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

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.

Screening for Pathogenic Variants in Cardiomyopathy Genes Predicts Mortality and Composite Outcomes in UK Biobank

“…Several of these criteria are met: criteria (1) importance, (3) a recognizable latent stage; (4) a suitable test; and (10) need for continuing surveillance. Several criteria are partially met: criterion (2) regarding natural history of CMPs is understood for adult-onset disease but not as much in pediatric forms of CMP; criterion (6) regarding policy and criterion (7) on acceptable treatments are partially met for established disease, such as cardiomyopathies, heart failure and arrhythmias but remain unclear for genotype-positive/-phenotype-negative individuals. Criterion (8) regarding the availability of facilities for diagnosis and (9) for the screening methodology being economically balanced, are not met yet.…”

“…(4)(5)(6) Identifying individuals at risk for CMP-associated complications remains a challenge despite the enormous progress in diagnostic modalities, as a significant proportion of affected patients are diagnosed postmortem. (7) Underlying genotype is increasingly recognized as an important determinant of disease-related outcomes in clinically diagnosed patients. (2,8) With the decreasing cost of whole exome and whole genome sequencing (WES/WGS), a 'genotype-first' approach whereby individuals are evaluated based on their genetic variation, irrespective of phenotype, is emerging as a potentially powerful tool to solve such issues.…”

Cardiomyopathy Genes and Idiopathic VF: A Known Unknown?

“…In this edition of the journal, Neves et al 1 report on the yield of testing for 24 well-established cardiomyopathy genes in a cohort of 38 unexplained cardiac arrest (UCA) survivors and 68 cases of autopsy-negative sudden unexplained death in the young. In the cardiac arrest survivors, no diagnosis had been made following both clinical evaluation and testing for a panel of 17 genes that cause ion channel diseases commonly associated with sudden cardiac arrest: long QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia.…”

Genetic Testing for Inherited Heart Disease in the Era of Next-Generation Sequencing: Now, Next, and Beyond

“…Additional cardiomyopathyassociated genes, including RBM20, ACTN2, and BAG3, which are known to have significant arrhythmic risk, were not included in the risk-genes in this study. [6][7][8] Exclusion of these genes may underestimate the prevalence of arrhythmogenic variants. Genetic Testing for Heart Disease Circ Genom Precis Med.…”

“…Indeed, variants in cardiomyopathy-associated genes have been identified in both apparently idiopathic sudden cardiac arrest survivors and unexplained sudden cardiac death victims, driving calls for a broader approach to genetic testing in these cohorts which have been acknowledged in recent guidelines. 7,9,[12][13][14][15] So, to take a step even further: "what of the proposition of population screening?" Population databases with genetic and clinical information have been used to investigate the prevalence and penetrance of inherited heart diseases.…”