The added value of molecular-based diagnostics in the African forensic medical setting.

Sudden unexpected infant death (SUDI) is reported to be an extraordinarily high burden in sub-Saharan Africa, with the incidence rate in South Africa among the highest in the world. It is common for the cause of many such infant deaths to remain unexplained even after a full medico-legal death investigation, and then to be categorised as a sudden unexplained infant death (SUID). Fortunately, advances in molecular-based diagnostics allow researchers to identify numerous underlying inherited cardiac arrhythmogenic disorders in many SUDI cases, with a predominance of variants identified in the SCN5A gene. Such cardiac arrhythmogenic-related sudden deaths generally present with no structural alterations of the heart that are macroscopically identifiable at autopsy, therefore highlighting the importance of post mortem genetic testing. We report on a significant genetic finding that was made on a SUDI case in which the cause was ascribed to an acute bacterial pneumonia but it was still subjected to post mortem genetic testing of the SCN5A gene. The literature shows that many SUDI cases diagnosed with inherited cardiac arrhythmogenic disorders have demonstrated a viral prodrome within days of their death. It is therefore not uncommon for these cardiac disorders in infants to be mistaken for flu, viral upper respiratory tract infection or pneumonia, and without the incorporation of post mortem genetic testing, any other contributory causes of these deaths are often disregarded. This study highlights the need for research reporting on the genetics of inherited cardiac disorders in Africa.

Feasibility of analysis of the SCN5A gene in paraffin embedded samples in sudden infant death cases at the Pretoria Medico-Legal Laboratory, South Africa.

To determine variations in the SCN5A gene linked to inherited cardiac arrhythmogenic disorders in sudden, unexplained infant death (SUID) cases examined at the Pretoria Medico-Legal Laboratory, South Africa. A retrospective study was conducted on SUID cases and controls, analyzing DNA extracted from archived formalin-fixed, paraffin-embedded (FFPE) myocardial tissue samples as well as blood samples. A total of 48 FFPE tissue samples (cases), 10 control FFPE tissue samples and nine control blood samples were included. DNA extracted from all samples was used to test for variations in the SCN5A gene by using high resolution melt (HRM) real-time PCR and sequencing. Genetic analysis showed 31 different single nucleotide variants in the entire study population (n = 67). Five previously reported variants of known pathogenic significance, and 14 variants of benign clinical significance, were identified. The study found 12 different variants in the cases that were not published in any database or literature and were considered novel. Of these novel variants, two were predicted as "probably damaging" with a high level of certainty (found in four case samples), one (identified in another case sample) was predicted to be "possibly damaging" with a 50% chance of being disease-causing, and nine were predicted to be benign. This study shows the significant added value of using genetic testing in determining the cause of death in South African SUID cases. Considering the high heritability of these arrhythmic disorders, post mortem genetic testing could play an important role in the understanding of the pathogenesis thereof and could also aid in the diagnosis and treatment of family members at risk, ultimately preventing similar future cases.

Long QT syndrome and sudden unexpected infant death.

Long QT syndrome (LQTS) is an inheritable primary electric disease of the heart characterised by abnormally long QT intervals and a propensity to develop atrial and ventricular tachyarrhythmias. It is caused by an inherited channelopathy responsible for sudden cardiac death in individuals with structurally normal hearts. Long QT syndrome can present early in life, and some studies suggest that it may be associated with up to 20% of sudden unexplained infant death (SUID), particularly when associated with external stressors such as asphyxia, which is commonly seen in many infant death scenes. With an understanding of the genetic defects, it has now been possible to retrospectively analyse samples from infants who have presented to forensic pathology services with a history of unexplained sudden death, which may, in turn, enable the implementation of preventative treatment for siblings previously not known to have pathogenic genetic variations. In this viewpoint article, we will discuss SUID, LQTS and postmortem genetic analysis.