Massively parallel sequencing in sudden unexpected death in infants: A case report in South Africa

Abstract

Sudden unexpected death in infants (SUDI) is a devastating event for a family, and unfortunately occurs relatively frequently in South Africa. These cases are referred for a forensic post-mortem investigation to establish the cause of death; however, despite thorough analyses, some cases remain undetermined. Internationally, a molecular autopsy has assisted in resolving these types of cases by revealing genetic variants which contributed to the demise. Motivated by lack of local research in this field, a study was launched at the University of Cape Town (South Africa) in 2015 to explore the use of molecular autopsies in the medico-legal investigation of local SUDI cases. An ethical framework was established and used to prospectively recruit SUDI cases from one of the busiest forensic facilities: Salt River Mortuary. A next generation sequencing approach was used to assess 43 genes previously associated with cardiac arrhythmias. In a particular infant, a putative pathogenic variant was identified (rs750771811 T/T) in the SCN10A gene. The variant is rare, but was homozygous in this infant, and appears to be the first time it has been observed in a SUDI victim. Previous functional studies on the amino-acid residue suggested that this variant may reduce SCN5A activity, which has been linked to Brugada syndrome. A genetic counselling session was arranged with the parents; a full family history was obtained, which revealed that the parents had a previous miscarriage and had recently had a second SUDI. The parents have subsequently been enrolled in the study for genetic screening and have been referred for electrocardiogram assessments. The findings highlight a new possible candidate variant to assess in SUDI cases, and also demonstrate the value of molecular autopsies to families.