Sudden unexpected death in infants: a forensic genetic investigation in a South African cohort

Sudden unexpected death in infants (SUDI) is a devastating event, and unfortunately occurs frequently in South Africa. The emerging molecular autopsy has added value to SUDI investigations by revealing genetic variants which contributed to their demise. Motivated by the value of this concept to family members as well as the limited research of SUDI locally, the aim of this study was to explore molecular autopsies in the medico-legal investigation of SUDI cases in South Africa. A 5-year retrospective study of 1.199 SUDI admissions to Salt River Mortuary, Cape Town showed that 110 (9.%) cases were still under investigation, while most had infectious causes of death. An ethical framework was established and used to prospectively recruit 201 SUDI cases from Salt River Mortuary. A pilot quality assessment of DNA from blood, buccal cells and formalin fixed paraffin embedded tissue motivated the prospective collection of blood samples. Three variants previously associated with the risk of infections (IL-6 rs1800795.G>C; TNF-α rs1800629.G>A; TLR4 rs4986790.A>G) were genotyped in the sampled cohort. The allele frequency data generated suggested a possible association between each of these variants and an infection-related cause of death in SUDI. Targeted genotyping of candidate variants revealed several pathogenic mutations, including a twin who was homozygous T/T for a founder mutation, GALT rs111033690.C>G/T, causative of galactosaemia (previously undiagnosed). Follow up with the family revealed that the other twin had subsequently demised. Additionally, 43 genes previously associated with cardiac arrhythmias, were sequenced in a subset of cases (n.=.19) and parental samples. Putative pathogenic variants were identified in four infants, and four additional novel variants were found. Lastly, using a hypothesis-free approach, clinical exome sequencing was performed on two cases, which suggested one infant was immune-compromised and the second may have had bronchopulmonary dysplasia. The findings in this study highlight possible new candidate variants to assess in SUDI cases, and has directly contributed to the development of a molecular autopsy which is locally relevant. It is evident that until newborn screening becomes routine and accessible in South Africa, molecular autopsies should include testing for inherited metabolic disorders, as it holds potential to save lives