Cardiac channelopathy testing in 274 ethnically diverse sudden unexplained deaths

Wang, Dawei; Shah, Kavisha; Um, Sung Yon; Eng, Lucy S.; Zhou, Bo; Ying, Lin; Mitchell, Adele A.; Nicaj, Leze; Prinz, Mechthild; McDonald, Thomas V.; Sampson, Barbara A.; Tang, Yingying

doi:10.1016/j.forsciint.2014.01.014

Cited by 70 publications

(72 citation statements)

References 37 publications

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“…3 They and others also identified that between 2% and 12% of Sudden Infant Death Syndrome (SIDS) cases were caused by mutations in the LQTS genes. [4][5][6][7] In New Zealand, an LQTS molecular autopsy was first tested in a retrospective cohort of individuals #35 years old, with DNA from the long-deceased victims being extracted from the archived neonatal screening (Guthrie) card. 8 Twenty-two percent of them were positive.…”

Section: Cardiac Genetic Investigation Of Autopsy-negative Sudden Deamentioning

confidence: 99%

“…5 However, such features were also common in a large US series with a likely diagnostic rate of 13%. 7 A good cardiac genetic service is multidisciplinary, usually led by cardiology or pediatric cardiology, with access to electrophysiological expertise, clinical and molecular genetics, genetic counseling, and psychological support. 14 In New Zealand, a senior forensic pathologist forms part of the team.…”

Section: Cardiac Genetic Servicesmentioning

confidence: 99%

“…7,9 Death during In Asian countries, death during sleep in young males is typically due to Brugada syndrome, sometimes linked to the cardiac sodium channel gene SCN5A.…”

Section: Triggers For Sudden Deathmentioning

confidence: 99%

“…The protein is involved in the sarcoplasmic release of calcium, triggering cellular contraction; ^the overall total is taken from combined papers; data from these studies. [3][4][5][6][7][8][9] Abbreviations: SiDS, Sudden infant Death Syndrome; SUDY, sudden unexplained death in the young; CPvT, catecholaminergic polymorphic ventricular tachycardia; eCG, electrocardiography. …”

Section: Resuscitated Sudden Cardiac Deathmentioning

confidence: 99%

“…Diagnostic yield in 144 infants was 13.5% and in 133 noninfants was 19.5%. 7 Not one individual died during strenuous activity. Cost and availability will vary by region, but in general costs are coming down rapidly, and the number of genes we can test is going up exponentially.…”

Section: Which Genes Should Be Tested?mentioning

confidence: 99%

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Cardiac genetic investigation of sudden cardiac death: advances and remaining limitations

Skinner¹,

Morrow²

2015

RRFMS

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Directing a thorough postmortem investigation of a young sudden unexpected death is one opportunity that a forensic pathologist has to save lives. Achieving a diagnosis of an inherited heart condition in the decedent means that family members can be screened for the condition and effective protective therapies can be put into place. Since these conditions are almost always autosomal dominant, 50% of family members are at risk. Diagnosis is achieved through a thorough high-quality autopsy examination, storage and analysis of DNA, and involvement of the family in the investigation, including cardiac tests upon them. Forensic pathologists should form a partnership with a cardiac genetic service and liaise with them in cases of sudden unexplained death, particularly in 1-to 40-year olds, and when cardiomyopathy is diagnosed at autopsy. The molecular autopsy in sudden unexplained death should include the most common long QT genes and RyR2, the cardiac ryanodine gene linked to catecholaminergic polymorphic ventricular tachycardia. Alternatively or in addition, genetic testing can be guided by cardiac findings in first-degree relatives. With such an approach, a diagnosis can be achieved in up to 50%. Most sudden death in young people occurs at sleep, rest or light activity, and not during sport. Pathologists should be aware that long QT and catecholaminergic polymorphic ventricular tachycardia can be misdiagnosed as epilepsy in life. These ion channelopathies and the cardiomyopathies such as hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy can present with drowning in a competent swimmer, straight road car accidents, and death that can be triggered by certain medications or toxins.

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Section: Cardiac Genetic Investigation Of Autopsy-negative Sudden Deamentioning

confidence: 99%

Section: Cardiac Genetic Servicesmentioning

confidence: 99%

“…7,9 Death during In Asian countries, death during sleep in young males is typically due to Brugada syndrome, sometimes linked to the cardiac sodium channel gene SCN5A.…”

Section: Triggers For Sudden Deathmentioning

confidence: 99%

Section: Resuscitated Sudden Cardiac Deathmentioning

confidence: 99%

Section: Which Genes Should Be Tested?mentioning

confidence: 99%

See 3 more Smart Citations

Cardiac genetic investigation of sudden cardiac death: advances and remaining limitations

Skinner¹,

Morrow²

2015

RRFMS

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Genomic Autopsy of Sudden Deaths in Young Individuals

et al. 2021

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IMPORTANCEPostmortem genetic testing of young individuals with sudden death has previously identified pathogenic gene variants. However, prior studies primarily considered highly penetrant monogenic variants, often without detailed decedent and family clinical information.OBJECTIVE To assess genotype and phenotype risk in a diverse cohort of young decedents with sudden death and their families.DESIGN, SETTING, AND PARTICIPANTS Pathological and whole-genome sequence analysis was conducted in a cohort referred from a national network of medical examiners. Cases were accrued prospectively from May 2015 to March 2019 across 24 US states. Analysis began September 2016 and ended November 2020.EXPOSURES Evaluation of autopsy and clinical data integrated with whole-genome sequence data and family member evaluation.RESULTS A total of 103 decedents (mean [SD] age at death, 23.7 [11.9] years; age range, 1-44 years), their surviving family members, and 140 sex-and genetic ancestry-matched controls were analyzed. Among 103 decedents, autopsy and clinical data review categorized 36 decedents with postmortem diagnoses, 23 decedents with findings of uncertain significance, and 44 with sudden unexplained death. Pathogenic/likely pathogenic (P/LP) genetic variants in arrhythmia or cardiomyopathy genes were identified in 13 decedents (12.6%). A multivariable analysis including decedent phenotype, ancestry, and sex demonstrated that younger decedents had a higher burden of P/LP variants and select variants of uncertain significance (effect size, −1.64; P = .001). These select, curated variants of uncertain significance in cardiac genes were more common in decedents than controls (83 of 103 decedents [86%] vs 100 of 140 controls [71%]; P = .005), and decedents harbored more rare cardiac variants than controls (2.3 variants per individual vs 1.8 in controls; P = .006). Genetic testing of 31 parent-decedent trios and 14 parent-decedent dyads revealed 8 transmitted P/LP variants and 1 de novo P/LP variant. Incomplete penetrance was present in 6 of 8 parents who transmitted a P/LP variant.CONCLUSIONS AND RELEVANCE Whole-genome sequencing effectively identified P/LP variants in cases of sudden death in young individuals, implicating both arrhythmia and cardiomyopathy genes. Genomic analyses and familial phenotype association suggest potentially additive, oligogenic risk mechanisms for sudden death in this cohort.

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A SNaPshot assay for detection of 45 mutations in the SCN5A gene in the Chinese Han Population

Wang

Wang²,

et al. 2018

Electrophoresis

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Sudden cardiac death (SCD) occurs frequently in forensic practice and results in no visible pathological changes that can be detected in an autopsy. In recent years, the genetic background has been emphasized when examining SCD cases. The aim of this study is to establish a feasible system to detect SCD-related genes for forensic DNA laboratories. Forty-five reported SCD-associated SNPs from sodium voltage-gated channel alpha subunit 5 (SCN5A) were considered in our experiment. We established a SNaPshot assay for the typing of 45 SNPs using multiplex PCR and the minisequencing technique. Two multiplex PCRs were performed and optimized to cover 14 and 16 DNA fragments. The SCD victims came from the Chinese Han population residing in Shanxi and Chongqing provinces and were examined and compared with a non-SCD group and with normal healthy individuals. A missense mutation at rs1805124 (H558R) was detected in the Chinese Han population in this study. A SNaPshot assay can be performed in any forensic DNA laboratory and would be capable of meeting the increasing demand for SCD detection. This method would also be beneficial for screening at-risk in family members of SCD victims.

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Cardiac channelopathy testing in 274 ethnically diverse sudden unexplained deaths

Cited by 70 publications

References 37 publications

Cardiac genetic investigation of sudden cardiac death: advances and remaining limitations

Cardiac genetic investigation of sudden cardiac death: advances and remaining limitations

Genomic Autopsy of Sudden Deaths in Young Individuals

A SNaPshot assay for detection of 45 mutations in the SCN5A gene in the Chinese Han Population

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