Abstract
Mitochondrial disease can be attributed to both mitochondrial and nuclear gene mutations. It has a heterogeneous clinical and biochemical profile, which is compounded by the diversity of the genetic background. Disease-based epidemiological information has expanded significantly in recent decades, but little information is known that clarifies the aetiology in African patients. The aim of this study was to investigate mitochondrial DNA variation and pathogenic mutations in the muscle of diagnosed paediatric patients from South Africa. A cohort of 71 South African paediatric patients was included and a high-throughput nucleotide sequencing approach was used to sequence full-length muscle mtDNA. The average coverage of the mtDNA genome was 81±26 per position. After assigning haplogroups, it was determined that although the nature of non-haplogroup-defining variants was similar in African and non-African haplogroup patients, the number of substitutions were significantly higher in African patients. We describe previously reported disease-associated and novel variants in this cohort. We observed a general lack of commonly reported syndrome-associated mutations, which supports clinical observations and confirms general observations in African patients when using single mutation screening strategies based on (predominantly non-African) mtDNA disease-based information. It is finally concluded that this first extensive report on muscle mtDNA sequences in African paediatric patients highlights the need for a full-length mtDNA sequencing strategy, which applies to all populations where specific mutations is not present. This, in addition to nuclear DNA gene mutation and pathogenicity evaluations, will be required to better unravel the aetiology of these disorders in African patients.
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Acknowledgements
We acknowledge the supporting contribution of the clinical staff of the Department of Paediatrics and Child Health, Steve Biko Academic Hospital, University of Pretoria, South Africa, as well as Charlotte Alston, Emma Watson and John Yarham of the Mitochondrial Research Group, Institute for Ageing and Health, Newcastle University. We are grateful for the financial support of the Department of Science and Technology and Medical Research Council of South Africa. RWT and DMT are funded by a Wellcome Trust Programme Grant (074454/Z/04/Z) and the UK NHS Specialised Services ‘Rare Mitochondrial Disorders of Adults and Children’ Diagnostic Service (http://www.mitochondrialncg.nhs.uk). FHvdW is supported by a Newcastle University Research Committee Visiting Professorship bursary.
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van der Walt, E., Smuts, I., Taylor, R. et al. Characterization of mtDNA variation in a cohort of South African paediatric patients with mitochondrial disease. Eur J Hum Genet 20, 650–656 (2012). https://doi.org/10.1038/ejhg.2011.262
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DOI: https://doi.org/10.1038/ejhg.2011.262
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