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Exome Sequencing Highlights a Potential Role for Concealed Cardiomyopathies in Youthful Sudden Cardiac Death.

Neves, R; Tester, DJ; Simpson, MA; Behr, ER; Ackerman, MJ; Giudicessi, JR (0222) Exome Sequencing Highlights a Potential Role for Concealed Cardiomyopathies in Youthful Sudden Cardiac Death. Circ Genom Precis Med, 15 (1). e003497. ISSN 2574-8300 https://doi.org/10.1161/CIRCGEN.121.003497
SGUL Authors: Behr, Elijah Raphael

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Abstract

BACKGROUND: Sudden cardiac arrest (SCA) and sudden unexplained death (SUD) are feared sequelae of many genetic heart diseases. In rare circumstances, pathogenic variants in cardiomyopathy-susceptibility genes may result in electrical instability leading to SCA/SUD before any structural manifestations of underlying cardiomyopathy are evident. METHODS: Collectively, 38 unexplained SCA survivors (21 males; mean age at SCA 26.4±13.1 years), 68 autopsy-inconclusive SUD cases (49 males; mean age at death 20.4±9.0 years) without disease-causative variants in the channelopathy genes, and 973 ostensibly healthy controls were included. Following exome sequencing, ultrarare (minor allele frequency ≤0.00005 in any ethnic group within Genome Aggregation Database [gnomAD, n=141 456 individuals]) nonsynonymous variants identified in 24 ClinGen adjudicated definitive/strong evidence cardiomyopathy-susceptibility genes were analyzed. Eligible variants were adjudicated as pathogenic, likely pathogenic, or variant of uncertain significance in accordance with current American College of Medical Genetics and Genomics guidelines. RESULTS: Overall, 7 out of 38 (18.4%) SCA survivors and 14 out of 68 (20.5%) autopsy-inconclusive, channelopathic-negative SUD cases had at least one pathogenic/likely pathogenic or a variant of uncertain significance nonsynonymous variant within a strong evidence, cardiomyopathy-susceptibility gene. Following American College of Medical Genetics and Genomics criterion variant adjudication, a pathogenic or likely pathogenic variant was identified in 3 out of 38 (7.9%; P=0.05) SCA survivors and 8 out of 68 (11.8%; P=0.0002) autopsy-inconclusive SUD cases compared to 20 out of 973 (2.1%) European controls. Interestingly, the yield of pathogenic/likely pathogenic variants was significantly greater in autopsy-inconclusive SUD cases with documented interstitial fibrosis (4/11, 36%) compared with only 4 out of 57 (7%, P<0.02) SUD cases without ventricular fibrosis. CONCLUSION: Our data further supports the inclusion of strongevidence cardiomyopathy-susceptibility genes on the genetic testing panels used to evaluate unexplained SCA survivors and autopsy-inconclusive/negative SUD decedents. However, to avoid diagnostic miscues, the careful interpretation of genetic test results in patients without overt phenotypes is vital.

Item Type: Article
Additional Information: This is a non-final version of an article published in final form in Neves, R; Tester, DJ; Simpson, MA; Behr, ER; Ackerman, MJ; Giudicessi, JR (0222) Exome Sequencing Highlights a Potential Role for Concealed Cardiomyopathies in Youthful Sudden Cardiac Death. Circ Genom Precis Med, 15 (1). e003497.
Keywords: autopsy, cardiomyopathies, death, genetic testing, survivors, autopsy, cardiomyopathies, death, genetic testing, survivors
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Circ Genom Precis Med
ISSN: 2574-8300
Language: eng
Dates:
DateEvent
February 0222Published
24 December 2021Published Online
24 November 2021Accepted
Publisher License: Publisher's own licence
PubMed ID: 34949102
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/114001
Publisher's version: https://doi.org/10.1161/CIRCGEN.121.003497

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