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. 2020 May;22(5):917-926.
doi: 10.1038/s41436-019-0746-0. Epub 2020 Jan 22.

Interpretation of mitochondrial tRNA variants

Lee-Jun C Wong #  1   2 , Ting Chen #  3   4 , Jing Wang  3   5 , Sha Tang  3   6 , Eric S Schmitt  3   7 , Megan Landsverk  3   8 , Fangyuan Li  3   9 , Yue Wang  3   7 , Shulin Zhang  3   10 , Victor Wei Zhang  3   11 , William J Craigen  3   7
Affiliations
Free article

Interpretation of mitochondrial tRNA variants

Lee-Jun C Wong et al. Genet Med. 2020 May.
Free article

Erratum in

Abstract

Purpose: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: MitoTIP; mt-tRNA variants interpretation; tRNA variants classification criteria.

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References

    1. Smeitink J, van den Heuvel L, DiMauro S. The genetics and pathology of oxidative phosphorylation. Nat Rev Genet. 2001;2:342–352. - DOI
    1. 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 .
    1. Frazier AE, Thorburn DR, Compton AG. Mitochondrial energy generation disorders: genes, mechanisms, and clues to pathology. J Biol Chem. 2019;294:5386–5395. - DOI
    1. 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. - DOI
    1. Lott MT, Leipzig JN, Derbeneva O, et al. mtDNA variation and analysis using Mitomap and Mitomaster. Curr Protoc Bioinformatics. 2013;44:1–23. - DOI

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