Comprehensive screening of eight known causative genes in congenital hypothyroidism with gland-in-situ
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info:eu-repo/semantics/openAccessAttribution 4.0 Internationalhttps://creativecommons.org/licenses/by/4.0/Date
2016Author
Nicholas, Adeline K.Serra, Eva Goncalves
Cangül, Hakan
Al-Yaarubi, Saif
Ullah, Irfan
Schoenmakers, Erik
Deeb, Asma
Habeb, Abdelhadi M.
Almaghamsi, Mohammad
Peters, Catherine
Nathwani, Nisha
Aycan, Zehra
Sağlam, Halil
Bober, Ece
Dattani, Mehul
Shenoy, Savitha
Murray, Philip G.
Babiker, Amir
Willemsen, Ruben
Thankamony, Ajay
Lyons, Greta
Irwin, Rachael
Padidela, Raja
Tharian, Kavitha
Davies, Justin Huw
Puthi, Vijith
Park, Soo-Mi
Massoud, Ahmed F.
Gregory, John W.
Albanese, Assunta
Pease-Gevers, Evelien
Martin, Howard
Brugger, Kim
Maher, Eamonn R.
Chatterjee, V. Krishna K.
Anderson, Carl A.
Schoenmakers, Nadia
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Nicholas, 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.2016-1879Abstract
Context: 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.