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Lookup NU author(s): Dr Helen GriffinORCiD, Dr Angela Pyle, Dr Charlotte Alston, Dr Jennifer Duff, Professor Gavin Hudson, Professor Rita HorvathORCiD, Dr Ian Wilson, Dr Mauro Santibanez Koref, Professor Robert Taylor, Professor Patrick Chinnery
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
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.
Author(s): Griffin HR, Pyle A, Blakely EL, Alston CL, Duff J, Hudson G, Horvath R, Wilson IJ, Santibanez-Koref M, Taylor RW, Chinnery PF
Publication type: Article
Publication status: Published
Journal: Genetics in Medicine
Year: 2014
Volume: 16
Issue: 12
Pages: 962-971
Print publication date: 01/12/2014
Online publication date: 05/06/2014
Acceptance date: 06/05/2014
Date deposited: 02/07/2015
ISSN (print): 1098-3600
ISSN (electronic): 1530-0366
Publisher: Nature Publishing Group
URL: http://dx.doi.org/10.1038/gim.2014.66
DOI: 10.1038/gim.2014.66
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