Investigating genetic variants present in a sudden unexpected death of an infant case through molecular autopsy and co-segregation analysis

Mostert, Suné

Investigating genetic variants present in a sudden unexpected death of an infant case through molecular autopsy and co-segregation analysis

Thesis / Dissertation

2026

Publisher

University of Cape Town

Department

Department of Pathology

Faculty

Faculty of Health Sciences

Abstract

Sudden, unexpected deaths must undergo a post-mortem investigation according to South African legislation. Unfortunately, there remain cases where, even after the post-mortem investigation, the cause of death cannot be determined. One hypothesis is that the cause of death is due to molecular changes caused by genetic variants, which cannot be detected using conventional methods. We, therefore, performed a systematic literature review to identify some of these genetic variants associated with sudden unexpected death in infant cases with African ancestry. We looked at some of the disease phenotypes associated with these genetic variants as well as the genetic methods used when performing these assessments. We identified 43 variants in 14 cardiac genes, 16 variants in eight genes previously associated with neurological disorders, and four variants in four genes related to the metabolic system. Finally, we investigated a sudden unexpected death of an infant case using a molecular autopsy. The clinical exomes of the infant and parents were sequenced using the Illumina TruSight One panel for ~4800 genes. After filtering for quality, variants were prioritised, which resulted in 14 variants where pathogenicity was assessed using the American College of Medical Genetics and Genomics and the Association for Molecular Pathology criteria. Five of these variants were of interest within the case context and were thus confirmed in the proband using Sanger sequencing, and segregation analysis was carried out using parental DNA. However, all five of these variants were of unknown significance. Assigning pathogenicity to variants can prove incredibly difficult and time-consuming with limited functional analysis and limited case information, as was proved by this case study. Although the molecular autopsy provides valuable insight and can aid in case investigation, there are currently crucial gaps in the extensive amount of variants that are currently being reported and their interpretation. Furthermore, due to the complex nature of this case, which includes the infant's prematurity, low birth weight, lower respiratory tract infection, and antiretroviral therapy, it would be difficult to confidently link any genetic variant with the cause of death.

Keywords

sudden infant death

genetics

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Masters

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