{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,30]],"date-time":"2025-11-30T22:05:05Z","timestamp":1764540305260,"version":"3.37.3"},"reference-count":31,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,7,17]],"date-time":"2020-07-17T00:00:00Z","timestamp":1594944000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,7,17]],"date-time":"2020-07-17T00:00:00Z","timestamp":1594944000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Baylor Hopkins Center for Mendelian Genetics","award":["NHGRI 1U54HG006542","UM1HG006542","NHGRI 1U54HG006542","UM1HG006542","NHGRI 1U54HG006542","UM1HG006542"],"award-info":[{"award-number":["NHGRI 1U54HG006542","UM1HG006542","NHGRI 1U54HG006542","UM1HG006542","NHGRI 1U54HG006542","UM1HG006542"]}]},{"DOI":"10.13039\/501100004681","name":"Higher Education Commission, Pakistan","doi-asserted-by":"publisher","award":["3288"],"award-info":[{"award-number":["3288"]}],"id":[{"id":"10.13039\/501100004681","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Hearing loss affects 380 million people worldwide due to environmental or genetic causes. Determining the cause of deafness in individuals without previous family history of hearing loss is challenging and has been relatively unexplored in Pakistan. We investigated the spectrum of genetic variants in hearing loss in a cohort of singleton affected individuals born to consanguineous parents. Twenty-one individuals with moderate to severe hearing loss were recruited. We performed whole-exome sequencing on DNA samples from the participants, which identified seventeen variants in ten known deafness genes and one novel candidate gene. All identified variants were homozygous except for two. Eleven of the variants were novel, including one multi-exonic homozygous deletion in<jats:italic>OTOA<\/jats:italic>. A missense variant in<jats:italic>ESRRB<\/jats:italic>was implicated for recessively inherited moderate to severe hearing loss. Two individuals were heterozygous for variants in<jats:italic>MYO7A<\/jats:italic>and<jats:italic>CHD7<\/jats:italic>, respectively, consistent with de novo variants or dominant inheritance with incomplete penetrance as the reason for their hearing loss. Our results indicate that similar to familial cases of deafness, variants in a large number of genes are responsible for moderate to severe hearing loss in sporadic individuals born to consanguineous couples.<\/jats:p>","DOI":"10.1038\/s41598-020-68779-5","type":"journal-article","created":{"date-parts":[[2020,7,17]],"date-time":"2020-07-17T14:23:54Z","timestamp":1594995834000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Spectrum of genetic variants in moderate to severe sporadic hearing loss in Pakistan"],"prefix":"10.1038","volume":"10","author":[{"given":"Memoona","family":"Ramzan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rasheeda","family":"Bashir","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Midhat","family":"Salman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ghulam","family":"Mujtaba","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nara","family":"Sobreira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P. Dane","family":"Witmer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"Baylor-Hopkins Center for Mendelian Genomics","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sadaf","family":"Naz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,7,17]]},"reference":[{"key":"68779_CR1","doi-asserted-by":"publisher","first-page":"879","DOI":"10.1016\/S0140-6736(05)71047-3","volume":"365","author":"RJ Smith","year":"2005","unstructured":"Smith, R. J. et al. Sensorineural hearing loss in children. Lancet 365, 879\u2013890 (2005).","journal-title":"Lancet"},{"key":"68779_CR2","doi-asserted-by":"publisher","first-page":"2151","DOI":"10.1056\/NEJMra050700","volume":"354","author":"CC Morton","year":"2006","unstructured":"Morton, C. C. et al. Newborn hearing screening: A silent revolution. N. Engl. J. Med. 354, 2151\u20132164 (2006).","journal-title":"N. Engl. J. Med."},{"key":"68779_CR3","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1097\/MOP.0b013e3283588f5e","volume":"24","author":"AE Shearer","year":"2012","unstructured":"Shearer, A. E. et al. Genetics: Advances in genetic testing for deafness. Curr. Opin. Pediatr. 24, 679 (2012).","journal-title":"Curr. Opin. Pediatr."},{"key":"68779_CR4","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1146\/annurev.genom.4.070802.110347","volume":"4","author":"TB Friedman","year":"2003","unstructured":"Friedman, T. B. et al. Human nonsyndromic sensorineural deafness. Annu. Rev. Genom. Hum. Genet. 4, 341\u2013402 (2003).","journal-title":"Annu. Rev. Genom. Hum. Genet."},{"key":"68779_CR5","doi-asserted-by":"publisher","first-page":"901","DOI":"10.1038\/gim.2014.213","volume":"17","author":"NK Kim","year":"2015","unstructured":"Kim, N. K. et al. Whole-exome sequencing reveals diverse modes of inheritance in sporadic mild to moderate sensorineural hearing loss in a pediatric population. Genet. Med. 17, 901 (2015).","journal-title":"Genet. Med."},{"key":"68779_CR6","doi-asserted-by":"publisher","first-page":"45973","DOI":"10.1038\/srep45973","volume":"7","author":"J Jung","year":"2017","unstructured":"Jung, J. et al. Genetic predisposition to sporadic congenital hearing loss in a pediatric population. Sci. Rep. 7, 45973 (2017).","journal-title":"Sci. Rep."},{"key":"68779_CR7","first-page":"1","volume":"36","author":"M Hashemzadeh Chaleshtori","year":"2007","unstructured":"Hashemzadeh Chaleshtori, M. et al. Familial and sporadic GJB2-related deafness in Iran: Review of gene mutations. Iran. J. Public Health 36, 1\u201314 (2007).","journal-title":"Iran. J. Public Health"},{"key":"68779_CR8","doi-asserted-by":"publisher","first-page":"588","DOI":"10.1111\/cge.12431","volume":"87","author":"X Gu","year":"2015","unstructured":"Gu, X. et al. Genetic testing for sporadic hearing loss using targeted massively parallel sequencing identifies 10 novel mutations. Clin. Genet. 87, 588\u2013593 (2015).","journal-title":"Clin. Genet."},{"key":"68779_CR9","doi-asserted-by":"crossref","first-page":"e917","DOI":"10.1002\/mgg3.917","volume":"7","author":"A Khan","year":"2019","unstructured":"Khan, A. et al. Sequence variants in genes causing nonsyndromic hearing loss in a Pakistani cohort. Mol. Genet. Genom. Med. 7, e917 (2019).","journal-title":"Mol. Genet. Genom. Med."},{"key":"68779_CR10","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1002\/ajmg.a.34391","volume":"158","author":"LJ Francey","year":"2012","unstructured":"Francey, L. J. et al. Genome-wide SNP genotyping identifies the Stereocilin (STRC) gene as a major contributor to pediatric bilateral sensorineural hearing impairment. Am. J. Med. Genet. Part A 158, 298\u2013308 (2012).","journal-title":"Am. J. Med. Genet. Part A"},{"key":"68779_CR11","doi-asserted-by":"publisher","first-page":"2071","DOI":"10.1007\/s00405-015-3523-y","volume":"272","author":"M Salman","year":"2015","unstructured":"Salman, M. et al. Mutations of GJB2 encoding connexin 26 contribute to non-syndromic moderate and severe hearing loss in Pakistan. Eur. Arch. Otorhinolaryngol. 272, 2071\u20132075 (2015).","journal-title":"Eur. Arch. Otorhinolaryngol."},{"key":"68779_CR12","doi-asserted-by":"publisher","first-page":"e61592","DOI":"10.1371\/journal.pone.0061592","volume":"8","author":"SY Kim","year":"2013","unstructured":"Kim, S. Y. et al. Prevalence of p. V37I variant of GJB2 in mild or moderate hearing loss in a pediatric population and the interpretation of its pathogenicity. PLoS ONE 8, e61592 (2013).","journal-title":"PLoS ONE"},{"key":"68779_CR13","first-page":"18101","volume":"92","author":"BA Marosy","year":"2017","unstructured":"Marosy, B. A. et al. Generating exome enriched sequencing libraries from formalin-fixed, paraffin-embedded tissue DNA for next-generation sequencing. Curr. Protoc. Hum. Genet. 92, 18101\u2013181025 (2017).","journal-title":"Curr. Protoc. Hum. Genet."},{"key":"68779_CR14","doi-asserted-by":"publisher","first-page":"928","DOI":"10.1002\/humu.22844","volume":"36","author":"N Sobreira","year":"2015","unstructured":"Sobreira, N. et al. GeneMatcher: A matching tool for connecting investigators with an interest in the same gene. Hum. Mutat. 36, 928\u2013930 (2015).","journal-title":"Hum. Mutat."},{"key":"68779_CR15","doi-asserted-by":"publisher","first-page":"2747","DOI":"10.1093\/bioinformatics\/bts526","volume":"28","author":"V Plagnol","year":"2012","unstructured":"Plagnol, V. et al. A robust model for read count data in exome sequencing experiments and implications for copy number variant calling. Bioinformatics 28, 2747\u20132754 (2012).","journal-title":"Bioinformatics"},{"key":"68779_CR16","doi-asserted-by":"publisher","first-page":"3572","DOI":"10.1093\/bioinformatics\/bty304","volume":"34","author":"V Geoffroy","year":"2018","unstructured":"Geoffroy, V. et al. AnnotSV: An integrated tool for structural variations annotation. Bioinformatics 34, 3572\u20133574 (2018).","journal-title":"Bioinformatics"},{"key":"68779_CR17","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","volume":"17","author":"S Richards","year":"2015","unstructured":"Richards, S. et al. 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. Genet. Med. 17, 405\u2013423 (2015).","journal-title":"Genet. Med."},{"key":"68779_CR18","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1016\/j.ajhg.2009.07.003","volume":"85","author":"S Riazuddin","year":"2009","unstructured":"Riazuddin, S. et al. Molecular basis of DFNB73: Mutations of BSND can cause nonsyndromic deafness or Bartter syndrome. Am. J. Hum. Genet. 85, 273\u2013280 (2009).","journal-title":"Am. J. Hum. Genet."},{"key":"68779_CR19","doi-asserted-by":"publisher","first-page":"781","DOI":"10.1210\/jc.2002-021398","volume":"88","author":"N Miyamura","year":"2003","unstructured":"Miyamura, N. et al. Atypical Bartter syndrome with sensorineural deafness with G47R mutation of the \u03b2-subunit for ClC-Ka and ClC-Kb chloride channels, barttin. J. Clin. Endocrinol. Metab. 88, 781\u2013786 (2003).","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"68779_CR20","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1080\/00039896.1973.10666215","volume":"26","author":"EM Scott","year":"1973","unstructured":"Scott, E. M. Genetic disorders in isolated populations. Arch. Environ. Health Int. J. 26, 32\u201335 (1973).","journal-title":"Arch. Environ. Health Int. J."},{"key":"68779_CR21","first-page":"43","volume":"1","author":"AH Bittles","year":"2005","unstructured":"Bittles, A. H. Population stratification and genetic association studies in South Asia. J. Mol. Genet. Med. Int. J. Biomed. Res. 1, 43 (2005).","journal-title":"J. Mol. Genet. Med. Int. J. Biomed. Res."},{"key":"68779_CR22","doi-asserted-by":"publisher","first-page":"S10","DOI":"10.3342\/ceo.2012.5.S1.S10","volume":"5","author":"J-W Shin","year":"2012","unstructured":"Shin, J.-W. et al. Genetic screening of GJB2 and SLC26A4 in Korean cochlear implantees: Experience of soree Ear clinic. Clin. Exp. Otorhinolaryngol. 5, S10 (2012).","journal-title":"Clin. Exp. Otorhinolaryngol."},{"key":"68779_CR23","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1186\/s13023-014-0167-8","volume":"9","author":"JH Park","year":"2014","unstructured":"Park, J. H. et al. Exploration of molecular genetic etiology for Korean cochlear implantees with severe to profound hearing loss and its implication. Orphanet J. Rare Dis. 9, 167 (2014).","journal-title":"Orphanet J. Rare Dis."},{"key":"68779_CR24","doi-asserted-by":"publisher","first-page":"4815","DOI":"10.1242\/dev.02664","volume":"133","author":"L Feng","year":"2006","unstructured":"Feng, L. et al. Requirement for Bhlhb5 in the specification of amacrine and cone bipolar subtypes in mouse retina. Development 133, 4815\u20134825 (2006).","journal-title":"Development"},{"key":"68779_CR25","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1016\/j.neuron.2011.09.035","volume":"73","author":"SE Ross","year":"2012","unstructured":"Ross, S. E. et al. Bhlhb5 and Prdm8 form a repressor complex involved in neuronal circuit assembly. Neuron 73, 292\u2013303 (2012).","journal-title":"Neuron"},{"key":"68779_CR26","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1006\/geno.2002.6833","volume":"80","author":"Z-P Xu","year":"2002","unstructured":"Xu, Z.-P. et al. Functional and structural characterization of the human gene BHLHB5, encoding a basic helix\u2013loop\u2013helix transcription factor. Genomics 80, 311\u2013318 (2002).","journal-title":"Genomics"},{"key":"68779_CR27","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1016\/j.jmb.2009.10.001","volume":"395","author":"S Tungtur","year":"2010","unstructured":"Tungtur, S. et al. Comparing the functional roles of nonconserved sequence positions in homologous transcription repressors: Implications for sequence\/function analyses. J. Mol. Biol. 395, 785\u2013802 (2010).","journal-title":"J. Mol. Biol."},{"key":"68779_CR28","doi-asserted-by":"publisher","first-page":"502","DOI":"10.1002\/humu.20677","volume":"29","author":"S Riazuddin","year":"2008","unstructured":"Riazuddin, S. et al. Mutation spectrum of MYO7A and evaluation of a novel nonsyndromic deafness DFNB2 allele with residual function. Hum. Mutat. 29, 502\u2013511 (2008).","journal-title":"Hum. Mutat."},{"key":"68779_CR29","doi-asserted-by":"publisher","first-page":"e55178","DOI":"10.1371\/journal.pone.0055178","volume":"8","author":"Q Sang","year":"2013","unstructured":"Sang, Q. et al. Identification and functional study of a new missense mutation in the motor head domain of myosin VIIA in a family with autosomal dominant hearing impairment (DFNA11). PLoS ONE 8, e55178 (2013).","journal-title":"PLoS ONE"},{"key":"68779_CR30","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1186\/1750-1172-8-85","volume":"8","author":"T Yang","year":"2013","unstructured":"Yang, T. et al. Genetic etiology study of the non-syndromic deafness in Chinese Hans by targeted next-generation sequencing. Orphanet J. Rare Dis. 8, 85 (2013).","journal-title":"Orphanet J. Rare Dis."},{"key":"68779_CR31","doi-asserted-by":"publisher","first-page":"21104","DOI":"10.1073\/pnas.1012989107","volume":"107","author":"AE Shearer","year":"2010","unstructured":"Shearer, A. E. et al. Comprehensive genetic testing for hereditary hearing loss using massively parallel sequencing. Proc. Natl. Acad. Sci. 107, 21104\u201321109 (2010).","journal-title":"Proc. Natl. Acad. Sci."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-68779-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-68779-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-68779-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,4]],"date-time":"2023-10-04T11:14:34Z","timestamp":1696418074000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-68779-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,17]]},"references-count":31,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["68779"],"URL":"https:\/\/doi.org\/10.1038\/s41598-020-68779-5","relation":{},"ISSN":["2045-2322"],"issn-type":[{"type":"electronic","value":"2045-2322"}],"subject":[],"published":{"date-parts":[[2020,7,17]]},"assertion":[{"value":"11 February 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 April 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 July 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"11902"}}