Interpretation of mitochondrial tRNA variants

  • A Correction to this article was published on 05 March 2020
  • A Correction to this article was published on 09 April 2020

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.

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Fig. 1

Change history

  • 23 February 2020

    The original version of this Article contained an error in the spelling of "Criteria for mt-tRNA variants" in the top right column header of Table 2, which was incorrectly given as "mt-mRNA". This has now been corrected in both the PDF and HTML versions of the Article.

  • 09 April 2020

    The original version of this Article contained errors in the third row of the last column (PS2) of Table 1. Whereby “>2 different tissues” should read “>=2 different tissues” and the two instances of “0%” should be “not detected”. These have now been corrected in both the PDF and HTML versions of the Article.

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Correspondence to Lee-Jun C. Wong PhD.

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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

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Key words

  • mt-tRNA variants interpretation
  • tRNA variants classification criteria
  • MitoTIP

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