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Pathogenic Mitochondrial t RNA Point Mutations: Nine Novel Mutations Affirm Their Importance as a Cause of Mitochondrial Disease
Author(s) -
Blakely Emma L.,
Yarham John W.,
Alston Charlotte L.,
Craig Kate,
Poulton Joanna,
Brierley Charlotte,
Park SooMi,
Dean Andrew,
Xuereb John H.,
Anderson Kirstie N.,
Compston Alistair,
Allen Chris,
Sharif Saba,
Enevoldson Peter,
Wilson Martin,
Hammans Simon R.,
Turnbull Douglass M.,
McFarland Robert,
Taylor Robert W.
Publication year - 2013
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22358
Subject(s) - biology , genetics , mitochondrial dna , transfer rna , point mutation , mitochondrial disease , mutation , pathogenicity , proband , rna , gene , microbiology and biotechnology
Mutations in the mitochondrial genome, and in particular the mt‐t RNA s, 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 studies—outlined in a validated pathogenicity scoring system—is therefore invaluable in determining whether novel or rare mt‐t RNA variants are pathogenic. Here, we describe the identification of nine novel mt‐t RNA 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).