Journal
HUMAN MUTATION
Volume 34, Issue 9, Pages 1260-1268Publisher
WILEY-BLACKWELL
DOI: 10.1002/humu.22358
Keywords
mitochondrial tRNA; single-fiber studies; mitochondrial disease; segregation
Categories
Funding
- Wellcome Trust [096919/Z/11/Z]
- UK NHS Highly Specialised Rare Mitochondrial Disorders of Adults and Children Service
- Medical Research Council (UK)
- MRC Centre for Neuromuscular Diseases [G0601943]
- MRC Centre for Translational Research in Neuromuscular Disease Mitochondrial Disease Patient Cohort (UK) [G0800674]
- HEFCE/DoH
- MRC [G0800674, G108/539, MR/K000608/1, G0700718, G0601943] Funding Source: UKRI
- Medical Research Council [G0601943, G0700718, G0800674, G108/539, MR/K000608/1] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0508-10335, NIHR-HCS-D12-03-04] Funding Source: researchfish
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Mutations in the mitochondrial genome, and in particular the mt-tRNAs, are an important cause of human disease. Accurate classification of the pathogenicity of novel variants is vital to allow accurate genetic counseling for patients and their families. The use of weighted criteria based on functional studiesoutlined in a validated pathogenicity scoring systemis therefore invaluable in determining whether novel or rare mt-tRNA variants are pathogenic. Here, we describe the identification of nine novel mt-tRNA variants in nine families, in which the probands presented with a diverse range of clinical phenotypes including mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes, isolated progressive external ophthalmoplegia, epilepsy, deafness and diabetes. Each of the variants identified (m.4289T>C, MT-TI; m.5541C>T, MT-TW; m.5690A>G, MT-TN; m.7451A>T, MT-TS1; m.7554G>A, MT-TD; m.8304G>A, MT-TK; m.12206C>T, MT-TH; m.12317T>C, MT-TL2; m.16023G>A, MT-TP) was present in a different tRNA, with evidence in support of pathogenicity, and where possible, details of mutation transmission documented. Through the application of the pathogenicity scoring system, we have classified six of these variants as definitely pathogenic mutations (m.5541C>T, m.5690A>G, m.7451A>T, m.12206C>T, m.12317T>C, and m.16023G>A), whereas the remaining three currently lack sufficient evidence and are therefore classed as possibly pathogenic' (m.4289T>C, m.7554G>A, and m.8304G>A). (C) 2013 Wiley Periodicals, Inc.
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