A novel variant of SLC26A4 and first report of the c.716T>A variant in Iranian pedigrees with non-syndromic sensorineural hearing loss

The autosomal recessive non-syndromic hearing loss (ARNSHL) can be associated with variants in solute carrier family 26, member 4 (SLC26A4) gene and is the second most common cause of ARNSHL worldwide. Therefore, this study aims to determine the contribution of the SLC26A4 genotype in the hearing loss (HL) of 40 ARNSHL pedigrees in Iran. A cohort of the 40 Iranian pedigrees with ARNSHL, having no mutation in the GJB2 gene, was selected. The linkage analysis with five short tandem repeat (STR) markers linked to SLC26A4 was performed for the 40 ARNSHL pedigrees. Then, two out of the 40 pedigrees with ARNSHL that linked to DFNB4 locus were further screened to determine the variants in all exons of SLC26A4 gene by direct DNA sequencing. The 21 exons of SCL26A4 were analyzed for the two pedigrees. A known variant (c.716T>A homozygote), it is the first reported incidence in Iran, a novel variant (c.493A>C homozygote) were detected in the two pedigrees and pathogenesis of c.493A>C confirmed in this study with review 100 hearing ethnically matched controls by PCR-RFLP analysis. The present study suggests that the SLC26A4 gene plays a crucial role in the HL occurring in Iranian pedigrees. Also, the results probably support the specificity and unique spectrum of SLC26A4 variants among Iranian HL patients. Molecular study of SLC26A4 gene may lead to elucidation of the profile of the population-specific variants which has importance in diagnostics of HL

Applying Two Different Bioinformatic Approaches to Discover Novel Genes Associated with Hereditary Hearing Loss via Whole-Exome Sequencing: ENDEAVOUR and HomozygosityMapper.

Background: Hearing loss (HL) is a highly prevalent heterogeneous deficiency of sensory-neural system with involvement of several dozen genes. Whole-exome sequencing (WES) is capable of discovering known and novel genes involved with HL. Materials and Methods: Two pedigrees with HL background from Khuzestan province of Iran were selected. Polymerase chain reaction-sequencing of GJB2 and homozygosity mapping of 16 DFNB loci were performed. One patient of the first and two affected individuals from the second pedigree were subjected to WES. The result files were analyzed using tools on Ubuntu 16.04. Short reads were mapped to reference genome (hg19, NCBI Build 37). Sorting and duplication removals were done. Variants were obtained and annotated by an online software tool. Variant filtration was performed. In the first family, ENDEAVOUR was applied to prioritize candidate genes. In the second family, a combination of shared variants, homozygosity mapping, and gene expression were implemented to launch the disease-causing gene. Results: GJB2 sequencing and linkage analysis established no homozygosity-by-descent at any DFNB loci. Utilizing ENDEAVOUR, BBX: C.C857G (P.A286G), and MYH15: C.C5557T (P.R1853C) were put forward, but none of the variants co-segregated with the phenotype. Two genes, UNC13B and TRAK1, were prioritized in the homozygous regions detected by HomozygosityMapper. Conclusion: WES is regarded a powerful approach to discover molecular etiology of Mendelian inherited disorders, but as it fails to enrich GC-rich regions, incapability of capturing noncoding regulatory regions and limited specificity and accuracy of copy number variations detection tools from exome data, it is assumed an insufficient procedure

=مجلة دانشگاه علوم پزشكي بابل، سال سوم، شمارة 3 (پي‏درپي11)، صفحه الي ، تابستان 1380

ABSTRACT BACKGROUND AND OBJECTIVE: Congenital hearing loss is the most common sensorineural defect in human. The most common genetic mutations in this disease are GJB2 mutations which are followed by SLC26A4 mutations. Following a report for the first time in the world insist on CABP2 gene interference in hearing loss production, the present study was launched to analyze this mutation in Iranian patients with hereditary hearing loss. METHODS: This is a cross sectional study. Among samples with autosomal recessive familial hearing loss pattern, regarding pedigree and audiometric data 253 patients with moderate to profound hearing loss were selected and studied. The mutation c. 637+1G>T was investigated using PCR-RFLP method