Journal
GENETICS IN MEDICINE
Volume 16, Issue 12, Pages 962-971Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/gim.2014.66
Keywords
exome; mitochondrial disorders; mitochondrial DNA; point mutation; sequencing
Categories
Funding
- Wellcome Trust Senior Fellow in Clinical Science [101876/Z/13/Z]
- National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre based at Newcastle upon Tyne Hospitals NHS Foundation Trust
- EU FP7 TIRCON
- Wellcome Trust Centre for Mitochondrial Research [096919Z/11/Z]
- Medical Research Council (UK) Neuromuscular Centre [G0601943]
- MRC Centre for Neuromuscular Diseases [G0601943]
- UK NHS Highly Specialised Rare Mitochondrial Disorders of Adults and Children Service
- NIHR/CSO Healthcare Science Research Fellowship from the National Institute for Health Research
- Newcastle University
- Medical Research Council [MR/K000608/1, G0601943] Funding Source: researchfish
- National Institute for Health Research [NIHR-HCS-D12-03-04] Funding Source: researchfish
- Parkinson's UK [F-1202] Funding Source: researchfish
- MRC [G0601943, MR/K000608/1] Funding Source: UKRI
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Purpose: Mitochondrial disorders are a common cause of inherited metabolic disease and can be due to mutations affecting mitochondrial DNA or nuclear DNA. The current diagnostic approach involves the targeted resequencing of mitochondrial DNA and candidate nuclear genes, usually proceeds step by step, and is time consuming and costly. Recent evidence suggests that variations in mitochondrial DNA sequence can be obtained from whole-exome sequence data, raising the possibility of p. comprehensive single diagnostic test to detect pathogenic point mutations. Methods: We compared the mitochondrial DNA sequence derived from off-target exome reads with conventional mitochondrial DNA Sanger sequencing in 46 subjects. Results: Mitochondrial DNA sequences can be reliably obtained using three different whole-exome sequence capture kits. Coverage correlates with the relative amount of mitochondrial DNA in the original genomic DNA sample, heteroplasmy levels can be determined using variant and total read depths, and-providing there is a minimum read depth of 20-fold-rare sequencing errors occur at a rate similar to that observed with conventional Sanger sequencing. Conclusion: This offers the prospect of using whole-exome sequence in a diagnostic setting to screen not only all protein coding nuclear genes but also all mitochondrial DNA genes for pathogenic mutations. Off-target mitochondrial DNA reads can also be used to assess quality control and maternal ancestry, inform on ethnic origin, and allow genetic disease association studies not previously anticipated with existing whole-exome data sets.
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