{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T11:46:58Z","timestamp":1784202418818,"version":"3.55.0"},"reference-count":50,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2023,8,10]],"date-time":"2023-08-10T00:00:00Z","timestamp":1691625600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Autosomal recessive non-syndromic hearing loss (ARNSHL) is a public health concern in the Iranian population, with an incidence of 1 in 166 live births. In the present study, the whole exome sequencing (WES) method was applied to identify the mutation spectrum of NSHL patients negative for<jats:italic>GJB2<\/jats:italic>gene mutations. First, using ARMS PCR followed by Sanger sequencing of the<jats:italic>GJB2<\/jats:italic>gene, 63.15% of mutations in patients with NSHL were identified. Among the identified mutations in<jats:italic>GJB2<\/jats:italic>:p.Val43Met and p.Gly21Arg were novel. The remaining patients were subjected to WES, which identified novel mutations including<jats:italic>MYO15A<\/jats:italic>:p.Gly39LeufsTer188,<jats:italic>ADGRV1<\/jats:italic>:p.Ser5918ValfsTer23,<jats:italic>MYO7A<\/jats:italic>: c.5856+2T&gt;c (splicing mutation),<jats:italic>FGF3<\/jats:italic>:p.Ser156Cys. The present study emphasized the application of WES as an effective method for molecular diagnosis of NSHL patients negative for<jats:italic>GJB2<\/jats:italic>gene mutations in the Iranian population.<\/jats:p>","DOI":"10.1371\/journal.pone.0289247","type":"journal-article","created":{"date-parts":[[2023,8,10]],"date-time":"2023-08-10T17:48:06Z","timestamp":1691689686000},"page":"e0289247","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":10,"title":["Exome sequencing identifies novel variants associated with non-syndromic hearing loss in the Iranian population"],"prefix":"10.1371","volume":"18","author":[{"given":"Jalal","family":"Vallian Broojeni","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arezu","family":"Kazemi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Halimeh","family":"Rezaei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5151-5923","authenticated-orcid":true,"given":"Sadeq","family":"Vallian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,8,10]]},"reference":[{"issue":"20","key":"pone.0289247.ref001","doi-asserted-by":"crossref","first-page":"2151","DOI":"10.1056\/NEJMra050700","article-title":"Newborn hearing screening\u2014a silent revolution","volume":"354","author":"C.C. Morton","year":"2006","journal-title":"N Engl J Med"},{"issue":"4","key":"pone.0289247.ref002","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/S1525-1578(10)60522-3","article-title":"Hereditary non-syndromic sensorineural hearing loss: transforming silence to sound","volume":"6","author":"I. Schrijver","year":"2004","journal-title":"J Mol Diagn"},{"issue":"8","key":"pone.0289247.ref003","doi-asserted-by":"crossref","first-page":"e808","DOI":"10.1002\/mgg3.808","article-title":"Identification of novel variants in MYO15A, OTOF, and RDX with hearing loss by next-generation sequencing","volume":"7","author":"X. Bai","year":"2019","journal-title":"Mol Genet Genomic Med"},{"issue":"4","key":"pone.0289247.ref004","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1016\/j.ygeno.2018.05.008","article-title":"A novel pathogenic variant in the MARVELD2 gene causes autosomal recessive non-syndromic hearing loss in an Iranian family","volume":"111","author":"A. Taghipour-Sheshdeh","year":"2019","journal-title":"Genomics"},{"key":"pone.0289247.ref005","doi-asserted-by":"crossref","first-page":"e4","DOI":"10.1017\/S001667231500004X","article-title":"Whole-exome sequencing and its impact in hereditary hearing loss","volume":"97","author":"T. Atik","year":"2015","journal-title":"Genet Res (Camb)"},{"issue":"6","key":"pone.0289247.ref006","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1080\/14992020802607449","article-title":"Statistical study of 35delG mutation of GJB2 gene: a meta-analysis of carrier frequency","volume":"48","author":"N. Mahdieh","year":"2009","journal-title":"Int J Audiol"},{"issue":"1\u20132","key":"pone.0289247.ref007","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/S0378-1119(97)00365-X","article-title":"Upstream genomic sequence of the human connexin26 gene","volume":"199","author":"D.T. Kiang","year":"1997","journal-title":"Gene"},{"issue":"1","key":"pone.0289247.ref008","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1007\/s10549-018-05126-3","article-title":"ID2 and GJB2 promote early-stage breast cancer progression by regulating cancer stemness","volume":"175","author":"Y. Liu","year":"2019","journal-title":"Breast Cancer Res Treat"},{"key":"pone.0289247.ref009","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.lungcan.2021.06.001","article-title":"Integrative analyses identified ion channel genes GJB2 and SCNN1B as prognostic biomarkers and therapeutic targets for lung adenocarcinoma","volume":"158","author":"A. Lu","year":"2021","journal-title":"Lung Cancer"},{"key":"pone.0289247.ref010","doi-asserted-by":"crossref","first-page":"637431","DOI":"10.3389\/fonc.2021.637431","article-title":"Comprehensive Study of Germline Mutations and Double-Hit Events in Esophageal Squamous Cell Cancer","volume":"11","author":"B. Zeng","year":"2021","journal-title":"Front Oncol"},{"issue":"6","key":"pone.0289247.ref011","first-page":"3645","article-title":"Gap junction \u03b2\u20112 expression is negatively associated with the estrogen receptor status in breast cancer tissues and is a regulator of breast tumorigenesis","volume":"40","author":"A. Shettar","year":"2018","journal-title":"Oncol Rep"},{"issue":"5","key":"pone.0289247.ref012","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/j.mcp.2015.03.008","article-title":"Non-syndromic hearing loss gene identification: A brief history and glimpse into the future","volume":"29","author":"B. Vona","year":"2015","journal-title":"Molecular and Cellular Probes"},{"issue":"8","key":"pone.0289247.ref013","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1136\/jmg.38.8.515","article-title":"A common founder for the 35delG GJB2 gene mutation in connexin 26 hearing impairment","volume":"38","author":"L. Van Laer","year":"2001","journal-title":"Journal of medical genetics"},{"issue":"1","key":"pone.0289247.ref014","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1002\/1096-8628(20001106)95:1<53::AID-AJMG11>3.0.CO;2-2","article-title":"Contribution of connexin 26 mutations to nonsyndromic deafness in Ashkenazi patients and the variable phenotypic effect of the mutation 167delT","volume":"95","author":"I. Lerer","year":"2000","journal-title":"Am J Med Genet"},{"issue":"1","key":"pone.0289247.ref015","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1136\/jmg.37.1.41","article-title":"Prevalent connexin 26 gene (GJB2) mutations in Japanese","volume":"37","author":"S. Abe","year":"2000","journal-title":"Journal of medical genetics"},{"issue":"5","key":"pone.0289247.ref016","doi-asserted-by":"crossref","first-page":"e68","DOI":"10.1136\/jmg.40.5.e68","article-title":"Contribution of connexin26 (GJB2) mutations and founder effect to non-syndromic hearing loss in India","volume":"40","author":"M. RamShankar","year":"2003","journal-title":"J Med Genet"},{"key":"pone.0289247.ref017","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ijporl.2019.06.012","article-title":"A systematic review of SLC26A4 mutations causing hearing loss in the Iranian population","volume":"125","author":"M. Koohiyan","year":"2019","journal-title":"Int J Pediatr Otorhinolaryngol"},{"key":"pone.0289247.ref018","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.ijporl.2019.01.036","article-title":"An update of spectrum and frequency of GJB2 mutations causing hearing loss in the south of Iran: A literature review","volume":"119","author":"M. koohiyan","year":"2019","journal-title":"International Journal of Pediatric Otorhinolaryngology"},{"issue":"5","key":"pone.0289247.ref019","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1007\/s00405-015-3684-8","article-title":"GJB2 mutations in deaf population of Ilam (Western Iran): a different pattern of mutation distribution","volume":"273","author":"N. Mahdieh","year":"2016","journal-title":"Eur Arch Otorhinolaryngol"},{"issue":"10","key":"pone.0289247.ref020","doi-asserted-by":"crossref","first-page":"1758","DOI":"10.1097\/00005537-200310000-00018","article-title":"Connexin 26 mutations and nonsyndromic hearing impairment in northern Finland","volume":"113","author":"T. L\u00f6pp\u00f6nen","year":"2003","journal-title":"Laryngoscope"},{"key":"pone.0289247.ref021","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s12863-016-0354-9","article-title":"The high frequency of GJB2 gene mutation c.313_326del14 suggests its possible origin in ancestors of Lithuanian population","volume":"17","author":"V. Mikstiene","year":"2016","journal-title":"BMC Genet"},{"issue":"5","key":"pone.0289247.ref022","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1089\/gtmb.2009.0073","article-title":"GJB2 mutations in patients with nonsyndromic hearing loss from Croatia","volume":"13","author":"I. Sansovi\u0107","year":"2009","journal-title":"Genet Test Mol Biomarkers"},{"issue":"1\u20132","key":"pone.0289247.ref023","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.heares.2004.11.022","article-title":"GJB2 mutations in Turkish patients with ARNSHL: prevalence and two novel mutations","volume":"203","author":"E. Kalay","year":"2005","journal-title":"Hear Res"},{"issue":"1","key":"pone.0289247.ref024","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1111\/j.1399-0004.2005.00379.x","article-title":"Low prevalence of Connexin 26 (GJB2) variants in Pakistani families with autosomal recessive non-syndromic hearing impairment","volume":"67","author":"R.L. Santos","year":"2005","journal-title":"Clin Genet"},{"issue":"6","key":"pone.0289247.ref025","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1002\/humu.1233","article-title":"Absence of deafness-associated connexin-26 (GJB2) gene mutations in the Omani population","volume":"18","author":"M. Simsek","year":"2001","journal-title":"Hum Mutat"},{"issue":"12","key":"pone.0289247.ref026","doi-asserted-by":"crossref","first-page":"2026","DOI":"10.1016\/j.ijporl.2014.08.036","article-title":"Genetics of non-syndromic hearing loss in the Middle East","volume":"78","author":"H. Najmabadi","year":"2014","journal-title":"Int J Pediatr Otorhinolaryngol"},{"issue":"3","key":"pone.0289247.ref027","doi-asserted-by":"crossref","first-page":"172","DOI":"10.5582\/irdr.2019.01070","article-title":"Genetics of hereditary hearing loss in east Iran population: A systematic review of GJB2 mutations","volume":"8","author":"M. Koohiyan","year":"2019","journal-title":"Intractable Rare Dis Res"},{"issue":"2","key":"pone.0289247.ref028","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.ijporl.2011.11.019","article-title":"Spectrum of GJB2 (Cx26) gene mutations in Iranian Azeri patients with nonsyndromic autosomal recessive hearing loss","volume":"76","author":"B. Davarnia","year":"2012","journal-title":"Int J Pediatr Otorhinolaryngol"},{"issue":"3","key":"pone.0289247.ref029","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1093\/nar\/16.3.1215","article-title":"A simple salting out procedure for extracting DNA from human nucleated cells","volume":"16","author":"S.A. Miller","year":"1988","journal-title":"Nucleic acids research"},{"issue":"7","key":"pone.0289247.ref030","first-page":"599","article-title":"Guidelines for the tetra-primer ARMS-PCR technique development","volume":"56","author":"R.F. Medrano","year":"2014","journal-title":"Mol Biotechnol"},{"issue":"5","key":"pone.0289247.ref031","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"S. Richards","year":"2015","journal-title":"Genet Med"},{"issue":"Web Server issue","key":"pone.0289247.ref032","doi-asserted-by":"crossref","first-page":"W452","DOI":"10.1093\/nar\/gks539","article-title":"SIFT web server: predicting effects of amino acid substitutions on proteins","volume":"40","author":"N.L. Sim","year":"2012","journal-title":"Nucleic Acids Res"},{"key":"pone.0289247.ref033","article-title":"Predicting functional effect of human missense mutations using PolyPhen-2","volume":"7","author":"I. Adzhubei","year":"2013","journal-title":"Curr Protoc Hum Genet"},{"issue":"4","key":"pone.0289247.ref034","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1038\/nmeth.2890","article-title":"MutationTaster2: mutation prediction for the deep-sequencing age","volume":"11","author":"J.M. Schwarz","year":"2014","journal-title":"Nature Methods"},{"issue":"16","key":"pone.0289247.ref035","doi-asserted-by":"crossref","first-page":"2745","DOI":"10.1093\/bioinformatics\/btv195","article-title":"PROVEAN web server: a tool to predict the functional effect of amino acid substitutions and indels","volume":"31","author":"Y. Choi","year":"2015","journal-title":"Bioinformatics"},{"issue":"3","key":"pone.0289247.ref036","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1093\/bioinformatics\/btx536","article-title":"FATHMM-XF: accurate prediction of pathogenic point mutations via extended features","volume":"34","author":"M.F. Rogers","year":"2018","journal-title":"Bioinformatics"},{"issue":"D1","key":"pone.0289247.ref037","doi-asserted-by":"crossref","first-page":"D886","DOI":"10.1093\/nar\/gky1016","article-title":"CADD: predicting the deleteriousness of variants throughout the human genome","volume":"47","author":"P. Rentzsch","year":"2018","journal-title":"Nucleic Acids Research"},{"key":"pone.0289247.ref038","unstructured":"Hall, T.A.BIOEDIT: A USER-FRIENDLY BIOLOGICAL SEQUENCE ALIGNMENT EDITOR AND ANALYSIS PROGRAM FOR WINDOWS 95\/98\/ NT. 1999."},{"issue":"4","key":"pone.0289247.ref039","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/j.ijporl.2012.01.014","article-title":"Compound heterozygosity of the novel c.292C>T (p.R98W) and the c.35delG GJB2 mutations in postlingual, non-syndromic, sensorineural deafness","volume":"76","author":"M.B. Petersen","year":"2012","journal-title":"Int J Pediatr Otorhinolaryngol"},{"issue":"4","key":"pone.0289247.ref040","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1097\/00125817-200207000-00006","article-title":"Effectiveness of sequencing connexin 26 (GJB2) in cases of familial or sporadic childhood deafness referred for molecular diagnostic testing","volume":"4","author":"B.L. Wu","year":"2002","journal-title":"Genet Med"},{"issue":"1\u20132","key":"pone.0289247.ref041","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.heares.2005.04.012","article-title":"Prevalence of GJB2 mutations and the del(GJB6-D13S1830) in Argentinean non-syndromic deaf patients","volume":"207","author":"V. Dalam\u00f3n","year":"2005","journal-title":"Hear Res"},{"issue":"4","key":"pone.0289247.ref042","doi-asserted-by":"crossref","first-page":"C966","DOI":"10.1152\/ajpcell.00008.2008","article-title":"Connexin26 deafness associated mutations show altered permeability to large cationic molecules","volume":"295","author":"G. Me\u015fe","year":"2008","journal-title":"Am J Physiol Cell Physiol"},{"issue":"10","key":"pone.0289247.ref043","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1002\/humu.23042","article-title":"Mutational Spectrum of MYO15A and the Molecular Mechanisms of DFNB3","volume":"37","author":"A.U. Rehman","year":"2016","journal-title":"Human Deafness. Hum Mutat"},{"issue":"1","key":"pone.0289247.ref044","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1159\/000498843","article-title":"Identification and Clinical Implications of a Novel MYO15A Variant in a Consanguineous Iranian Family by Targeted Exome Sequencing","volume":"24","author":"N. Zarepour","year":"2019","journal-title":"Audiol Neurootol"},{"issue":"11","key":"pone.0289247.ref045","doi-asserted-by":"crossref","first-page":"1610","DOI":"10.1016\/j.ijporl.2012.07.030","article-title":"Screening of OTOF mutations in Iran: a novel mutation and review","volume":"76","author":"N. Mahdieh","year":"2012","journal-title":"Int J Pediatr Otorhinolaryngol"},{"issue":"1","key":"pone.0289247.ref046","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1002\/humu.22205","article-title":"A novel deletion in SMPX causes a rare form of X-linked progressive hearing loss in two families due to a founder effect","volume":"34","author":"N. Abdelfatah","year":"2013","journal-title":"Hum Mutat"},{"issue":"2","key":"pone.0289247.ref047","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1086\/510920","article-title":"Homozygous mutations in fibroblast growth factor 3 are associated with a new form of syndromic deafness characterized by inner ear agenesis, microtia, and microdontia","volume":"80","author":"M. Tekin","year":"2007","journal-title":"Am J Hum Genet"},{"issue":"1","key":"pone.0289247.ref048","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/s12881-019-0790-2","article-title":"Genotype-phenotype correlation analysis of MYO15A variants in autosomal recessive non-syndromic hearing loss","volume":"20","author":"J. Zhang","year":"2019","journal-title":"BMC Medical Genetics"},{"issue":"1","key":"pone.0289247.ref049","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1159\/000480458","article-title":"Dual Diagnosis of Ellis-van Creveld Syndrome and Hearing Loss in a Consanguineous Family","volume":"9","author":"B. Vona","year":"2017","journal-title":"Mol Syndromol"},{"issue":"2","key":"pone.0289247.ref050","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1111\/ahg.12354","article-title":"GJB2-related hearing loss in central Iran: Review of the spectrum and frequency of gene mutations","volume":"84","author":"M. Koohiyan","year":"2020","journal-title":"Ann Hum Genet"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0289247","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,18]],"date-time":"2023-12-18T21:33:44Z","timestamp":1702935224000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0289247"}},"subtitle":[],"editor":[{"given":"Nader","family":"Al-Dewik","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,8,10]]},"references-count":50,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,8,10]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0289247","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,10]]}}}