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A Comparative Analysis Approach to Determining the Pathogenicity of Mitochondrial tRNA Mutations

Lookup NU author(s): John Yarham, Dr Charlotte Alston, Professor Robert Taylor, Dr Joanna Elson, Professor Bobby McFarlandORCiD


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Distinguishing pathogenic from polymorphic changes poses significant problems for geneticists and despite 30 years of postgenomic experience this remains the case in mitochondrial genetics. Base substitutions in mitochondrial tRNA (mt-tRNA) genes are particularly difficult, but important, because they are common causes of pathology and associated with high rates of transmission. Providing accurate genetic advice to patients and their families is of paramount importance in disease prevention, and brings into sharp focus the factors used to distinguish pathogenic from polymorphic variants. We have reevaluated our pathogenicity scoring system for mt-tRNA mutations following a considerable increase in the number reported since the system was devised in 2004. This allowed us to address notable issues including the underestimation of "definitely pathogenic" mutations resulting from insufficient data collection. We illustrate the robustness of our revised scoring system using novel pathogenic and previously reported polymorphic changes and conclude that while clear evidence from single-fiber and/or trans-mitochondrial cybrid studies remains the gold standard for assigning pathogenicity, our scoring system is valuable for deciding which mt-tRNA mutations to investigate further using these labor-intensive techniques. Hum Mutat 32: 1319-1325, 2011. (C) 2011 Wiley Periodicals, Inc.

Publication metadata

Author(s): Yarham JW, Al-Dosary M, Blakely EL, Alston CL, Taylor RW, Elson JL, McFarland R

Publication type: Article

Publication status: Published

Journal: Human Mutation

Year: 2011

Volume: 32

Issue: 11

Pages: 1319-1325

Print publication date: 19/09/2011

ISSN (print): 1059-7794

ISSN (electronic): 1098-1004

Publisher: John Wiley & Sons, Inc.


DOI: 10.1002/humu.21575


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Funder referenceFunder name
Medical Research Council (UK)
Research Council UK
074454/Z/04/ZWellcome Trust
G0800674MRC Centre for Translational Research in Neuromuscular Disease, Mitochondrial Disease Patient Cohort (UK)