), dilated cardiomyopathy (N = 29), arrhythmogenic right-ventricular cardiomyopathy (N = 22), catecholaminergic polymorphic ventricular tachycardia (N = 4), aortopathies (N = 1), and long-QT syndrome (N = 39). Among 119 carriers, two died from presumed sudden/rapid cardiac deaths during follow-up (1.7%); both with pathogenic variants in long-QT syndrome genes (KCNQ1, SCN5A). Among non-carriers, the rate of sudden/rapid cardiac deaths was significantly lower (0.08%, 11/12936, p < 0.001). Variants associated with inherited cardiovascular disorders are found in asymptomatic individuals aged 70 years and older without a history of cardiovascular disease.
format	article
author	Paul Lacaze Robert Sebra Moeen Riaz Jodie Ingles Jane Tiller Bryony A. Thompson Paul A. James Diane Fatkin Christopher Semsarian Christopher M. Reid Andrew M. Tonkin Ingrid Winship Eric Schadt John J. McNeil
author_facet	Paul Lacaze Robert Sebra Moeen Riaz Jodie Ingles Jane Tiller Bryony A. Thompson Paul A. James Diane Fatkin Christopher Semsarian Christopher M. Reid Andrew M. Tonkin Ingrid Winship Eric Schadt John J. McNeil
author_sort	Paul Lacaze
title	Genetic variants associated with inherited cardiovascular disorders among 13,131 asymptomatic older adults of European descent
title_short	Genetic variants associated with inherited cardiovascular disorders among 13,131 asymptomatic older adults of European descent
title_full	Genetic variants associated with inherited cardiovascular disorders among 13,131 asymptomatic older adults of European descent
title_fullStr	Genetic variants associated with inherited cardiovascular disorders among 13,131 asymptomatic older adults of European descent
title_full_unstemmed	Genetic variants associated with inherited cardiovascular disorders among 13,131 asymptomatic older adults of European descent
title_sort	genetic variants associated with inherited cardiovascular disorders among 13,131 asymptomatic older adults of european descent
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/3e5b23d8d40846fe86c233e0dbe01b83
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Genetic variants associated with inherited cardiovascular disorders among 13,131 asymptomatic older adults of European descent

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