Comprehensive screening of eight known causative genes in congenital hypothyroidism with gland-in-situ

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dc.contributor.authorNicholas, Adeline K.
dc.contributor.authorSerra, Eva Goncalves
dc.contributor.authorCangül, Hakan
dc.contributor.authorAl-Yaarubi, Saif
dc.contributor.authorUllah, Irfan
dc.contributor.authorSchoenmakers, Erik
dc.contributor.authorDeeb, Asma
dc.contributor.authorHabeb, Abdelhadi M.
dc.contributor.authorAlmaghamsi, Mohammad
dc.contributor.authorPeters, Catherine
dc.contributor.authorNathwani, Nisha
dc.contributor.authorAycan, Zehra
dc.contributor.authorSağlam, Halil
dc.contributor.authorBober, Ece
dc.contributor.authorDattani, Mehul
dc.contributor.authorShenoy, Savitha
dc.contributor.authorMurray, Philip G.
dc.contributor.authorBabiker, Amir
dc.contributor.authorWillemsen, Ruben
dc.contributor.authorThankamony, Ajay
dc.contributor.authorLyons, Greta
dc.contributor.authorIrwin, Rachael
dc.contributor.authorPadidela, Raja
dc.contributor.authorTharian, Kavitha
dc.contributor.authorDavies, Justin Huw
dc.contributor.authorPuthi, Vijith
dc.contributor.authorPark, Soo-Mi
dc.contributor.authorMassoud, Ahmed F.
dc.contributor.authorGregory, John W.
dc.contributor.authorAlbanese, Assunta
dc.contributor.authorPease-Gevers, Evelien
dc.contributor.authorMartin, Howard
dc.contributor.authorBrugger, Kim
dc.contributor.authorMaher, Eamonn R.
dc.contributor.authorChatterjee, V. Krishna K.
dc.contributor.authorAnderson, Carl A.
dc.contributor.authorSchoenmakers, Nadia
dc.date.accessioned10.07.201910:49:13
dc.date.accessioned2019-07-10T19:57:41Z
dc.date.available10.07.201910:49:13
dc.date.available2019-07-10T19:57:41Z
dc.date.issued2016
dc.departmentİstanbul Medipol Üniversitesi, Rektörlük, Rejeneratif ve Restoratif Tıp Araştırmaları Merkezi (REMER)
dc.descriptionWOS: 000390951000004
dc.descriptionPubMed ID: 27525530
dc.description.abstractContext: Lower TSH screening cutoffs have doubled the ascertainment of congenital hypothyroidism (CH), particularly cases with a eutopically located gland-in-situ (GIS). Although mutations in known dyshormonogenesis genes or TSHR underlie some cases of CH with GIS, systematic screening of these eight genes has not previously been undertaken. Objective: Our objective was to evaluate the contribution and molecular spectrum of mutations in eight known causative genes (TG, TPO, DUOX2, DUOXA2, SLC5A5, SLC26A4, IYD, and TSHR) in CH cases with GIS. Patients, Design, and Setting:We screened 49 CH cases with GIS from 34 ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silica. Results: Twenty-nine cases harbored likely disease-causing mutations. Monogenic defects (19 cases) most commonly involved TG (12), TPO (four), DUOX2 (two), and TSHR (one). Ten cases harbored triallelic (digenic) mutations: TG and TPO (one); SLC26A4 and TPO (three), and DUOX2 and TG (six cases). Novel variants overall included 15 TG, six TPO, and three DUOX2 mutations. Genetic basis was not ascertained in 20 patients, including 14 familial cases. Conclusions: The etiology of CH with GIS remains elusive, with only 59% attributable to mutations in TSHR or known dyshormonogenesis-associated genes in a cohort enriched for familial cases. Biallelic TG or TPO mutations most commonly underlie severe CH. Triallelic defects are frequent, mandating future segregation studies in larger kindreds to assess their contribution to variable phenotype. A high proportion (-41%) of unsolved or ambiguous cases suggests novel genetic etiologies that remain to be elucidated.
dc.description.sponsorshipWellcome Trust [100585/Z/12/Z, 095564/Z/11/Z, 098051, WT091310]; National Institute for Health Research Cambridge Biomedical Research Center; Medical Research Council [MC_UU_12012/5/B]en_US
dc.description.sponsorshipThis work was supported by Wellcome Trust Grants 100585/Z/12/Z (to N.S.), and 095564/Z/11/Z (to V.K.C.); the National Institute for Health Research Cambridge Biomedical Research Center (to V.K.C., N.S.). E.G.S and C.A.A. are supported by the Wellcome Trust (098051). This study made use of data generated by the UK10K Project (www.uk10k.org). Funding for the UK10K Project was provided by the Wellcome Trust under award WT091310. A full list of UK10K Consortium members can be found at the UK10K Project website.en_US
dc.identifier.citationNicholas, A. K., Serra, E. G., Cangül, H., Al-Yaarubi, S., Ullah, I., Schoenmakers, E. ... Schoenmakers, N. (2016). Comprehensive screening of eight known causative genes in congenital hypothyroidism with gland-in-situ. Journal Of Clinical Endocrinology & Metabolism, 101(12), 4521-4531. https://dx.doi.org/10.1210/jc.2016-1879
dc.identifier.doi10.1210/jc.2016-1879
dc.identifier.endpage4531
dc.identifier.issn0021-972X
dc.identifier.issn1945-7197
dc.identifier.issue12
dc.identifier.scopusqualityQ1
dc.identifier.startpage4521
dc.identifier.urihttps://dx.doi.org/10.1210/jc.2016-1879
dc.identifier.urihttps://hdl.handle.net/20.500.12511/3027
dc.identifier.volume101
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherEndocrine Society
dc.relation.ispartofJournal Of Clinical Endocrinology & Metabolismen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/openAccess
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.subjectCongenital Hypothyroidism
dc.subjectGenetic Screening
dc.subjectGene
dc.titleComprehensive screening of eight known causative genes in congenital hypothyroidism with gland-in-situ
dc.typeArticle

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