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Updated: Jun 13, 2025
Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
Published on: January 16, 2019
Identifying the Pathogenic Variants in Heart Genes in Vietnamese Sudden Unexplained Death Victims by Next-Generation
Tho Nguyen Tat1, Nguyen Thi Kim Lien2, Hung Luu Sy1
1Department of Forensic Medicine, Hanoi Medical University, 1 Ton That Tung Str., Dongda, Hanoi 100000, Vietnam.
Insights
Next-generation sequencing identified genetic variants in 15 of 40 young sudden unexplained death cases. This research aids in understanding inherited cardiovascular diseases and screening at-risk family members.
Area of Science:
- Forensic Genetics
- Cardiovascular Genetics
- Molecular Diagnostics
Background:
- Sudden unexplained deaths (SUDs) in young individuals (<40 years) often lack clear causes after autopsy.
- Inherited cardiovascular diseases are frequently implicated in a majority of these SUD cases.
- Identifying genetic underpinnings is crucial for understanding SUD etiology and preventing future occurrences.
Purpose of the Study:
- To investigate the genetic basis of sudden unexplained deaths in young individuals with non-diagnostic cardiac abnormalities.
- To identify pathogenic variants associated with inherited cardiomyopathies and channelopathies in SUD cases.
- To assess the utility of targeted next-generation sequencing (NGS) in diagnosing SUDs.
Main Methods:
- Targeted next-generation sequencing (NGS) was employed.
- 167 genes linked to inherited cardiomyopathies and channelopathies were analyzed.
- 40 young SUD cases with non-diagnostic structural cardiac abnormalities were studied.
Main Results:
- Genetic variants were identified in 15 out of 40 cases (37.5%).
- Seventeen variants were found in genes including *AKAP9*, *MYBPC3*, *RYR2*, and *SCN5A*.
- Four novel variants were predicted as pathogenic, while three require further experimental validation.
Conclusions:
- Targeted NGS is a valuable tool for identifying pathogenic variants in sudden unexplained death victims.
- The findings contribute to understanding the genetic causes of SUDs.
- This research provides a basis for genetic screening in families of SUD victims to assess sudden death risk.
Abstract:
In forensics, one-third of sudden deaths remain unexplained after a forensic autopsy. A majority of these sudden unexplained deaths (SUDs) are considered to be caused by inherited cardiovascular diseases. In this study, we investigated 40 young SUD cases (<40 years), with non-diagnostic structural cardiac abnormalities, using Targeted NGS (next-generation sequencing) for 167 genes previously associated with inherited cardiomyopathies and channelopathies. Fifteen cases identified 17 variants on related genes including the following: AKAP9, CSRP3, GSN, HTRA1, KCNA5, LAMA4, MYBPC3, MYH6, MYLK, RYR2, SCN5A, SCN10A, SLC4A3, TNNI3, TNNI3K, and TNNT2. Of these, eight variants were novel, and nine variants were reported in the ClinVar database. Five were determined to be pathogenic and four were not evaluated. The novel and unevaluated variants were predicted by using in silico tools, which revealed that four novel variants (c.5187_5188dup, p.Arg1730llefsTer4 in the AKAP9 gene; c.1454A>T, p.Lys485Met in the MYH6 gene; c.2535+1G>A in the SLC4A3 gene; and c.10498G>T, p.Asp3500Tyr in the RYR2 gene) were pathogenic and three variants (c.292C>G, p.Arg98Gly in the TNNI3 gene; c.683C>A, p.Pro228His in the KCN5A gene; and c.2275G>A, p.Glu759Lys in the MYBPC3 gene) still need to be further verified experimentally. The results of our study contributed to the general understanding of the causes of SUDs. They provided a scientific basis for screening the risk of sudden death in family members of victims. They also suggested that the Targeted NGS method may be used to identify the pathogenic variants in SUD victims.
