A novel variant in MITF in a child from Yunnan-Guizhou Plateau with autosomal dominant inheritance of nonsyndromic hearing loss: A case report

Abstract

Deafness and hearing loss may have functional, economic, social and emotional impacts on humans, including the ability of an individual to communicate with others, feelings of isolation and frustration, and health sector costs. The World Health Organization reported that there are 32 million children worldwide with hearing loss. In order to investigate genetic mutations in children of 26 nationalities with hearing loss in Yunnan, Sanger sequencing was employed to screen for mutations in four of the most common pathological genes, including gap junction protein β2 and 3, solute carrier family 26 member 4 and mitochondrial DNA. Whole exome sequencing was used to detect the mutation in the proband of a family in which these four genes were normal. Subsequently, the mutation was identified by Sanger sequencing. The present study reports a novel mutation, c.718C>G; p. (Arg240Gly) in the melanogenesis associated transcription factor gene, in Han people with hearing loss. The results of the present study may provide parents and children an accurate diagnosis, which may allow physicians to how to rehabilitate children's hearing.

Predicting pathogenicity for novel hearing loss mutations based on genetic and protein structure approaches

“…Notably, none of the four affected members of this family presented any other signs in addition to profound HL. This finding is in accordance with some reports in which variants in the MITF gene cause only hearing loss 25 , 26 . The variable phenotype expression could be explained by the presence of modifier genes, as well as interactions with environmental factors 27 , 28 .…”

Increased diagnostic yield by reanalysis of data from a hearing loss gene panel

“…The reclassification of p.Arg341Cys in turn supported the pathogenicity of Arg341Gly. Two years later, p.Arg341Gly was reported as a pathogenic variant in a Chinese family in June 2018 [23], and in a Indian family in November 2018 [24], further supporting its pathogenicity. It is worth noting that NM_198159.2( MITF ):c.1021C > T (p.Arg341Cys) was discovered from original file of an unreported VUS in patient 5, who presented only congenital profound hearing loss when they were referred for genetic testing.…”

“…First, transcript discrepancy can lead to inaccurate variant interpretation [33]. For example, an autosomal dominant variant was curated as NM_198159.2( MITF ):c.1021C > G in patient 6, whereas it was reported as NM_000248.3( MITF ):c.718C > G [23], creating a significant barrier to discovery for geneticists. Many genes produce multiple transcripts, and determining which should be used as a reference for evaluating the impact of a variant often presents a challenge [34].…”

MITF variants cause nonsyndromic sensorineural hearing loss with autosomal recessive inheritance

“…The presence of the GJB2 -Val37Ile allele in our patients could represent a coincidental finding because the Val37Ile variant is prevalent in the Thai population with an allele frequency of 8.5% 32 . A different mutation at the codon 341, heterozygous p.Arg341Gly compounded with an unidentified mutation in the other allele has been reported in two hearing-impaired siblings from a consanguineous family, whereas both parents showed normal physical and hearing phenotypes, and only the mother carried Arg341Gly 33 .…”