{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T16:56:03Z","timestamp":1782838563867,"version":"3.54.5"},"reference-count":37,"publisher":"BMJ","issue":"5","license":[{"start":{"date-parts":[[2024,1,31]],"date-time":"2024-01-31T00:00:00Z","timestamp":1706659200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100013365","name":"West China Hospital, Sichuan University","doi-asserted-by":"publisher","award":["ZYJC20002"],"award-info":[{"award-number":["ZYJC20002"]}],"id":[{"id":"10.13039\/501100013365","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2024,1,10]]},"published-print":{"date-parts":[[2024,5]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Townes-Brocks syndrome (TBS) is a rare genetic disorder characterised by multiple malformations. Due to its phenotypic heterogeneity and rarity, diagnosis and recognition of TBS can be challenging and there has been a lack of investigation of patients with atypical TBS in large cohorts and delineation of their phenotypic characteristics.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We screened <jats:italic>SALL1<\/jats:italic> and <jats:italic>DACT1<\/jats:italic> variants using next-generation sequencing in the China Deafness Genetics Consortium (CDGC) cohort enrolling 20\u2009666 unrelated hearing loss (HL) cases. Comprehensive clinical evaluations were conducted on seven members from a three-generation TBS family. Combining data from previously reported cases, we also provided a landscape of phenotypes and genotypes of patients with TBS.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We identified five novel and two reported pathogenic\/likely pathogenic (P\/LP) <jats:italic>SALL1<\/jats:italic> variants from seven families. Audiological features in patients differed in severity and binaural asymmetry. Moreover, previously undocumented malformations in the middle and inner ear were detected in one patient. By comprehensive clinical evaluations, we further provide evidence for the causal relationship between <jats:italic>SALL1<\/jats:italic> variation and certain endocrine abnormalities. Penetrance analysis within familial contexts revealed incomplete penetrance among first-generation patients with TBS and a higher disease burden among their affected offspring.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>This study presents the first insight of genetic screening for patients with TBS in a large HL cohort. We broadened the phenotypic-genotypic spectrum of TBS and our results supported an underestimated prevalence of TBS. Due to the rarity and phenotypic heterogeneity of rare diseases, broader spectrum molecular tests, especially whole genome sequencing, can improve the situation of underdiagnosis and provide effective recommendations for clinical management.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmg-2023-109579","type":"journal-article","created":{"date-parts":[[2024,1,31]],"date-time":"2024-01-31T13:30:16Z","timestamp":1706707816000},"page":"459-468","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":7,"title":["Molecular diagnosis, clinical evaluation and phenotypic spectrum of Townes-Brocks syndrome: insights from a large Chinese hearing loss cohort"],"prefix":"10.1136","volume":"61","author":[{"given":"Xiaohong","family":"Yan","sequence":"first","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China"},{"name":"Institute of Rare Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China"},{"name":"Institute of Rare Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China"},{"name":"Institute of Rare Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linke","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China"},{"name":"Institute of Rare Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China"},{"name":"Institute of Rare Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8443-7231","authenticated-orcid":false,"given":"Jia","family":"Geng","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China"},{"name":"Institute of Rare Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Rare Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingjun","family":"Zhong","sequence":"additional","affiliation":[{"name":"Institute of Rare Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyu","family":"Xiong","sequence":"additional","affiliation":[{"name":"Institute of Rare Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengxiao","family":"Bu","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China"},{"name":"Institute of Rare Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China"},{"name":"Institute of Rare Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8746-0125","authenticated-orcid":false,"given":"Jing","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China"},{"name":"Institute of Rare Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huijun","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China"},{"name":"Institute of Rare Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2024,1,31]]},"reference":[{"key":"2025101715131608000_61.5.459.1","first-page":"57","article-title":"The Townes-Brocks syndrome in Spain: the epidemiological aspects in a consecutive series of cases","volume":"50","author":"Mart\u00ednez-Fr\u00edas","year":"1999","journal-title":"An Esp Pediatr"},{"key":"2025101715131608000_61.5.459.2","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1002\/humu.23171","article-title":"Heterozygous pathogenic variant in DACT1 causes an autosomal-dominant syndrome with features overlapping Townes-Brocks syndrome","volume":"38","author":"Webb","year":"2017","journal-title":"Hum Mutat"},{"key":"2025101715131608000_61.5.459.3","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1007\/s00439-022-02481-6","article-title":"Heterozygous variants in the DVL2 interaction region of DACT1 cause CAKUT and features of Townes-Brocks syndrome 2","volume":"142","author":"Christians","year":"2023","journal-title":"Hum Genet"},{"key":"2025101715131608000_61.5.459.4","unstructured":"Kohlhase J , Adam MP , Ardinger HH , et al . Townes-Brocks syndrome. In: Adam MP , Ardinger HH , Pagon RA , eds. GeneReviews((R)). Seattle (WA), 1993."},{"key":"2025101715131608000_61.5.459.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.jgg.2021.07.013"},{"key":"2025101715131608000_61.5.459.6","doi-asserted-by":"publisher","DOI":"10.1101\/gr.107524.110"},{"key":"2025101715131608000_61.5.459.7","doi-asserted-by":"publisher","DOI":"10.1126\/science.abj6987"},{"key":"2025101715131608000_61.5.459.8","doi-asserted-by":"crossref","DOI":"10.1186\/s13059-016-0974-4","article-title":"The Ensembl variant effect predictor","volume":"17","author":"McLaren","year":"2016","journal-title":"Genome Biol"},{"key":"2025101715131608000_61.5.459.9","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkq603","article-title":"ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic Acids Res"},{"key":"2025101715131608000_61.5.459.10","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"2025101715131608000_61.5.459.11","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23630"},{"key":"2025101715131608000_61.5.459.12","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23626"},{"key":"2025101715131608000_61.5.459.13","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gks003","article-title":"cn.MOPS: mixture of poissons for discovering copy number variations in next-generation sequencing data with a low false discovery rate","volume":"40","author":"Klambauer","year":"2012","journal-title":"Nucleic Acids Res"},{"key":"2025101715131608000_61.5.459.14","doi-asserted-by":"publisher","DOI":"10.1101\/gr.114876.110"},{"key":"2025101715131608000_61.5.459.15","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btv710"},{"key":"2025101715131608000_61.5.459.16","doi-asserted-by":"publisher","DOI":"10.1038\/ng0198-81"},{"key":"2025101715131608000_61.5.459.17","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-013-1358-4"},{"key":"2025101715131608000_61.5.459.18","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx1153"},{"key":"2025101715131608000_61.5.459.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2018.08.006"},{"key":"2025101715131608000_61.5.459.20","doi-asserted-by":"crossref","DOI":"10.1136\/jmg.40.11.e127","article-title":"High incidence of the R276X SALL1 mutation in sporadic but not familial Townes-Brocks syndrome and report of the first familial case","volume":"40","author":"Kohlhase","year":"2003","journal-title":"J Med Genet"},{"key":"2025101715131608000_61.5.459.21","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21438"},{"key":"2025101715131608000_61.5.459.22","unstructured":"Otologic referral criteria for occupational hearing conservation programs. Washington, DC American Academy Otolaryngology-Head Neck Surgery; 1997."},{"key":"2025101715131608000_61.5.459.23","doi-asserted-by":"publisher","DOI":"10.1002\/1096-8628(20010815)102:3<250::AID-AJMG1479>3.0.CO;2-Q"},{"key":"2025101715131608000_61.5.459.24","doi-asserted-by":"publisher","DOI":"10.1002\/humu.9476I"},{"key":"2025101715131608000_61.5.459.25","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.37.4.303"},{"key":"2025101715131608000_61.5.459.26","doi-asserted-by":"crossref","first-page":"e75","DOI":"10.1111\/ped.12426","article-title":"16Q12 microdeletion syndrome in two Japanese boys","volume":"56","author":"Morisada","year":"2014","journal-title":"Pediatr Int"},{"key":"2025101715131608000_61.5.459.27","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfp014"},{"key":"2025101715131608000_61.5.459.28","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.3892\/etm.2016.3035","article-title":"Delayed diagnosis of Townes-Brocks syndrome with multicystic kidneys and renal failure caused by a novel SALL1 nonsense mutation: a case report","volume":"11","author":"Lin","year":"2016","journal-title":"Exp Ther Med"},{"key":"2025101715131608000_61.5.459.29","doi-asserted-by":"crossref","first-page":"2588","DOI":"10.1002\/ajmg.a.31699","article-title":"Kidney failure in Townes-Brocks syndrome: an under recognized phenomenon","volume":"143A","author":"Reardon","year":"2007","journal-title":"Am J Med Genet A"},{"key":"2025101715131608000_61.5.459.30","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1002\/ajmg.a.62050","article-title":"Adult diagnosis of Townes-Brocks syndrome with renal failure: two related cases and review of literature","volume":"185","author":"Beaudoux","year":"2021","journal-title":"Am J Med Genet A"},{"key":"2025101715131608000_61.5.459.31","doi-asserted-by":"crossref","DOI":"10.1186\/s12920-021-00871-9","article-title":"Whole-exome sequencing identified a novel heterozygous mutation of SALL1 and a new homozygous mutation of PTPRQ in a Chinese family with Townes-Brocks syndrome and hearing loss","volume":"14","author":"Yang","year":"2021","journal-title":"BMC Med Genomics"},{"key":"2025101715131608000_61.5.459.32","doi-asserted-by":"publisher","DOI":"10.1086\/302238"},{"key":"2025101715131608000_61.5.459.33","doi-asserted-by":"publisher","DOI":"10.1097\/00125817-200107000-00007"},{"key":"2025101715131608000_61.5.459.34","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1016\/j.ejmg.2009.09.001","article-title":"Obstructive Apneas and severe dysphagia in a girl with Townes-Brocks syndrome and atypical feet involvement","volume":"52","author":"van Bever","year":"2009","journal-title":"Eur J Med Genet"},{"key":"2025101715131608000_61.5.459.35","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/j.jpedsurg.2007.09.079","article-title":"Two coding single nucleotide polymorphisms in the SALL1 gene in Townes-Brocks syndrome: a case report and review of the literature","volume":"43","author":"Liang","year":"2008","journal-title":"J Pediatr Surg"},{"key":"2025101715131608000_61.5.459.36","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22858"},{"key":"2025101715131608000_61.5.459.37","doi-asserted-by":"publisher","DOI":"10.1177\/01945998941113P103"}],"container-title":["Journal of Medical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jmg-2023-109579","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T22:13:26Z","timestamp":1760739206000},"score":1,"resource":{"primary":{"URL":"https:\/\/jmg.bmj.com\/lookup\/doi\/10.1136\/jmg-2023-109579"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,31]]},"references-count":37,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2024,4,19]]},"published-print":{"date-parts":[[2024,5]]}},"alternative-id":["10.1136\/jmg-2023-109579"],"URL":"https:\/\/doi.org\/10.1136\/jmg-2023-109579","relation":{},"ISSN":["0022-2593","1468-6244"],"issn-type":[{"value":"0022-2593","type":"print"},{"value":"1468-6244","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,31]]}}}