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

Document Type : Original Article


1 Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

2 Department of Bioinformatics, School of Advanced Technologies in Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

3 Isfahan Cardiovascular Research Center, Isfahan Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran

4 Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran

5 Department of Genetics and Molecular Biology, School of Medicine; Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Noncommunicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran


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.


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