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. 2022 Apr;10(4):e1887.
doi: 10.1002/mgg3.1887. Epub 2022 Feb 1.

Report of rare and novel mutations in candidate genes in a cohort of hearing-impaired patients

Min Liu  1 , Yue Liang  1 , Bixue Huang  1 , Jincangjian Sun  1 , Kaitian Chen  1
Affiliations

Report of rare and novel mutations in candidate genes in a cohort of hearing-impaired patients

Min Liu et al. Mol Genet Genomic Med. 2022 Apr.

Abstract

Background: Many hearing-impaired patients carry mutations in rare or novel genes undetected in regular genetic hot regions/genes screening.

Methods: We collected clinical and genetic data from subjects with hearing loss who visited our department for genetic counseling. Next-generation sequencing was conducted after 154 deafness-related genes were captured using a designed genes panels in 14 unrelated families (37 participants). The results were filtered and assessed with in silico tools, in combination with pedigree mapping.

Results: Ten mutations in regular deafness genes (GJB2, SLC26A4) and uncommon genes (OTOF, MYO7A, MYO15A, and KARS) were detected, which constituted 57.2% of yielded rate. In particular, two patients with nonsyndromic deafness carried biallelic KARS mutations. In addition, we identified an unreported digenic mutational inheritance in GRP98/USH2A genes in a proband with isolated hearing loss. Functional analyses and molecular modeling suggested the damaging consequence of these variants on encoded proteins. According to the variant pathogenicity guidelines, the 17 identified variants in total were classified as "pathogenic" or "likely pathogenic."

Conclusion: The candidate mutations in deafness genes were suggested to be co-segregated in at least 57.2% of the studied pedigrees. This is the new report of rare/novel mutations causing inherited hearing loss in Chinese.

Keywords: hearing loss; mutations; sensorineural hearing loss.

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Conflict of interest statement

The authors have declared no conflict of interest.

Figures

FIGURE 1
FIGURE 1
(a) The mutational spectrum yielded by the deafness panel. (b) Five pedigrees with clear genetic etiology are presented. +, Wild‐type nucleotide; VUS, variant with unknown significance. GJB2 (NM_004004.5), GPR98 (NM_032119), KARS (NM_001130089.1), MYO7A (NM_000260.3), MYO15A (NM_016239.3), OTOF (NM_194248.2), SLC26A4 (NM_000441.1), and USH2A (NM_206933.2)
FIGURE 2
FIGURE 2
The sequences of novel and rare mutations identified in this study are shown. (a). The MYO7A c.1003+1G>A disrupts the splice site (GT), and mRNA mis‐splicing occurs. The KARS frameshift mutations c.1212_1220del caused the alteration of amino acids. (b–d) The DNA sequences, conservation analysis and predicted protein structures of MYO7A, KARS and MYO15A. KARS (NM_001130089.2), MYO7A (NM_000260.3), MYO15A (NM_016239.3)
FIGURE 3
FIGURE 3
A pedigree #9 with suspected double genes inheritance GPR98/USH2A is shown (a). The mutated residue is highly conserved (b). (c) Profound hearing loss was detected in this 5‐year‐old proband, without any detectable ophthalmic symptoms at the latest follow‐up. (d) The co‐expression between GPR98 and USH2A were predicted by STRING network. GPR98 (NM_032119), USH2A (NM_206933.2)
See this image and copyright information in PMC

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