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

Adeline K. Nicholas, Eva G. Serra, Hakan Cangul, Saif Alyaarubi, Irfan Ullah, Erik Schoenmakers, Asma Deeb, Abdelhadi M. Habeb, Mohammad Almaghamsi, Catherine Peters, Nisha Nathwani, Zehra Aycan, Halil Saglam, Ece Bober, Mehul Dattani, Savitha Shenoy, Philip G. Murray, Amir Babiker, Ruben Willemsen, Ajay ThankamonyGreta Lyons, Rachael Irwin, Raja Padidela, Kavitha Tharian, Justin H. Davies, Vijith Puthi, Soo Mi Park, Ahmed F. Massoud, John W. Gregory, Assunta Albanese, Evelien Pease-Gevers, Howard Martin, Kim Brugger, Eamonn R. Maher, V. Krishna K Chatterjee, Carl A. Anderson, Nadia Schoenmakers

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Abstract

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 ofCHwith 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:Wescreened 49 CH cases with GIS from 34 ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silico. 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.

Original languageEnglish
Pages (from-to)4521-4531
Number of pages11
JournalJournal of Clinical Endocrinology and Metabolism
Volume101
Issue number12
DOIs
Publication statusPublished - Dec 1 2016

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ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

Cite this

Nicholas, A. K., Serra, E. G., Cangul, H., Alyaarubi, S., Ullah, I., Schoenmakers, E., Deeb, A., Habeb, A. M., Almaghamsi, M., Peters, C., Nathwani, N., Aycan, Z., Saglam, H., Bober, E., Dattani, M., Shenoy, S., Murray, P. G., Babiker, A., Willemsen, R., ... Schoenmakers, N. (2016). Comprehensive screening of eight known causative genes in congenital hypothyroidism with gland-in-situ. Journal of Clinical Endocrinology and Metabolism, 101(12), 4521-4531. https://doi.org/10.1210/jc.2016-1879