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Genetic screening in sudden cardiac death in the young can save future lives.

ABSTRACT: BACKGROUND:Autopsy of sudden cardiac death (SCD) in the young shows a structurally and histologically normal heart in about one third of cases. Sudden death in these cases is believed to be attributed in a high percentage to inherited arrhythmogenic diseases. The purpose of this study was to investigate the value of performing post-mortem genetic analysis for autopsy-negative sudden unexplained death (SUD) in 1 to 35 year olds. METHODS AND RESULTS:From January 2009 to December 2011, samples from 15 cases suffering SUD were referred to the Department of Clinical Genetics, Umeå University Hospital, Sweden, for molecular genetic evaluation. PCR and bidirectional Sanger sequencing of genes important for long QT syndrome (LQTS), short QT syndrome (SQTS), Brugada syndrome type 1 (BrS1), and catecholaminergic polymorphic ventricular tachycardia (CPVT) (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, and RYR2) was performed. Multiplex ligation-dependent probe amplification (MLPA) was used to detect large deletions or duplications in the LQTS genes. Six pathogenic sequence variants (four LQTS and two CPVT) were discovered in 15 SUD cases (40%). Ten first-degree family members were found to be mutation carriers (seven LQTS and three CPVT). CONCLUSION:Cardiac ion channel genetic testing in autopsy-negative sudden death victims has a high diagnostic yield, with identification of the disease in 40 of families. First-degree family members should be offered predictive testing, clinical evaluation, and treatment with the ultimate goal to prevent sudden death.

SUBMITTER: Stattin EL

PROVIDER: S-EPMC4712238 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Genetic screening in sudden cardiac death in the young can save future lives.

Stattin Eva-Lena EL Westin Ida Maria IM Cederquist Kristina K Jonasson Jenni J Jonsson Björn-Anders BA Mörner Stellan S Norberg Anna A Krantz Peter P Wisten Aase A

International journal of legal medicine 20150731 1

<h4>Background</h4>Autopsy of sudden cardiac death (SCD) in the young shows a structurally and histologically normal heart in about one third of cases. Sudden death in these cases is believed to be attributed in a high percentage to inherited arrhythmogenic diseases. The purpose of this study was to investigate the value of performing post-mortem genetic analysis for autopsy-negative sudden unexplained death (SUD) in 1 to 35 year olds.<h4>Methods and results</h4>From January 2009 to December 201 ...[more]

PMID: 26228265

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Project description:BackgroundInclusion of 12-lead electrocardiography (ECG) in preparticipation screening of young athletes is controversial because of concerns about cost-effectiveness.ObjectiveTo evaluate the cost-effectiveness of ECG plus cardiovascular-focused history and physical examination compared with cardiovascular-focused history and physical examination alone for preparticipation screening.DesignDecision-analysis, cost-effectiveness model.Data sourcesPublished epidemiologic and preparticipation screening data, vital statistics, and other publicly available data.Target populationCompetitive athletes in high school and college aged 14 to 22 years.Time horizonLifetime.PerspectiveSocietal.InterventionNonparticipation in competitive athletic activity and disease-specific treatment for identified athletes with heart disease.Outcome measureIncremental health care cost per life-year gained.Results of base-case analysisAddition of ECG to preparticipation screening saves 2.06 life-years per 1000 athletes at an incremental total cost of $89 per athlete and yields a cost-effectiveness ratio of $42 900 per life-year saved (95% CI, $21 200 to $71 300 per life-year saved) compared with cardiovascular-focused history and physical examination alone. Compared with no screening, ECG plus cardiovascular-focused history and physical examination saves 2.6 life-years per 1000 athletes screened and costs $199 per athlete, yielding a cost-effectiveness ratio of $76 100 per life-year saved ($62 400 to $130 000).Results of sensitivity analysisResults are sensitive to the relative risk reduction associated with nonparticipation and the cost of initial screening.LimitationsEffectiveness data are derived from 1 major European study. Patterns of causes of sudden death may vary among countries.ConclusionScreening young athletes with 12-lead ECG plus cardiovascular-focused history and physical examination may be cost-effective.Primary funding sourceStanford Cardiovascular Institute and the Breetwor Foundation.

Project description:BackgroundSudden unexpected death in children is a tragic event. Understanding the genetics of sudden death in the young (SDY) enables family counseling and cascade screening. The objective of this study was to characterize genetic variation in an SDY cohort using whole genome sequencing.MethodsThe SDY Case Registry is a National Institutes of Health/Centers for Disease Control and Prevention surveillance effort to discern the prevalence, causes, and risk factors for SDY. The SDY Case Registry prospectively collected clinical data and DNA biospecimens from SDY cases < 20 years of age. SDY cases were collected from medical examiner and coroner offices spanning 13 US jurisdictions from 2015 to 2019. The cohort included 211 children (median age 0.33 year; range 0-20 years), determined to have died suddenly and unexpectedly and from whom DNA biospecimens for DNA extractions and next-of-kin consent were ascertained. A control cohort consisted of 211 randomly sampled, sex- and ancestry-matched individuals from the 1000 Genomes Project. Genetic variation was evaluated in epilepsy, cardiomyopathy, and arrhythmia genes in the SDY and control cohorts. American College of Medical Genetics/Genomics guidelines were used to classify variants as pathogenic or likely pathogenic. Additionally, pathogenic and likely pathogenic genetic variation was identified using a Bayesian-based artificial intelligence (AI) tool.ResultsThe SDY cohort was 43% European, 29% African, 3% Asian, 16% Hispanic, and 9% with mixed ancestries and 39% female. Six percent of the cohort was found to harbor a pathogenic or likely pathogenic genetic variant in an epilepsy, cardiomyopathy, or arrhythmia gene. The genomes of SDY cases, but not controls, were enriched for rare, potentially damaging variants in epilepsy, cardiomyopathy, and arrhythmia-related genes. A greater number of rare epilepsy genetic variants correlated with younger age at death.ConclusionsWhile damaging cardiomyopathy and arrhythmia genes are recognized contributors to SDY, we also observed an enrichment in epilepsy-related genes in the SDY cohort and a correlation between rare epilepsy variation and younger age at death. These findings emphasize the importance of considering epilepsy genes when evaluating SDY.

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Genetic screening in sudden cardiac death in the young can save future lives.

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Genetic screening in sudden cardiac death in the young can save future lives.

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