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Updated: Aug 18, 2026
Extraction of Diatom DNA from Water Samples and Tissues
Published on: November 10, 2023
Pathogenesis of unexplained drowning: new insights from a molecular autopsy
David J Tester1, Laura J Kopplin, Wendy Creighton
1Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, Minn 55905, USA.
Objective:
To perform a molecular autopsy involving the RyR2-encoded cardiac ryanodine receptor/calcium release channel to determine whether mutations responsible for catecholaminergic polymorphic ventricular tachycardia (CPVT) represent a novel pathogenic basis for unexplained drownings.
Methods:
A cardiac channel molecular autopsy was performed on 2 individuals who died of unexplained drowning and whose cases were referred to the Sudden Death Genomics Laboratory at the Mayo Clinic in Rochester, Minn. Comprehensive mutational analysis of all 60 protein-encoded exons of the 5 long QT syndrome-causing cardiac channel genes and a targeted analysis of 18 RyR2 exons known to host RyR2-mediated CPVT-causing mutations (CPVT1) was performed using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing.
Results:
Both individuals harbored novel mutations in RyR2. Postmortem mutational analysis revealed a familial missense mutation in exon 14, R414C, in a 16-year-old girl. A 9-year-old boy possessed a sporadic missense mutation in exon 49, V2475F. Both amino acid positions involve highly conserved residues that localize to critical functional domains in the calcium release channel. Neither substitution was present in 1000 reference alleles.
Conclusions:
This molecular autopsy study provides proof of principle that RyR2 mutations can underlie some unexplained drownings. A population-based genetic epidemiology study that involves molecular autopsies of individuals who die of unexplained drowning is needed to determine the prevalence and spectrum of KCNQ1 and now RyR2 mutations as potential pathogenic mechanisms for drowning.
Insights
Genetic analysis of RyR2 mutations in unexplained drowning cases revealed novel variants. This suggests a new cause for sudden cardiac death in young individuals, highlighting the need for broader genetic screening.
Area of Science:
- Cardiovascular Genetics
- Molecular Autopsy
- Sudden Death Genomics
Background:
- Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic heart rhythm disorder.
- Unexplained drownings represent a significant cause of mortality, particularly in younger individuals.
- Genetic mutations in cardiac ion channels are increasingly recognized as causes of sudden cardiac death.
Observation:
- A molecular autopsy was conducted on two individuals who died from unexplained drowning.
- Comprehensive genetic analysis focused on cardiac channel genes, including RyR2.
- Novel mutations in the RyR2 gene were identified in both cases.
Findings:
- One individual had a familial missense mutation (R414C) in RyR2 exon 14.
- The second individual had a sporadic missense mutation (V2475F) in RyR2 exon 49.
- These mutations occurred at conserved residues within critical functional domains of the calcium release channel.
Implications:
- RyR2 mutations can serve as a novel pathogenic basis for some unexplained drownings.
- This study provides proof of principle for RyR2's role in sudden cardiac death.
- Further population-based genetic studies are warranted to determine the prevalence of RyR2 and KCNQ1 mutations in drowning fatalities.
