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

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., Thankamony, A., Lyons, G., Irwin, R., Padidela, R., Tharian, K., Davies, J.H., Puthi, V., Park, S.-M., Massoud, A.F., Gregory, J.W., Albanese, A., Pease-Gevers, E., Martin, H., Brugger, K., Maher, E.R., Chatterjee, K., Anderson, C.A. and 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. (doi:10.1210/jc.2016-1879).

Abstract

Context: lower thyroid-stimulating hormone (TSH) screening cut-offs 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 the thyroid-stimulating hormone receptor (TSHR) underlie some cases of CH with GIS, systematic screening of these eight genes has not previously been undertaken.

Objective: 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 forty-nine CH cases with GIS from thirty-four 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 (nineteen cases) most commonly involved TG (twelve), TPO (four), DUOX2 (two) and TSHR (one case). Ten cases harboured triallelic (digenic) mutations: TG and TPO (one); SLC26A4 and TPO (three) and DUOX2 and TG (six cases). Novel variants overall included fifteen TG, six TPO, and three DUOX2 mutations. Genetic basis was not ascertained in twenty patients, including fourteen familial cases.

Conclusions: the aetiology ofCHwith GIS remains elusive, with only59%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 aetiologies that remain to be elucidated
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