Postmortem genetic analysis of sudden unexplained death syndrome under 50 years of age: A next-generation sequencing study

Hata, Yukiko; Kinoshita, Koshi; Mizumaki, Koichi; Yamaguchi, Yoshiaki; Hirono, Keiichi; Ichida, Fukiko; Takasaki, Asami; Mori, Hisashi; Nishida, Naoki

doi:10.1016/j.hrthm.2016.03.038

Cited by 45 publications

(38 citation statements)

References 31 publications

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“…Our study supports the findings of others with evidence that concealed cardiomyopathy and channelopathy may also result in SUD of young adults. 7,11,12 …”

Section: Discussionmentioning

confidence: 99%

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An Autopsy Case of Sudden Unexpected Death of a Young Adult in a Hot Bath: Molecular Analysis Using Next-Generation DNA Sequencing

Hata

Kinoshita

Nishida

2017

Clin Med Insights Case Rep

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We report a case of sudden unexpected death of a young woman who was found in a bathtub of hot water. The autopsy concluded that all possible causes of sudden loss of consciousness, except cardiac origin, could be excluded. However, the heart did not show any obvious pathological changes. We used next-generation DNA sequencing (NGS) to examine 73 genes and detected 3 rare, potentially pathogenic variants with minor allele frequencies ⩽1.0%. The pathogenicity of these variants was evaluated using 8 in silico predictive algorithms, and SCN5A_p.Gly289Ser, CACNB2_p.Ser502Leu, and MYH11_p.Lys1573Glu were detected as possible pathogenic variants. Inherited heart disease is a likely cause of sudden unexpected deaths of young people in hot baths, even before the clinical manifestation of the disease. In the future, molecular analysis by NGS may help to predict young to early middle-aged people who could be at risk of sudden arrhythmogenic fatality in hot baths.

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“…Our study supports the findings of others with evidence that concealed cardiomyopathy and channelopathy may also result in SUD of young adults. 7,11,12 …”

Section: Discussionmentioning

confidence: 99%

“…Such findings may prompt further genetic analysis, even if the observed pathological changes do not fulfill the commonly used diagnostic criteria of structural heart diseases. 7,15 …”

Section: Discussionmentioning

confidence: 99%

An Autopsy Case of Sudden Unexpected Death of a Young Adult in a Hot Bath: Molecular Analysis Using Next-Generation DNA Sequencing

Hata

Kinoshita

Nishida

2017

Clin Med Insights Case Rep

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“…Recent studies show NGS to be useful for considering the mechanism of SUD or severe arrhythmogenic events ; however, population database and/or in silico predictive tools are frequently needed to evaluate the pathogenicity of candidate variants without confirmation of a positive relationship between clinical presentation and genetic variation. Further, Le Scouarnec and Kapplinger recently reported that many of the same variants were identified in Brugada syndrome patients and controls, indicating that identification of a variant does not demonstrate the presence of disease.…”

Section: Discussionmentioning

confidence: 99%

“…In the general population, it can be difficult to diagnose arrhythmogenic SUD by routine autopsy examination, because some cases do not show any significant pathological change . Recently, arrhythmogenic events due to inherited heart disease have been considered a significant cause of SUD and molecular analyses at autopsy of “negative” or “unexplained” SUD cases, termed “molecular autopsy”, have been performed . These examinations, mainly targeting cardiac channel‐related genes, detected several gene variants .…”

Section: Introductionmentioning

confidence: 99%

“…Coll et al showed the significance of using NGS for genetic analysis of SUDEP cases. We recently reported that the combination of careful pathological examination and molecular autopsy using NGS is useful for detecting subclinical or early clinical signs of non‐channelopathy inherited heart disease in cases of sudden unexplained death syndrome (SUDS) . Here, we attempted detailed pathological examination of the heart and genetic screening using NGS to detect arrhythmogenic potential in the victims of epilepsy‐related SUD.…”

Section: Introductionmentioning

confidence: 99%

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Epilepsy‐related sudden unexpected death: targeted molecular analysis of inherited heart disease genes using next‐generation DNA sequencing

et al. 2016

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Inherited heart disease causing electric instability in the heart has been suggested to be a risk factor for sudden unexpected death in epilepsy (SUDEP). The purpose of this study was to reveal the correlation between epilepsy-related sudden unexpected death (SUD) and inherited heart disease. Twelve epilepsy-related SUD cases (seven males and five females, aged 11-78 years) were examined. Nine cases fulfilled the criteria of SUDEP, and three cases died by drowning. In addition to examining three major epilepsy-related genes, we used next-generation sequencing (NGS) to examine 73 inherited heart disease-related genes. We detected both known pathogenic variants and rare variants with minor allele frequencies of <0.5%. The pathogenicity of these variants was evaluated and graded by eight in silico predictive algorithms. Six known and six potential rare variants were detected. Among these, three known variants of LDB3, DSC2 and KCNE1 and three potential rare variants of MYH6, DSP and DSG2 were predicted by in silico analysis as possibly highly pathogenic in three of the nine SUDEP cases. Two of three cases with desmosome-related variants showed mild but possible significant right ventricular dysplasia-like pathology. A case with LDB3 and MYH6 variants showed hypertrabeculation of the left ventricle and severe fibrosis of the cardiac conduction system. In the three drowning death cases, one case with mild prolonged QT interval had two variants in ANK2. This study shows that inherited heart disease may be a significant risk factor for SUD in some epilepsy cases, even if pathological findings of the heart had not progressed to an advanced stage of the disease. A combination of detailed pathological examination of the heart and gene analysis using NGS may be useful for evaluating arrhythmogenic potential of epilepsy-related SUD.

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Molecular autopsy in Chinese sudden cardiac death in the young

Kwok,

Ho,

Shih

et al. 2024

American J of Med Genetics Pt A

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Inherited cardiovascular conditions are significant causes of sudden cardiac death in the young (SCDY), making their investigation using molecular autopsy and prevention a public health priority. However, the molecular autopsy data in Chinese population is lacking. The 5‐year result (2017–2021) of molecular autopsy services provided for victims of SCDY (age 1–40 years) was reviewed. The outcome of family cascade genetic screening and clinical evaluation was reviewed. A literature review of case series reporting results of molecular autopsy on SCDY in 2016–2023 was conducted. Among the 41 decedents, 11 were found to carry 13 sudden cardiac death (SCD)‐causative genetic variants. Likely pathogenic (LP) variants were identified in the DSP, TPM1, TTN, and SCN5A genes. Cascade genetic testing identified four family members with LP variants. One family member with familial TPM1 variant was found to have hypertrophic cardiomyopathy upon clinical evaluation. This study provided insight into the genetic profile of molecular autopsy in a Chinese cohort of SCDY. The detection of important SCD‐causative variants through molecular autopsy has facilitated family cascade screening by targeted genetic testing and clinical evaluation of at‐risk family members. A literature review of the current landscape of molecular autopsy in the investigation of SCDY was conducted.

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Postmortem genetic analysis of sudden unexplained death syndrome under 50 years of age: A next-generation sequencing study

Cited by 45 publications

References 31 publications

An Autopsy Case of Sudden Unexpected Death of a Young Adult in a Hot Bath: Molecular Analysis Using Next-Generation DNA Sequencing

An Autopsy Case of Sudden Unexpected Death of a Young Adult in a Hot Bath: Molecular Analysis Using Next-Generation DNA Sequencing

Epilepsy‐related sudden unexpected death: targeted molecular analysis of inherited heart disease genes using next‐generation DNA sequencing

Molecular autopsy in Chinese sudden cardiac death in the young

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