Aim: To describe mitochondrial genetic variants found in the South African population in order to plan relevant prospective research. Methods: An audit of mitochondrial test results from 1994 – 2023 was performed. Clinical, laboratory and referral information were analysed. Carrier and prenatal testing results were excluded. Results There were 206 (10.6%) positive results from 1950 tests. Pathogenic mitochondrial DNA variants accounted for 135/206 (65.5%). These included: Mitochondrial Encephalopathy with Lactic Acidosis and Stroke-like episodes,(MELAS), and maternally inherited diabetes and deafness, (MIDD), n= 43 (31.9%), Leber’s Hereditary Optic Neuropathy, (LHON), n=28 (20.7%), single large mtDNA deletions, n=27 (20%) and Maternally Inherited Leigh Syndrome, (MILS), n=14(10.3%). Sixty six of 71 nuclear DNA positive results were homozygous (65) or compound heterozygous (1) for the MPV17 pathogenic variant c.106C>T (p.[Gln36Ter, Ser25Profs*49]), causing severe infantile neurohepatopathy. Isolated nuclear DNA variants occurred in POLG, TAZ1, CPT2, BOLA3 and SERAC1. None were identified in SURF1 and PDHA1. Conclusions: The chief finding is the large group with a novel homozygous variant in MPV17 causing severe infantile hepatocerebral disease in a non-consanguineous population. This emphasizes the importance of strengthening molecular diagnostic capability in understudied populations. The absence of commonly described pathogenic nuclear DNA variants may be due to reduced prevalence or insufficient testing. It is critical to develop diagnostic platforms on the African subcontinent so that population specific genetic variations can be identified. A natural history study is in progress for MPV17 and collaboration is being sought to determine the extent of this genetic variant in Sub Saharan Africa.

Gillian Riordan
Red Cross War Memorial Children's Hospital
South Africa

Kashief Khan
National Health Laboratory Service Groote Schuur Hospital
South Africa

Surita Meldau
National Health Laboratory Service and University of Cape Town
South Africa