Abstract
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 studies—outlined in a validated pathogenicity scoring system—is 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).
Highlights
Mutations in the mitochondrial genome give rise to a clinically and biochemically heterogeneous range of genetic disorders affecting children and, perhaps more significantly, adults [Schon et al, 2012; Tuppen et al, 2010]
Mt-tRNA point mutations have been associated with a diverse range of clinical phenotypes including epilepsy, deafness, diabetes, ophthalmoparesis, myopathy, cardiomyopathy, and encephalopathy [Florentz et al, 2003; Yarham et al, 2010]
Dual enzyme histochemistry performed on each of the proband’s skeletal muscle biopsies where available, revealed a significant number of COX-deficient fibers (Fig. 1), several of which were accompanied by evidence of subsarcolemmal mitochondrial accumulation associated with ragged-red fibers, which is indicative of mitochondrial disease
Summary
Mutations in the mitochondrial genome (mtDNA) give rise to a clinically and biochemically heterogeneous range of genetic disorders affecting children and, perhaps more significantly, adults [Schon et al, 2012; Tuppen et al, 2010]. Both the diagnosis of mitochondrial disease and the molecular characterization of underlying pathogenic mutations are complicated by the variability in penetrance and tissue specificity observed even between close family members, as well as the lack of a consistent genotype–phenotype correlation [McFarland et al, 2010; Ylikallio and Suomalainen, 2012].
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