Complete Mitochondrial Genome Analysis and Clinical Documentation of a Five-Generational Indian Family with Mitochondrial 1555A>G Mutation and Postlingual Hearing Loss

Abstract

SummaryHearing loss is the most common sensory disorder and is genetically heterogeneous. Apart from nuclear gene mutations, a number of inherited mitochondrial mutations have also been implicated. The m.1555A>G mutation in the mitochondrial MT-RNR1 gene is reported as the most common mutation causing nonsyndromic hearing loss in various ethnic populations. We report here for the first time the clinical, genetic and molecular characterisation of a single large five-generational Tamil-speaking South Indian family with maternally inherited nonsyndromic postlingual hearing loss. Molecular analysis led to identification of m.1555A>G in 28 maternal relatives with variable degree of phenotypic expression. The penetrance of hearing loss among the maternal relatives in this family was 55%. Sequence analysis of the complete mitochondrial genome in 36 members of this pedigree identified 25 known variants and one novel variant co-transmitted along with m.1555A>G mutation. The mtDNA haplotype analysis revealed that the maternal relatives carry the R * T 2 haplotype similar to Europeans and South Asians. Sequencing of the coding exon of GJB2 nuclear gene did not show any pathogenic mutations. The results suggest that other nuclear or environmental modifying factors could have played a role in the differential expression of mutation m.1555A>G in postlingual hearing loss in this family.

Analysis of Genetic Variations in Connexin 26 (GJB2) Gene among Nonsyndromic Hearing Impairment: Familial Study

“…Up to 25 dB (hearing level measured in decibels [dB]) Normal hearing is defined as 26 to 40 dB; mild hearing is defined as 41 to 70 dB; moderate hearing is defined as 71 to 90 dB; severe hearing is defined as >90 dB; and profound hearing is defined as >90 dB. 14 …”

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

“…In the South Indian population, this variant was observed among 0.6% of prelingual hearing impaired (Padma et al., ). Two multigenerational large families with postlingual hearing loss, hailing from South India were recently presented as case reports from this investigator's laboratory (Pavithra et al., ; Subathra et al., ). In contrast, this variant was not observed in North Indians (Bhalla et al., ).…”

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.…”