Whole exome sequencing identified mutations causing hearing loss in five consanguineous Pakistani families

Abstract

Background: Hearing loss is the most common sensory defect, and it affects over 6% of the population worldwide. Approximately 50%-60% of hearing loss patients are attributed to genetic causes. Currently, more than 100 genes have been reported to cause non-syndromic hearing loss. It is possible and efficient to screen all potential disease-causing genes for hereditary hearing loss by whole exome sequencing (WES).Methods: We collected 5 consanguineous pedigrees from Pakistan with hearing loss and applied WES in selected patients for each pedigree, followed by bioinformatics analysis and Sanger validation to identify the causal genes.Results: Variants in 7 genes were identified and validated in these pedigrees. We identified single candidate variant for 3 pedigrees: GIPC3 (c.937T>C), LOXHD1 (c.6136G>A) and TMPRSS3 (c.941T>C). The remaining 2 pedigrees each contained two candidate variants: TECTA (c.4045G>A) and MYO15A (c.3310G>T and c.9913G>C) for one pedigree and DFNB59 (c.494G>A) and TRIOBP (c.1952C>T) for the other pedigree. The candidate variants were validated in all available samples by Sanger sequencing.Conclusion: The candidate variants in hearing-loss genes were validated to be co-segregated in the pedigrees, and they may indicate the aetiologies of hearing loss in such patients. We also suggest that WES may be a suitable strategy for hearing-loss gene screening in clinical detection.

Pyroptosis, metabolism, and tumor immune microenvironment

“…DFNB59 is first identified as the causal gene of autosomal recessive deafness, which also plays key role during the signal transmit of auditory nerve 25 . As a hearing‐loss gene, variants of DFNB59 are linked with non‐syndromic hearing loss 141,184–187 . In addition, case reports have reported that PJVK also plays a role in other hearing‐related syndromes like auditory neuropathic spectrum disorder (ANSD) and poor cochlear implants performance 25,188 …”

“…25 As a hearing-loss gene, variants of DFNB59 are linked with non-syndromic hearing loss. 141,[184][185][186][187] In addition, case reports have reported that PJVK also plays a role in other hearing-related syndromes like auditory neuropathic spectrum disorder (ANSD) and poor cochlear implants performance. 25,188…”

A review of the mechanisms underlying the role of the GIPC3 gene in hereditary deafness

“…In summary, GIPC3 mutations have been shown to underlie NSHL associated with DFNB15, DFNB72 and DFNB95. In NSHL, biallelic, nonsense, and shift mutations were also observed in the GIPC3 gene (Chen et al, 1997;Ain et al, 2007;Charizopoulou et al, 2011;Rehman et al, 2011;Diaz-Horta et al, 2012;Sirmaci et al, 2012;Ramzan et al, 2013;Petrova et al, 2021), and more GIPC3 mutation loci are gradually being reported as research progresses (Siddiqi et al, 2014;Ammar-Khodja et al, 2015;Asgharzade et al, 2018;Khan et al, 2019;Bitarafan et al, 2020;Kannan-Sundhari et al, 2020;Zhou et al, 2020; Table 1).…”

Identification of Novel Compound Heterozygous MYO15A Mutations in Two Chinese Families with Autosomal Recessive Nonsyndromic Hearing Loss

“…Whole-exome capture was performed using the BGI-Exome kit V4 and sequenced by BGI-seq500 with 100 bp paired-end sequenc-ing. Sequenced reads were collected and aligned to the human genome reference (UCSCGRCh37/hg19) by the Burrows-Wheeler Aligner (BWA-MEM, version 0.7.10) [10]. In order to validate the mutations identified in the proband and confirm their cosegregation in the pedigree, DNA from all members of the family was performed Sanger sequenced.…”