Structured postmortem genetic counselling and testing in sudden unexpected death among young adults in the Netherlands: Results and implications regarding hereditary risk

Technical Summary: Structured Postmortem Genetic Counselling and Testing in Sudden Unexpected Death (NODOV Procedure)

Problem Statement
Sudden unexpected death (SUD) in young adults (aged 18–45) remains a critical clinical and forensic challenge. While conventional autopsy is the gold standard for determining cause of death, it fails to identify a cause in approximately 30–40% of cases, particularly those classified as Sudden Arrhythmic Death Syndrome (SADS). In these "autopsy-negative" cases, the underlying etiology is often a concealed hereditary cardiovascular disorder (e.g., channelopathies or cardiomyopathies). Without a definitive diagnosis, surviving relatives face uncertainty regarding the cause of death and remain at risk for undetected hereditary conditions, potentially leading to preventable sudden deaths within the family. Previous studies suggest postmortem genetic testing can identify pathogenic variants in roughly 22% of SUD cases, but the integration of such testing with structured genetic counselling in a standardized national framework requires evaluation.

Methodology
This multicentre prospective cohort study, conducted in the Netherlands between September 2022 and October 2025, evaluated the NODOV (Nader Onderzoek DoodsOorzaak Volwassenen) procedure. The study included 100 individuals aged 18–45 who experienced sudden, unexpected death of presumed natural origin.

The investigation protocol followed a structured, multidisciplinary approach:

1. Initial Screening: All cases underwent toxicological analysis, computed tomography (CT) imaging, and conventional autopsy.
2. Selection for Genetic Analysis: Genetic counselling and testing were offered to the next of kin in 50 cases where conventional modalities either failed to establish a cause of death or indicated a potential hereditary cardiovascular disorder (e.g., signs of cardiomyopathy, myocardial infarction, or unexplained death).
3. Pre-test Genetic Counselling: Before testing, a genetic counsellor reviewed the deceased's medical and family history, discussed potential outcomes, and obtained consent.
4. Genetic Testing Strategy:
   • Sample Source: DNA was extracted from freshly frozen or paraffin-embedded spleen tissue obtained during autopsy.
   • Technique: Molecular analyses primarily utilized Whole-Exome Sequencing (WES), filtered against targeted gene panels (arrhythmia, cardiomyopathy, dyslipidaemia, and phenotype-directed panels).
   • Phenotype-Guided Selection: Gene panel selection was tailored based on autopsy findings, suspected disease mechanisms, and family history. In select cases with known familial variants or affected surviving relatives, testing focused on specific variants or included copy number variant (CNV) analysis not possible on tissue DNA.
   • Classification: Variants were classified according to American College of Medical Genetics and Genomics (ACMG) guidelines.
5. Post-test Counselling: Results were communicated to families, followed by tailored recommendations for clinical screening and cascade testing for at-risk relatives.

Key Results

• Testing Success: Genetic testing was successfully performed in 46 out of the 50 eligible families (92%).
• Diagnostic Yield: Pathogenic or likely pathogenic variants were identified in 6 out of 46 cases (13.0%).
  • Genes Identified: CACNA1C, BAG3, MYBPC3, LDL-R, KCNJ2, and PKD1.
  • Correlation with Autopsy:
    • Two cases with channelopathy genes (CACNA1C, KCNJ2) were autopsy-negative.
    • Two cases with cardiomyopathy genes (BAG3, MYBPC3) showed visible cardiomyopathy signs at autopsy.
    • One case with LDL-R (familial hypercholesterolemia) presented with significant coronary artery disease (CAD).
    • One case with PKD1 (polycystic kidney disease) presented with polycystic kidneys, liver, and a brain aneurysm.
  • Variants of Uncertain Significance (VUS): Three additional cases yielded VUS.
• Family Recommendations:
  • For the 6 families with a positive genetic diagnosis, cascade genetic testing and specific clinical follow-up were recommended.
  • For the 43 families without a genetic diagnosis (gene-elusive), a clinical geneticist provided tailored advice based on the autopsy findings and clinical guidelines. Recommendations ranged from one-time extensive cardiac/vascular evaluation (for autopsy-negative cases) to periodic cardiovascular risk management (for gene-elusive CAD) or specialist follow-up (for autopsy-positive cases).
• Counselling Impact: Pre-test counselling was instrumental in guiding testing strategies, such as identifying families where testing affected relatives first allowed for the confirmation of a variant in the deceased's tissue later.

Significance and Claims
The paper posits that the NODOV procedure represents a significant advancement in the investigation of sudden unexpected death in young adults by integrating molecular autopsy with structured genetic counselling. The authors claim several key contributions:

1. Complementary Diagnostic Value: The study demonstrates that postmortem genetic testing provides critical diagnostic information even in cases where conventional autopsy is negative (15.4% yield in autopsy-negative cases in this cohort), supporting the complementary role of molecular investigations.
2. Structured Multidisciplinary Framework: The integration of toxicology, imaging, autopsy, and genetics into a single, standardized procedure (NODOV) improves the determination of the cause of death and identifies hereditary cardiovascular disorders that would otherwise remain undetected.
3. Preventive Potential: By combining comprehensive postmortem evaluation with phenotype-directed genetic testing, the procedure facilitates targeted cascade screening and individualized clinical follow-up for surviving relatives. This approach aims to reduce morbidity and mortality in at-risk families through early detection and management.
4. Ethical and Socioeconomic Accessibility: The study highlights the importance of removing financial barriers (providing services free of charge or via insurance) and ensuring voluntary participation with full autonomy, thereby enhancing the representativeness of the cohort and the ethical integrity of the research.

The authors conclude that while the diagnostic yield (13%) was lower than some previous broad estimates (22.1%), this may reflect a more precise, phenotype-driven selection of cases and the inclusion of toxicological causes. They assert that the NODOV procedure effectively extends the scope of postmortem investigation beyond establishing a cause of death to enabling preventive strategies for families, supporting the inclusion of genetic counselling and testing as integral components of standard SUD investigations.