Post-mortem genetic analysis of sudden unexplained death in a young cohort: a whole-exome sequencing study

Sudden unexplained death (SUD) constitutes a considerable portion of unexpected sudden death in the young. Molecular autopsy has proved to be an efficient diagnostic tool in the multidisciplinary management of SUD. Yet, many cases remain undiagnosed using the widely adopted targeted genetic screenin...

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Bibliographic Details
Published in:International journal of legal medicine 2023-11, Vol.137 (6), p.1661-1670
Main Authors: Wang, Shouyu, Chen, Yongsheng, Du, Jianghua, Wang, Zhimin, Lin, Zijie, Hong, Guanghui, Qu, Dong, Shen, Yiwen, Li, Liliang
Format: Article
Language:English
Subjects:
Adolescent
Adult
Autopsies
Cardiac arrhythmia
Cardiomyopathy
China
Cohort Studies
Criminal investigations
Death, Sudden - etiology
Exome Sequencing
Female
Forensic Medicine
Genes
Genetic Predisposition to Disease
Genetic Testing
Genomes
Genomics
Humans
Legal medicine
Male
Medical Law
Medicine
Medicine & Public Health
Muscular Diseases - genetics
Original Article
Substrates
Young Adult
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Summary:Sudden unexplained death (SUD) constitutes a considerable portion of unexpected sudden death in the young. Molecular autopsy has proved to be an efficient diagnostic tool in the multidisciplinary management of SUD. Yet, many cases remain undiagnosed using the widely adopted targeted genetic screening strategies. Here, we investigated the genetic substrates of a young SUD cohort (18–40 years old) from China using whole-exome sequencing (WES), with the primary aim to identify novel SUD susceptibility genes. Within 255 previously acknowledged SUD-associated genes, 21 variants with likely functional effects (pathogenic/likely pathogenic) were identified in 51.9% of the SUD cases. More importantly, a set of 33 candidate genes associated with myopathy were identified to be novel susceptibility genes for SUD. Comparative analysis of the cumulative PHRED-scaled CADD score and polygenetic burden score showed that the amount and deleteriousness of variants in the 255 SUD-associated genes and the 33 candidate genes identified by this study were significantly higher compared with 289 randomly selected genes. A significantly higher genetic burden of rare variants (MAF 
ISSN:0937-9827
1437-1596
1437-1596
DOI:10.1007/s00414-023-03075-1