Genetic Epidemiology of Mitochondrial Pathogenic Variants Causing Nonsyndromic Hearing Loss in a Large Cohort of South Indian Hearing Impaired Individuals

Abstract

Mitochondria play a critical role in the generation of metabolic energy in the form of ATP. Tissues and organs that are highly dependent on aerobic metabolism are involved in mitochondrial disorders including nonsyndromic hearing loss (NSHL). Seven pathogenic variants leading to NSHL have so far been reported on two mitochondrial genes: MT-RNR1 encoding 12SrRNA and MT-TS1 encoding tRNA for Ser((UCN)) . We screened 729 prelingual NSHL subjects to determine the prevalence of MT-RNR1 variants at position m.961, m.1555A>G and m.1494C>T, and MT-TS1 m.7445A>G, m.7472insC m.7510T>C and m.7511T>C variants. Mitochondrial pathogenic variants were found in eight probands (1.1%). Five of them were found to have the m.1555A>G variant, two others had m.7472insC and one proband had m.7444G>A. The extended relatives of these probands showed variable degrees of hearing loss and age at onset. This study shows that mitochondrial pathogenic alleles contribute to about 1% prelingual hearing loss. This study will henceforth provide the reference for the prevalence of mitochondrial pathogenic alleles in the South Indian population, which to date has not been estimated. The m.1555A>G variant is a primary predisposing genetic factor for the development of hearing loss. Our study strongly suggests that mitochondrial genotyping should be considered for all hearing impaired individuals and particularly in families where transmission is compatible with maternal inheritance, after ruling out the most common variants.

Genetics Landscape of Nonsyndromic Hearing Loss in Indian Populations

“…In addition to the above mutations, other variants including M1V, E147K, R184Q, R75Q, V84L, I35S, R32L, S19G, K15T, I20T, V37I, E42D, K105fsX109, E129fsX211, L105GfsX5, E120del, T55T, T86M, A88A, M195I, P225P, R75W, R143W, W172R, R184P, M195I, D159Y, F106F, D50N, Q80X, V95M, E114L, E147L, N206H, I111T, G12VfsX2, delE120 and V43M have also been found in GJB2, which have been involved in developing NSHL (►Table 1). 19,26,[33][34][35][36][37][38][39][40][41][42][43][44][45][46][47] Ten chromosomal or nucleotide mutations including 35delG, 51del12insA, 35insG, IVS1 þ 1G > A, 84T > C, 1067G > T, 1277T > C, 1152G > A, 167delT, 235delC have been reported in GJB2-associated NSHL cases. Of these, 35delG is the most frequent mutation in all the studied Indian populations with NSHL.…”

Ototoxicity: Old and New Foes

“…Mitochondrial pathologies induced by genetic mutations are often associated with hearing loss [70][71][72]. Similarly, substances known to damage mitochondria such as aminoglycosides or cisplatin are known as ototoxic and contribute significantly to the hearing loss and tinnitus [73].…”

PNPT1, MYO15A, PTPRQ, and SLC12A2‐associated genetic and phenotypic heterogeneity among hearing impaired assortative mating families in Southern India

“…Previous studies have implicated GJB2 variants as the most common genetic cause of HL, while CDH23 , SLC26A4 , TMC1 , and MYO15A comprise the second most common tier of genes (Amritkumar et al., 2018; Brownstein et al., 2011; Chandru et al., 2020; Duman & Tekin, 2012; Ganapathy et al., 2014; Vanniya et al., 2018). Although a number of studies have investigated specific auditory gene frequencies (Amritkumar et al., 2018; Chandru et al., 2020; Kalaimathi et al., 2020; Subathra et al., 2016; Vanniya et al., 2018; Yan et al., 2016), the complexity of HL in Indian families remains underexplored.…”