Characterization of mtDNA variation in a cohort of South African paediatric patients with mitochondrial disease

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.

Mitochondrial Genomics and Antiretroviral Therapy-Associated Metabolic Complications in HIV-Infected Black South Africans: A Pilot Study

“…However, the distribution of mitochondrial haplogroups we found was similar to a recently published South African study conducted in 71 children. 29 None of the participants analyzed belonged to the European mitochondrial haplogroups.…”

High-throughput sequencing in mitochondrial DNA research

“…So far, high-throughput sequencing has been used to study mitochondrial disorders (Calvo et al, 2012; Vasta et al, 2009); (Dames et al, 2013); (van der Walt et al, 2012), mitochondrial DNA mutations due to radiation (Guo et al, 2012a), heteroplasmy inheritance (Payne et al, 2013), cancer (Yang Ai et al, 2013); (Lam et al, 2012) and many other related fields. Next-generation methods targeting the mitochondrial genome result in very high depth mtDNA sequences, but the ability to detect low-level heteroplasmies is still limited by a number of quality control criteria that must be carefully handled.…”

Toward a mtDNA locus-specific mutation database using the LOVD platform

“…The advent of cheaper and quicker sequencing technologies is likely to make this even more frequent. Indeed, frequent complete mtDNA sequencing will almost certainly extend beyond nations that are currently offering extensive clinical genetics services [Smuts et al, 2010; van der Walt et al, 2012]. When conducted, complete mtDNA sequencing may reveal a known pathogenic variant, but in some cases no previously confirmed pathogenic mutation is identified, though one or more novel (and potentially pathogenic) changes may be observed.…”