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Identification of OSBPL2 As a Novel Candidate Gene for Progressive Nonsyndromic Hearing Loss by Whole-Exome Sequencing

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Identification of OSBPL2 As a Novel Candidate Gene for Progressive Nonsyndromic Hearing Loss by Whole-Exome Sequencing ORIGINAL RESEARCH ARTICLE © American College of Medical Genetics and Genomics Identification of OSBPL2 as a novel candidate gene for progressive nonsyndromic hearing loss by whole-exome sequencing Guangqian Xing, MD1, Jun Yao, PhD2, Bin Wu, MSc3, Tingting Liu, MD1, Qinjun Wei, MD2, Cheng Liu, MD1, Yajie Lu, MSc2, Zhibin Chen, MD1, Heng Zheng, PhD4, Xiaonan Yang, MSc3 and Xin Cao, PhD2 Purpose: Various forms of hearing loss have genetic causes, but ­predicted to lead to premature truncation of the OSBPL2 protein. many of the responsible genes have not yet been identified. Here, Modeling and structure-based analysis support the theory that we describe a large seven-generation Chinese family with autosomal this gene deletion is functionally deleterious. Our finding was fur- dominant nonsyndromic hearing loss that has been excluded as being ther confirmed by the detection of another missense mutation, a caused by known deafness gene mutations associated with autosomal c.583C>A transversion (p.Leu195Met) in exon 7 of OSBPL2, in an dominant nonsyndromic hearing loss with the aim of identifying a additional sporadic case of deafness. novel causative gene involved in deafness. Conclusion: Based on this study, OSBPL2 was identified as an excel- Methods: Whole-exome sequencing was conducted in three lent novel candidate gene for autosomal dominant nonsyndromic affected family members, and cosegregation analysis was performed hearing loss; this study is the first to implicate OSBPL2 mutations in on other members of the family. autosomal dominant nonsyndromic hearing loss. Results: Whole-exome sequencing and subsequent segregation anal- Genet Med advance online publication 31 July 2014 ysis identified a heterozygous frameshift mutation (c.153_154delCT, p.Gln53Argfs*100) in the oxysterol binding protein-like 2 (OSBPL2) Key Words: autosomal dominant inheritance; nonsyndromic gene in 25 affected family members. The deletion mutation is ­hearing loss; OSBPL2; whole-exome sequencing INTRODUCTION have been discovered to date using WES.11Several new NSHL- Hearing loss is one of the most common sensorial disorders, causative genes have also recently been revealed via WES, with an incidence of ~1 in 1,000 children. It is estimated that including GPSM2, DNMT1, BDP1, ELMOD3, TNC, GRXCR2, at least half of the cases are attributable to genetic factors, and and ADCY1.12–18 Thus, WES is a powerful approach for investi- more than two-thirds of this subset of cases are classified as gating the genetic basis of human disease. nonsyndromic hearing loss (NSHL) because of the absence of In the current study, using WES we identified a novel can- additional symptoms.1 NSHL is reportedly associated with dif- didate AD NSHL-causative gene, oxysterol binding protein- ferent genes in autosomal dominant (AD), autosomal recessive, like 2 (OSBPL2; NC_000020.11, NM_144498.2, NP_653081.1, X-linked, and maternal inheritance patterns. To date, more OMIM: 606731), in a large Chinese family (JSNY-028). Four than 64 genes have been linked to NSHL, including more than relatives (three affected individuals and one healthy spouse) of 27 AD NSHL genes. Because of the striking genetic heteroge- this family were included in the WES. Several lines of evidence neity of hearing loss and the exquisite sensitivity of the human supported the candidate role of this gene, including (i) a het- auditory system, however, it is estimated that the genetic causes erozygous frameshift mutation (c.153_154delCT) in exon 3 of listed above explain only less than half of the clinical cases in OSBPL2 was present in 25 available affected cases and absent in inheritance patterns2,3 (http://hereditaryhearingloss.org/). 26 unaffected family members, which completely cosegregated Therefore, many patients and families with hereditary hearing with the clinical phenotype of hearing loss in this family; (ii) loss have not received an explanation for additional unknown OSBPL2 mutations were not detected in 300 unaffected individ- causative genes. uals of matched ethnicity and geographic ancestry; (iii) a mis- Whole-exome sequencing (WES) has been successfully used sense mutation (c.583C>A) in exon 7 of OSBPL2 was detected to find disease-causing mutations in Mendelian disorders.4–19 in one of the 452 sporadic NSHL cases; (iv) the modeled struc- It is estimated that more than 230 novel rare disease genes ture of OSBPL2 also predicted that these two mutations were The first three authors contributed equally to this work. 1Department of Otolaryngology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, P.R. China; 2Department of Biotechnology, School of Basic Medical Science, Nanjing Medical University, Nanjing, P.R. China; 3BGI-Shenzhen, Guangdong, P.R. China; 4Department of Bioinformatics, School of Life Science and Technology, China Pharmaceutical University, Nanjing, P.R. China. Correspondence: Xin Cao ([email protected]) Submitted 30 January 2014; accepted 11 June 2014; advance online publication 31 July 2014. doi:10.1038/gim.2014.90 210 Volume 17 | Number 3 | March 2015 | GENETICS in mEDICINE Identification of OSBPL2 as a candidate gene for hearing loss | XING et al ORIGINAL RESEARCH ARTICLE functionally deleterious; and (v) strong expression of Osbpl2 This study was approved by the ethics committee of Nanjing was detected in mouse cochlea. To our knowledge, this is the Medical University, Jiangsu Province, and written consent was first report that shows that OSBPL2 is a candidate causative obtained from all participants or their guardians. All procedures gene for pedigrees and sporadic cases with NSHL and that it used in this study conformed to the tenets of the Declaration of is also the first AD NSHL-candidate gene identified on human Helsinki. chromosome 20. Whole-blood samples, including those from 51 members of the large family (25 available affected individuals, 14 unaffected MATERIALS AND METHODS relatives, and 12 spouses), 38 probands from unrelated AD Subjects and clinical investigation NSHL pedigrees, 452 sporadic NSHL cases, and 300 ethnicity- A large, seven-generation Chinese family of Han origin (desig- matched controls, were obtained. All DNA samples used for the nated as JSNY-028) with AD NSHL was recruited by a clinical study were extracted from whole blood. follow-up in August 2010, and the clinical data of all affected To identify the deafness-causative mutation in JSNY-028, members were updated (Supplementary Table S1 online; the reported causal genes of AD NSHL (http://hereditaryhear- Supplementary Figure S1 online). A pedigree of the family ingloss.org/; accessed: June 2011) were included in mutation is shown in Figure 1. Of note, 199 members in seven genera- screening by polymerase chain reaction (PCR)–based direct tions (176 members in four living generations) were described, sequencing. Considering that no variants of these genes were and 45 living members of the family were diagnosed as hav- detected in two affected individuals (V: 5, V: 20), it was suggested ing hereditary, progressive, sensorineural hearing loss without that an unknown mutation was responsible for AD NSHL. additional clinical symptoms. In this study blood samples from 25 affected individuals and 26 unaffected family members were Exome sequencing analysis collected and available for molecular analysis. All of the affected Three affected individuals (V: 5, VI: 4, and VI: 32) and one subjects underwent complete clinical examination and audio- normal-hearing family member (V: 4) were included in the logical evaluations, including pure-tone audiometry, immit- WES study. The genomic DNA extracted from whole blood was tance, auditory brainstem response, and distortion production fragmented, and the exomes were captured using the Agilent otoacoustic emissions. The audiological data were evaluated SureSelect Human All Exon Kit (Agilent, Santa Clara, CA). The based on the criteria established by the European Working captured DNA was sequenced with 90–base pair (bp) paired- Group on Genetics of Hearing Loss. A detailed medical history end reads on an Illumina HiSeq 2000 sequencing platform was also collected, including degree of hearing loss, age at onset, (Illumina, San Diego, CA) according to the manufacturer’s evolution of hearing impairment, use of hearing aids, presence protocol, and it was ensured that each sample was covered to of tinnitus, medication, noise exposure, pathologic changes in an average sequencing depth of at least 80-fold. Raw image the ear, and other relevant clinical manifestations. files were processed by Illumina base-calling software ver- Thirty-eight probands with hereditary hearing loss and sion 1.7 for base calling with default parameters. SOAPaligner 452 sporadic patients were recruited for future analysis. All 38 was used to align the sequenced raw data to the UCSC hg19 selected families exhibited typical AD NSHL, and audiological Burrows-Wheeler Aligner (0.5.9), and SOAPsnp was used to assessments of the affected individuals revealed bilateral, progres- calculate the likelihood of possible genotypes in target regions. sive, sensorineural hearing loss. A total of 452 sporadic cases with The low-quality variations were filtered out using the following NSHL participated in this study, including 250 deaf individuals criteria: (i) a quality score of <20; (ii) an average copy num- from the Nanjing City School for Deaf Children and 202 cases ber at the allele site ≥2; (iii) a distance between two adjacent from the otology clinic of the First Affiliated Hospital of Nanjing
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