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Re-evaluation of single nucleotide variants and identification of structural variants in a cohort of 45 sudden unexplained death cases
- Source :
- International Journal of Legal Medicine, 135 (4), International Journal of Legal Medicine
- Publication Year :
- 2021
- Publisher :
- ETH Zurich, 2021.
-
Abstract
- Sudden unexplained death (SUD) takes up a considerable part in overall sudden death cases, especially in adolescents and young adults. During the past decade, many channelopathy- and cardiomyopathy-associated single nucleotide variants (SNVs) have been identified in SUD studies by means of postmortem molecular autopsy, yet the number of cases that remain inconclusive is still high. Recent studies had suggested that structural variants (SVs) might play an important role in SUD, but there is no consensus on the impact of SVs on inherited cardiac diseases. In this study, we searched for potentially pathogenic SVs in 244 genes associated with cardiac diseases. Whole-exome sequencing and appropriate data analysis were performed in 45 SUD cases. Re-analysis of the exome data according to the current ACMG guidelines identified 14 pathogenic or likely pathogenic variants in 10 (22.2%) out of the 45 SUD cases, whereof 2 (4.4%) individuals had variants with likely functional effects in the channelopathy-associated genes SCN5A and TRDN and 1 (2.2%) individual in the cardiomyopathy-associated gene DTNA. In addition, 18 structural variants (SVs) were identified in 15 out of the 45 individuals. Two SVs with likely functional impairment were found in the coding regions of PDSS2 and TRPM4 in 2 SUD cases (4.4%). Both were identified as heterozygous deletions, which were confirmed by multiplex ligation-dependent probe amplification. In conclusion, our findings support that SVs could contribute to the pathology of the sudden death event in some of the cases and therefore should be investigated on a routine basis in suspected SUD cases.<br />International Journal of Legal Medicine, 135 (4)<br />ISSN:0937-9827<br />ISSN:1437-1596
- Subjects :
- Male
Exome sequencing
Muscle Proteins
340 Law
030204 cardiovascular system & hematology
NAV1.5 Voltage-Gated Sodium Channel
Cohort Studies
Death, Sudden
0302 clinical medicine
Medicine
Single nucleotide variant (SNV)
Young adult
Child
Exome
Genetics
0303 health sciences
Middle Aged
10218 Institute of Legal Medicine
Child, Preschool
Cohort
Female
Original Article
Identification (biology)
Switzerland
Adult
Adolescent
Heart Diseases
TRPM Cation Channels
610 Medicine & health
10071 Functional Genomics Center Zurich
Forensics
Massively parallel sequencing (MPS)
Structural variants (SV)
Copy number variation (CNV)
Polymorphism, Single Nucleotide
Sudden death
Pathology and Forensic Medicine
Open Reading Frames
03 medical and health sciences
510 Mathematics
Channelopathy
Humans
Gene
030304 developmental biology
Alkyl and Aryl Transferases
business.industry
Neuropeptides
Infant
medicine.disease
2734 Pathology and Forensic Medicine
Dystrophin-Associated Proteins
Genomic Structural Variation
Carrier Proteins
business
Subjects
Details
- Language :
- English
- ISSN :
- 09379827 and 14371596
- Database :
- OpenAIRE
- Journal :
- International Journal of Legal Medicine, 135 (4), International Journal of Legal Medicine
- Accession number :
- edsair.doi.dedup.....bd276e20a9c97b6b08ad3b3724a25f9c
- Full Text :
- https://doi.org/10.3929/ethz-b-000491072