Unveiling a sudden unexplained death case by whole exome sequencing and bioinformatic analysis.
Acyl-CoA Dehydrogenase, Long-Chain
/ genetics
Adult
Carrier Proteins
/ genetics
Computational Biology
/ methods
Connectin
/ genetics
Death, Sudden, Cardiac
/ etiology
Genetic Testing
/ methods
Heart Rate
/ genetics
Humans
Male
Mutation
Ryanodine Receptor Calcium Release Channel
/ genetics
Exome Sequencing
/ methods
arrhythmia
bioinformatics
sudden cardiac death
whole exome sequencing
Journal
Molecular genetics & genomic medicine
ISSN: 2324-9269
Titre abrégé: Mol Genet Genomic Med
Pays: United States
ID NLM: 101603758
Informations de publication
Date de publication:
04 2020
04 2020
Historique:
received:
16
08
2019
revised:
12
01
2020
accepted:
30
01
2020
pubmed:
27
2
2020
medline:
7
4
2021
entrez:
27
2
2020
Statut:
ppublish
Résumé
Sudden unexplained death (SUD) refers to cases of sudden death where autopsy fails to identify any cardiac or extracardiac underlying cause. Guideline-directed standard genetic testing identifies a disease-causing mutation in less than one-third of cases of SUD. Conversely, whole exome sequencing (WES) may provide the key to solve most cases of SUD even after several years from the subject's death. We report on a case of sudden unexpected death of a 37-year-old male, with inconclusive autopsy conducted 14 years ago. A recent reevaluation through WES was performed on DNA extracted from left ventricular samples. A multiple step process including several "in silico" tools was applied to identify potentially pathogenic variants. Data analysis was based on a 562 gene panel, including 234 candidate genes associated with sudden cardiac death or heart diseases, with the addition of 328 genes highly expressed in the heart. WebGestalt algorithms were used for association enrichment analysis of all genes with detected putative pathogenic variants. WES analysis identified four potentially pathogenic variants: RYR2:c.12168G>T, TTN:c.11821C>T (rs397517804), MYBPC3:c.1255C>T (rs368770848), and ACADVL:c.848T>C (rs113994167). WebGestalt algorithms indicated that their combination holds an unfavorable arrhythmic susceptibility which conceivably caused the occurrence of the events leading to our subject's sudden death. Associating WES technique with online prediction algorithms may allow the recognition of genetic mutations potentially responsible for otherwise unexplained deaths.
Sections du résumé
BACKGROUND
Sudden unexplained death (SUD) refers to cases of sudden death where autopsy fails to identify any cardiac or extracardiac underlying cause. Guideline-directed standard genetic testing identifies a disease-causing mutation in less than one-third of cases of SUD. Conversely, whole exome sequencing (WES) may provide the key to solve most cases of SUD even after several years from the subject's death.
METHODS
We report on a case of sudden unexpected death of a 37-year-old male, with inconclusive autopsy conducted 14 years ago. A recent reevaluation through WES was performed on DNA extracted from left ventricular samples. A multiple step process including several "in silico" tools was applied to identify potentially pathogenic variants. Data analysis was based on a 562 gene panel, including 234 candidate genes associated with sudden cardiac death or heart diseases, with the addition of 328 genes highly expressed in the heart. WebGestalt algorithms were used for association enrichment analysis of all genes with detected putative pathogenic variants.
RESULTS
WES analysis identified four potentially pathogenic variants: RYR2:c.12168G>T, TTN:c.11821C>T (rs397517804), MYBPC3:c.1255C>T (rs368770848), and ACADVL:c.848T>C (rs113994167). WebGestalt algorithms indicated that their combination holds an unfavorable arrhythmic susceptibility which conceivably caused the occurrence of the events leading to our subject's sudden death.
CONCLUSION
Associating WES technique with online prediction algorithms may allow the recognition of genetic mutations potentially responsible for otherwise unexplained deaths.
Identifiants
pubmed: 32101375
doi: 10.1002/mgg3.1182
pmc: PMC7196487
doi:
Substances chimiques
Carrier Proteins
0
Connectin
0
RyR2 protein, human
0
Ryanodine Receptor Calcium Release Channel
0
TTN protein, human
0
myosin-binding protein C
0
Acyl-CoA Dehydrogenase, Long-Chain
EC 1.3.8.8
ACADVL protein, human
EC 1.3.8.9
Types de publication
Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1182Informations de copyright
© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.
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