To develop criteria to interpret mitochondrial transfer RNA (mt-tRNA) variants based on unique characteristics of mitochondrial genetics and conserved structural/functional properties of tRNA.
We developed rules on a set of established pathogenic/benign variants by examining heteroplasmy correlations with phenotype, tissue distribution, family members, and among unrelated families from published literature. We validated these deduced rules using our new cases and applied them to classify novel variants.
Evaluation of previously reported pathogenic variants found that 80.6% had sufficient evidence to support phenotypic correlation with heteroplasmy levels among and within families. The remaining variants were downgraded due to the lack of similar evidence. Application of the verified criteria resulted in rescoring 80.8% of reported variants of uncertain significance (VUS) to benign and likely benign. Among 97 novel variants, none met pathogenic criteria. A large proportion of novel variants (84.5%) remained as VUS, while only 10.3% were likely pathogenic. Detection of these novel variants in additional individuals would facilitate their classification.
Proper interpretation of mt-tRNA variants is crucial for accurate clinical diagnosis and genetic counseling. Correlations with tissue distribution, heteroplasmy levels, predicted perturbations to tRNA structure, and phenotypes provide important evidence for determining the clinical significance of mt-tRNA variants.
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Smeitink J, van den Heuvel L, DiMauro S. The genetics and pathology of oxidative phosphorylation. Nat Rev Genet. 2001;2:342–352.
DiMauro S, Emmanuele V. The clinical spectrum of nuclear DNA-related mitochondrial disorders. In: Wong L-J C, editor. Mitochondrial disorders caused by nuclear genes. New York: Springer; 2013. p. 3–25 .
Frazier AE, Thorburn DR, Compton AG. Mitochondrial energy generation disorders: genes, mechanisms, and clues to pathology. J Biol Chem. 2019;294:5386–5395.
Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405.
Lott MT, Leipzig JN, Derbeneva O, et al. mtDNA variation and analysis using Mitomap and Mitomaster. Curr Protoc Bioinformatics. 2013;44:1–23.
Wong L-JC, Wong H, Liu A. Intergenerational transmission of pathogenic heteroplasmic mitochondrial DNA. Genet Med. 2002;4:78.
Wong LJC, Liang MH, Kwon H, Park J, Bai RK, Tan DJ. Comprehensive scanning of the entire mitochondrial genome for mutations. Clin Chem. 2002;48:1901–1912.
Kirchner S, Ignatova Z. Emerging roles of tRNA in adaptive translation, signalling dynamics and disease. Nat Rev Genet. 2015;16:98–112.
Helm M, Brulé H, Degoul F, et al. The presence of modified nucleotides is required for cloverleaf folding of a human mitochondrial tRNA. Nucleic Acids Res. 1998;26:1636–1643.
Yarham JW, Elson JL, Blakely EL, McFarland R, Taylor RW. Mitochondrial tRNA mutations and disease. Wiley Interdiscip Rev RNA. 2010;1:304–324.
Sonney S, Leipzig J, Lott MT, et al. Predicting the pathogenicity of novel variants in mitochondrial tRNA with MitoTIP. PLoS Comput Biol. 2017;13:1–8.
Silvestri G, Mongini T, Odoardi F, et al. A new mtDNA mutation associated with a progressive encephalopathy and cytochrome c oxidase deficiency. Neurology. 2000;54:1693–1696.
Zsurka G, Hampel KG, Nelson I, et al. Severe epilepsy as the major symptom of new mutations in the mitochondrial tRNAPhe gene. Neurology. 2010;74:507–512.
Connor TM, Hoer S, Mallett A, et al. Mutations in mitochondrial DNA causing tubulointerstitial kidney disease. PLoS Genet. 2017;13:1–17.
Cui H, Li F, Chen D, et al. Comprehensive next-generation sequence analyses of the entire mitochondrial genome reveal new insights into the molecular diagnosis of mitochondrial DNA disorders. Genet Med. 2013;15:388–394.
Cox R, Platt J, Chen LC, et al. Leigh syndrome caused by a novel m.4296G>A mutation in mitochondrial tRNA isoleucine. Mitochondrion. 2012;12:258–261.
McFarland R, Clark KM, Morris AAM, et al. Multiple neonatal deaths due to a homoplasmic mitochondrial DNA mutation. Nat Genet. 2002;30:145–146.
Rorbach J, Yusoff AA, Tuppen H, et al. Overexpression of human mitochondrial valyl tRNA synthetase can partially restore levels of cognate mt-tRNAVal carrying the pathogenic C25U mutation. Nucleic Acids Res. 2008;36:3065–3074.
Del Mar O’Callaghan M, Emperador S, López-Gallardo E, et al. New mitochondrial DNA mutations in tRNA associated with three severe encephalopamyopathic phenotypes: neonatal, infantile, and childhood onset. Neurogenetics. 2012;13:245–250.
Bosley TM, Brodsky MC, Glasier CM, et al. Sporadic bilateral optic neuropathy in children: the role of mitochondrial abnormalities. Investig Ophthalmol Vis Sci. 2008;49:5250–5256.
Abu-Amero KK, Bosley TM. Mitochondrial abnormalities in patients with LHON-like optic neuropathies. Investig Ophthalmol Vis Sci. 2006;47:4211–4220.
Bannwarth S, Procaccio V, Lebre AS, et al. Prevalence of rare mitochondrial DNA mutations in mitochondrial disorders. J Med Genet. 2013;50:704–714.
Garcia-Lozano J-R, Aguilera I, Bautista J, et al. A new mitochondrial DNA mutation in the tRNA leucine 1 gene (C3275A) in a patient with Leber’s hereditary optic neuropathy. Hum Mutat. 2000;15:120.
Zhang W, Cui H, Wong LJC. Comprehensive one-step molecular analyses of mitochondrial genome by massively parallel sequencing. Clin Chem. 2012;58:1322–1331.
Ingman M. mtDB: Human Mitochondrial Genome Database, a resource for population genetics and medical sciences. Nucleic Acids Res. 2005;34:D749–D751.
Mimaki M, Hatakeyama H, Ichiyama T, et al. Different effects of novel mtDNA G3242A and G3244A base changes adjacent to a common A3243G mutation in patients with mitochondrial disorders. Mitochondrion. 2009;9:115–122.
Lightowlers RN, Taylor RW, Turnbull DM. What is new in mitochondrial disease, and what challenges remain? Science. 2015;349:1494–1499.
Glatz C, D’Aco K, Smith S, et al. Mutation in the mitochondrial tRNAVal causes mitochondrial encephalopathy, lactic acidosis and stroke-like episodes. Mitochondrion. 2011;11:615–619.
Horváth R, Bender A, Abicht A, et al. Heteroplasmic mutation in the anticodon-stem of mitochondrial tRNA Val causing MNGIE-like gastrointestinal dysmotility and cachexia. J Neurol. 2009;256:810–815.
Uittenbogaard M, Wang H, Zhang VW, et al. The nuclear background influences the penetrance of the near-homoplasmic m.1630 A > G MELAS variant in a symptomatic proband and asymptomatic mother. Mol Genet Metab. 2019;126:429–438.
Sacconi S, Salviati L, Nishigaki Y. et al. A functionally dominant mitochondrial DNA mutation. Hum Mol Genet. 2008;17:1814–1820.
Roos S, Darin N, Kollberg G, et al. A novel mitochondrial tRNA Arg mutation resulting in an anticodon swap in a patient with mitochondrial encephalomyopathy. Eur J Hum Genet. 2012;21:571.
Anitori R, Manning K, Quan F, et al. Contrasting phenotypes in three patients with novel mutations in mitochondrial tRNA genes. Mol Genet Metab. 2005;84:176–188.
Kirino Y, Suzuki T. Human mitochondrial diseases associated with tRNA wobble modification deficiency. RNA Biol. 2005;2:41–44.
Ibba M, Söll D. Aminoacyl-tRNA synthesis. Annu Rev Biochem. 2000;69:617–650.
Moraes CT, Ciacci F, Bonilla E, et al. A mitochondrial tRNA anticodon swap associated with a muscle disease. Nat Genet. 1993;4:284–288.
Wang J, Venegas V, Li F, et al. Analysis of mitochondrial DNA point mutation heteroplasmy by ARMS quantitative PCR. Curr Protoc Hum Genet. 2011;68:19.6.1–19.6.16.
Santibanez-Koref M, Griffin H, Turnbull DM, et al. Assessing mitochondrial heteroplasmy using next generation sequencing: a note of caution. Mitochondrion. 2019;46:302–306.
Cardena MMSG, Mansur AJ, Pereira ADC, et al. A new duplication in the mitochondrially encoded tRNA proline gene in a patient with dilated cardiomyopathy. Mitochondrial DNA. 2013;24:46–49.
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Wong, L.C., Chen, T., Wang, J. et al. Interpretation of mitochondrial tRNA variants. Genet Med 22, 917–926 (2020). https://doi.org/10.1038/s41436-019-0746-0
- mt-tRNA variants interpretation
- tRNA variants classification criteria
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