Analysis of the Spectrum of the mtDNA Haplogroups in Patients with Hearing Loss Carrying the Likely Pathogenic Ultra-Rare m.1494C>T Variant in the MT-RNR1 Gene

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The contribution of the m.1494C>T variant of the MT-RNR1 gene associated with aminoglycoside-induced deafness (MT-RNR1, OMIM 561000) to the etiology of hearing loss (HL) is still poorly studied. In this regard, the aim of the study is screening of the m.1494C>T in the MT-RNR1 gene among patients with HL in the Republic of Buryatia followed by reconstruction of mitochondrial lineages with the m.1494C>T variant from different regions of the world. From available databases and the results of a genome-wide analysis of mtDNA of one patient with m.1494C>T detected in this study, we have reconstructed the mitochondrial lineages in 27 patients from different regions of the world in which the ultra-rare variant was obtained. As a result, 19 different mtDNA haplogroups were identified in patients, which likely indicates the independent origin of the m.1494C>T variant. However, in patients with m.1494C>T, a high frequency of haplogroup A* (18.5%, 5/27) was obtained, which was 13-fold higher (χ2 = 45.274; p < 0.001) than mean worldwide frequency of this haplogroup (1.45%, 519/35 748). The overrepresentation of haplogroup A* among patients with m.1494C>T may be due to their common ancestry. The possible influence of a founder effect on the prevalence of the MT-RNR1 increases the relevance of target screening for the m.1494C>T variant in previously unexplored cohorts of patients with HL, primarily, in regions where the haplogroups A* and its daughter branch A2 were found, i.e., in Asia and America.