Abstract
BackgroundHearing loss (HL) is the most common sensorineural disorder with high phenotypic and genotypic heterogeneity, which negatively affects life quality. Autosomal recessive non-syndromic hearing loss (ARNSHL) constitutes a major share of HL cases. In the present study, Whole exome sequencing (WES) was applied to investigate the underlying etiology of HL in an Iranian patient with ARNSHL.MethodsA proband from an Iranian consanguineous family was examined via WES, following GJB2 sequencing. WES was utilized to find possible genetic etiology of the disease. Various Bioinformatics tools were used to assess the pathogenicity of the variants. Co-segregation analysis of the candidate variant was carried out. Interpretation of variants was performed according to the American College of Medical Genetics and Genomics (ACMG) guidelines.ResultsWES results showed a novel frameshift (16 bp deletion) variant (p.Ala170Alafs*20) in the LRTOMT gene. This variant, which resides in exon 6, was found to be co-segregating in the family. It fulfils the criteria set by the ACMG guidelines of being pathogenic.ConclusionHere, we report successful application of WES to identify the molecular pathogenesis of ARNSHL, which is a genetically heterogeneous disorder, in a patient with ARNSHL.
Highlights
Hearing loss (HL) is the most common sensorineural disorder with high phenotypic and genotypic heterogeneity, which negatively affects life quality
The aim of this study was to identify the molecular pathology of congenital HL in a four-year-old boy using Whole exome sequencing (WES), which led to the identification of a novel frameshift mutation
It has been reported that Nonsyndromic HL (NSHL) due to mutations in the Leucine Rich Transmembrane and O-Methyl-Transferase (LRTOMT) gene are more likely to be assigned to the LRTOMT2 (COMT2) region rather than LRTOMT1 [28, 51]. These findings indicate mutations in LRTOMT2 are associated with hair cell defects and lead to severe-to-profound NSHL [21, 29, 30, 53]
Summary
Hearing loss (HL) is the most common sensorineural disorder with high phenotypic and genotypic heterogeneity, which negatively affects life quality. Hearing loss (HL) is the most common congenital sensorineural defect affecting about 1 of 500–1000 newborns worldwide. It represents a significant global health problem [1]. The average percentage of GJB2 mutations, as the cause of ARNSHL, in Iran is about 18.7% [15], with a higher frequency in the north (33%) and a lower frequency (4%) in the southern regions. In this region, mutations in SLC26A4 are more frequent [16]. Whole exome sequencing would be ideal to determine HL causing mutations [17]
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