Dataset Information

Postmortem genetic screening for the identification, verification, and reporting of genetic variants contributing to the sudden death of the young.

ABSTRACT: Each year in the United States, thousands of cases of sudden and unexpected deaths of infants, children, and young adults are assigned an undetermined cause of death after postmortem investigation and autopsy. Heritable genetic variants have been suggested as the cause of up to a third of sudden death (SD) cases. Elucidation of the genetic variants involved in SD cases is important to not only help establish cause and manner of death of these individuals, but to also aid in determining whether familial genetic testing should be considered. Previously, these types of postmortem screenings have not been a feasible option for most county medical examiners' and coroners' offices. We sequenced full exons of 64 genes associated with SD in the largest known cohort (351) of infant and young SD decedents using massively parallel sequencing at <$600 per sample. Genetic variants were assessed through literature review and clinical evaluation by a multidisciplinary consortium of experts. Thirteen individuals (3.7%), eight infants (2.8% of those <1 yr of age) and five children/young adults (7.0% of those >1 yr of age), were found to have a reportable genetic variant contributing to SD. These percentages represent an estimate lower than those previously reported. Overall yields and results likely vary between studies due to differences in evaluation techniques and reporting. Additionally, we recommend ongoing assessment of data, including nonreported novel variants, as technology and literature continually advance. This study demonstrates a strategy to implement molecular autopsies in medicolegal investigations of young SD decedents.

SUBMITTER: Methner DN

PROVIDER: S-EPMC5052040 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Postmortem genetic screening for the identification, verification, and reporting of genetic variants contributing to the sudden death of the young.

Methner D Nicole R DN Scherer Steven E SE Welch Katherine K Walkiewicz Magdalena M Eng Christine M CM Belmont John W JW Powell Mark C MC Korchina Viktoriya V Doddapaneni Harsha Vardhan HV Muzny Donna M DM Gibbs Richard A RA Wolf Dwayne A DA Sanchez Luis A LA Kahn Roger R

Genome research 20160719 9

Each year in the United States, thousands of cases of sudden and unexpected deaths of infants, children, and young adults are assigned an undetermined cause of death after postmortem investigation and autopsy. Heritable genetic variants have been suggested as the cause of up to a third of sudden death (SD) cases. Elucidation of the genetic variants involved in SD cases is important to not only help establish cause and manner of death of these individuals, but to also aid in determining whether f ...[more]

PMID: 27435932

Similar Datasets

Project description:BACKGROUND:Sudden cardiac death occurs in ?220,000 U.S. adults annually, the majority of whom have no prior symptoms or cardiovascular diagnosis. Rare pathogenic DNA variants in any of 49 genes can pre-dispose to 4 important causes of sudden cardiac death: cardiomyopathy, coronary artery disease, inherited arrhythmia syndrome, and aortopathy or aortic dissection. OBJECTIVES:This study assessed the prevalence of rare pathogenic variants in sudden cardiac death cases versus controls, and the prevalence and clinical importance of such mutations in an asymptomatic adult population. METHODS:The authors performed whole-exome sequencing in a case-control cohort of 600 adult-onset sudden cardiac death cases and 600 matched controls from 106,098 participants of 6 prospective cohort studies. Observed DNA sequence variants in any of 49 genes with known association to cardiovascular disease were classified as pathogenic or likely pathogenic by a clinical laboratory geneticist blinded to case status. In an independent population of 4,525 asymptomatic adult participants of a prospective cohort study, the authors performed whole-genome sequencing and determined the prevalence of pathogenic or likely pathogenic variants and prospective association with cardiovascular death. RESULTS:Among the 1,200 sudden cardiac death cases and controls, the authors identified 5,178 genetic variants and classified 14 as pathogenic or likely pathogenic. These 14 variants were present in 15 individuals, all of whom had experienced sudden cardiac death-corresponding to a pathogenic variant prevalence of 2.5% in cases and 0% in controls (p < 0.0001). Among the 4,525 participants of the prospective cohort study, 41 (0.9%) carried a pathogenic or likely pathogenic variant and these individuals had 3.24-fold higher risk of cardiovascular death over a median follow-up of 14.3 years (p = 0.02). CONCLUSIONS:Gene sequencing identifies a pathogenic or likely pathogenic variant in a small but potentially important subset of adults experiencing sudden cardiac death; these variants are present in ?1% of asymptomatic adults.

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.

Dataset Information

Postmortem genetic screening for the identification, verification, and reporting of genetic variants contributing to the sudden death of the young.

Publications

Postmortem genetic screening for the identification, verification, and reporting of genetic variants contributing to the sudden death of the young.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets