Genetic evaluation of sudden unexpected death in infants and children

The Dutch Postmortem Evaluation of Sudden Unexpected Death in Infants and Children (PESUDIC) procedure investigates cases of sudden unexpected death in infants and children (SUDI and SUDC). These deaths may have a genetic basis. This national retrospective study examined the yield of genetic testing in PESUDIC cases to provide recommendations for genetic evaluation of SUDI and SUDC. Children who underwent the PESUDIC procedure from 2016 to 2022 and had genetic testing performed were included. They were categorized into three groups: (A) cases where standard PESUDIC investigations yielded contributive findings; (B) cases with no contributive findings from standard investigations, but with comorbidities present; (C) cases without contributive findings from standard investigations or comorbidities. The indication and type of genetic testing were determined based on differential diagnostic considerations. Standardized data on medical history, postmortem diagnostic outcomes, and genetic testing outcomes were collected. Genetic testing was performed in 102 cases (median age 1.1 years, 52% male). Prevalence of (likely) pathogenic (LP/P) variants was 20% in group A (n = 66), 27% in group B (n = 11), and 28% in group C (n = 25). In 13 out of these 20 cases, these variants were considered contributive to the cause of death, involving both cardiac (8%) and non-cardiac pathways (5%).

We found a high diagnostic yield from genetic testing in cases of SUDI and SUDC, particularly when routine postmortem examination failed to identify a cause of death. These findings support the usefulness of comprehensive genetic evaluation in cases of unexpected paediatric death.

• Previous studies have identified both cardiac and non-cardiac genetic causes of death for cases with pediatric sudden death. • Identifying a genetic cause can have profound implications for family members, such as enabling targeted surveillance and preventive interventions for at-risk family members and informing reproductive decision-making.

• Genetic evaluation of infants and children with sudden unexpected death has a high diagnostic yield, especially when routine postmortem examinations did not identify a cause of death. • In a comprehensive postmortem investigation of sudden pediatric death broad genetic testing involving both cardiac and noncardiac pathways should be considered.