Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Baylor Genetics Laboratory, Houston, TX, USA.
Genet Med. 2020 May;22(5):917-926. doi: 10.1038/s41436-019-0746-0. Epub 2020 Jan 22.
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.
根据线粒体遗传学的独特特征和 tRNA 的保守结构/功能特性，制定解释线粒体转移 RNA（mt-tRNA）变体的标准。
我们通过检查来自已发表文献中的异质性与表型、组织分布、家族成员以及无关家族之间的相关性，为一组已建立的致病性/良性变体制定了规则。我们使用新病例验证了这些推断出的规则，并将其应用于分类新变体。
对先前报道的致病性变体的评估发现，80.6%的变体具有足够的证据支持表型与家族内和家族间异质性水平的相关性。其余变体由于缺乏类似证据而降级。经证实的标准的应用导致 80.8%的报告意义不明的变异（VUS）被重新分类为良性或可能良性。在 97 个新变体中，没有一个符合致病性标准。很大一部分新变体（84.5%）仍然是 VUS，而只有 10.3%可能是致病性的。在其他个体中检测到这些新变体将有助于对其进行分类。
正确解释 mt-tRNA 变体对于准确的临床诊断和遗传咨询至关重要。与组织分布、异质性水平、对 tRNA 结构的预测干扰以及表型的相关性为确定 mt-tRNA 变体的临床意义提供了重要证据。
