Post-mortem genetic analysis of sudden unexplained death in a young cohort: a whole-exome sequencing study.
Deleterious variants
Genetic burden
Sudden unexplained death
Susceptibility genes
Whole-exome sequencing
Journal
International journal of legal medicine
ISSN: 1437-1596
Titre abrégé: Int J Legal Med
Pays: Germany
ID NLM: 9101456
Informations de publication
Date de publication:
Nov 2023
Nov 2023
Historique:
received:
29
05
2023
accepted:
15
08
2023
pubmed:
25
8
2023
medline:
25
8
2023
entrez:
25
8
2023
Statut:
ppublish
Résumé
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 < 0.1%) in the 33 candidate genes also highlighted putative roles of these genes in SUD. After incorporating these novel genes, the genetic testing yields of the current SUD cohort elevated from 51.9 to 66.7%. Our study expands understanding of the genetic variants underlying SUD and presents insights that improve the utility of genetic screenings.
Identifiants
pubmed: 37624372
doi: 10.1007/s00414-023-03075-1
pii: 10.1007/s00414-023-03075-1
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1661-1670Subventions
Organisme : National Science Foundation of China
ID : 82070285
Organisme : National Science Foundation of China
ID : 82101971
Organisme : National Postdoctoral Science Foundation of China
ID : 2021M700815
Organisme : Student Scientific Research Program of Shanghai Medical College
ID : QF2203
Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
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