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Applying Two Different Bioinformatic Approaches to Discover Novel Genes Associated with Hereditary Hearing Loss Via Whole‑Exom

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Applying Two Different Bioinformatic Approaches to Discover Novel Genes Associated with Hereditary Hearing Loss Via Whole‑Exom Original Article Applying Two Different Bioinformatic Approaches to Discover Novel Genes Associated with Hereditary Hearing Loss via Whole‑Exome Sequencing: ENDEAVOUR and HomozygosityMapper Abstract Mohammad Reza Background: Hearing loss (HL) is a highly prevalent heterogeneous deficiency of sensory‑neural Pourreza1, system with involvement of several dozen genes. Whole‑exome sequencing (WES) is capable of Hannane discovering known and novel genes involved with HL. Materials and Methods: Two pedigrees with 2 HL background from Khuzestan province of Iran were selected. Polymerase chain reaction‑sequencing Mohammadi , 3 of GJB2 and homozygosity mapping of 16 DFNB loci were performed. One patient of the first and Ladan Sadeghian , two affected individuals from the second pedigree were subjected to WES. The result files were Samira analyzed using tools on Ubuntu 16.04. Short reads were mapped to reference genome (hg19, NCBI Asgharzadeh4, Build 37). Sorting and duplication removals were done. Variants were obtained and annotated by an Mohammadreza online software tool. Variant filtration was performed. In the first family, ENDEAVOUR was applied 2 to prioritize candidate genes. In the second family, a combination of shared variants, homozygosity Sehhati , mapping, and gene expression were implemented to launch the disease‑causing gene. Results: GJB2 Mohammad Amin sequencing and linkage analysis established no homozygosity‑by‑descent at any DFNB loci. Utilizing Tabatabaiefar1,5 ENDEAVOUR, BBX: C.C857G (P.A286G), and MYH15: C.C5557T (P.R1853C) were put forward, From the 1Department of but none of the variants co‑segregated with the phenotype. Two genes, UNC13B and TRAK1, Genetics and Molecular Biology, were prioritized in the homozygous regions detected by HomozygosityMapper. Conclusion: WES School of Medicine, Isfahan is regarded a powerful approach to discover molecular etiology of Mendelian inherited disorders, University of Medical Sciences, 2 but as it fails to enrich GC‑rich regions, incapability of capturing noncoding regulatory regions and Department of Bioinformatics, limited specificity and accuracy of copy number variations detection tools from exome data, it is School of Advanced Technologies in Medicine, Isfahan University assumed an insufficient procedure. of Medical Sciences, 3Isfahan Cardiovascular Research Center, Keywords: ENDEAVOUR, hearing loss, homozygosity mapping, Iran, whole‑exome sequencing Isfahan Cardiovascular Research Institute, Isfahan University of Medical Sciences, 5Pediatric Introduction into two main categories, syndromic and Inherited Diseases Research nonsyndromic. Syndromic HL manifests Center, Research Institute Hearing loss (HL) accounts for the most with involvement of other body organs, for Primordial Prevention of common sensory‑neural defect worldwide while deafness is the only symptom in Noncommunicable Disease, with an incidence of 1–2 new cases/1000 Isfahan University of Medical nonsyndromic form. About 75%–85% 4 newborns.[1] The disease incidence Sciences, Isfahan, Cellular and of nonsyndromic cases have autosomal Molecular Research Center, rises during childhood and adolescence recessive mode of inheritance. Autosomal Basic Health Sciences Institute, lifetime to 2.83 and 3.5/1000 individuals, dominant inheritance manner comprises Shahrekord University of respectively.[2,3] According to the World Medical Sciences, Shahrekord, 15%–24% of the patients. Rare causes, Health Organization estimations, there Iran X‑linked recessive and mitochondrial are about 360 million deaf individuals patterns, include 1%–2% of the affected Address for correspondence: throughout the world.[4] Due to the high rate Dr. Mohammad Amin individuals.[8] Lesions of outer ear cause of consanguineous marriages in Iran,[5] the Tabatabaiefar, conductive HL, while defects of the middle Department of Genetics and disease frequency is much higher and stands and inner ear lead to sensory‑neural HL. Molecular Biology, School of second among disabilities in the country.[6] According to age of onset HL is divided Medicine, Isfahan University of Patients with profound hearing difficulties Medical Sciences, Isfahan, Iran. into prelingual and postlingual. The severity suffer from poor linguistic communication, E‑mail: tabatabaiefar@med. of disease spectrum ranges from mild to mui.ac.ir social engagement, cognitive activity, and [9] [7] profound based on audiogram profile. low life quality. Access this article online More than 80 distinct loci and 60 genes More than 50% of the cases have a genetic have been discovered associated with Website: www.advbiores.net background. Hereditary HL is divided DOI: 10.4103/abr.abr_80_18 How to cite this article: Pourreza MR, Mohammadi H, Sadeghian L, Asgharzadeh S, Sehhati M, Quick Response Code: This is an open access journal, and articles are Tabatabaiefar MA. Applying Two Different Bioinformatic distributed under the terms of the Creative Commons Approaches to Discover Novel Genes Associated Attribution‑NonCommercial‑ShareAlike 4.0 License, which with Hereditary Hearing Loss via Whole-Exome allows others to remix, tweak, and build upon the work Sequencing: ENDEAVOUR and HomozygosityMapper. non‑commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. Adv Biomed Res 2018;7:141. For reprints contact: [email protected] Received: April, 2018. Accepted: May, 2018. © 2018 Advanced Biomedical Research | Published by Wolters Kluwer - Medknow 1 Pourreza, et al.: Discovering novel genes associated with hereditary hearing loss via whole‑exome sequencing autosomal recessive nonsyndromic HL (ARNSHL).[10] GJB2 blood (GeNet Bio, Korea) according to the manufacturer’s mutations at DFNB1 locus are the most common cause of instruction. the disease in most part of the world.[11,12] However, the Coding mutations of the GJB2 gene were screened by role of DFNB1 locus is variable because of existence of polymerase chain reaction (PCR)‑sequencing as described various ethnic groups in Iran.[13‑17] previously.[17] Whole‑exome sequencing (WES) is a high‑throughput More than 60 Short Tandem Repeat Polymorphic (STRP) technique which gives the opportunity to detect markers linked to DFNB1A/B, DFNB2, DFNB3, DFNB4, single‑nucleotide variants mainly in the coding regions of DFNB7/11, DFNB9, DFNB15, DFNB21, DFNB22, the genome.[18,19] To some extent, it has the capability of DFNB24, DFNB42, DFNB59, DFNB63, DFNB93, and finding copy number variations (CNVs) through special [20] DFNB101 were selected from NCBI Map Viewer and approaches. Since the development of this technology, UCSC genome browser. Primers were designed using several novel genes have been introduced involved with [21] Primer3 v. 0.4.0 (http://bioinfo.ut.ee/primer3–0.4.0/) ARNSHL. [Table 1] or selected through NCBI Probe. Specificity of Various genes associated with the same heritable disorder the primers was checked through NCBI Primer‑BLAST usually play a role in certain pathways or have structural (https://blast.ncbi.nlm.nih.gov/Blast.cgi). Touchdown PCR and functional similarities. Hence, based on previous was carried out to amplify STRP markers by 2X Master knowledge about HL‑associated genes, discovering novel Mix (Ampliqon®, Denmark). To genotype STRP markers, genes could be an appropriate selection. Obtaining exome PCR products were resolved on a nondenaturing 12%–15% data from different individuals in a family would help polyacrylamide gel and stained under standard silver nitrate to detect homozygous haplotypes and common variants, protocol. Genotypes were determined by visual inspection. with the same pattern of inheritance, among affected Haplotype reconstruction was done by HaploPainter individuals. v. 1.043. In this study, we selected two different approaches to Whole‑exome sequencing experiment, bioinformatics discover novel disease‑causing genes in two large Iranian analysis, and variant prioritization families affected with ARNSHL. In one family, WES One affected individual from Sho‑4 pedigree and two was performed for the proband and gene discovery was affected individuals from Ahv‑17 pedigree were subjected to based on variant filtering and similarity searching using high‑throughput sequencing. Genomic DNA was isolated from ENDEAVOR online software tool. In the second family, peripheral blood lymphocytes according to phenol–chloroform homozygosity mapping was performed by exome data of protocol. Using 1% agarose gel and Nanospec Cube two affected individuals. Common disruptive variants, Biophotometer (Nanolytik®, Dusseldorf, Germany) DNA expression pattern and gene function were considered to concentration, purity and integrity were checked. About prioritize candidate genes. 1 µg of genomic DNA of each individual was utilized to Materials and Methods prepare library sequencing in a solution‑phase targeted genomic enrichment by Agilent SureSelect Human All Exon Subjects kit v6 (Agilent Technologies, CA, USA) according to the manufacturer’s instruction. Sequencing was carried out by Two large pedigrees (Ahv‑17 and Sho‑4) from Khuzestan Illumina HiSeq 2000 (Illumina, San Diego, California, USA) province of Iran were ascertained with the history of several to generate 105 bp short reads. HL patients. Clinical investigations were accomplished including skeletal, eye, kidney, heart, and cutaneous Sequence reads were aligned against human reference examinations. In addition, magnetic resonance imaging genome (hg19, NCBI Build 37) by BWA v0.7.8‑r455 and computed tomography scan were performed
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