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Identification of PENDRIN (SLC26A4) mutations in patients with congenital hypothyroidism and "apparent" thyroid dysgenesis

Item Type:Article
Title:Identification of PENDRIN (SLC26A4) mutations in patients with congenital hypothyroidism and "apparent" thyroid dysgenesis
Creators Name:Kuehnen, P. and Turan, S. and Froehler, S. and Gueran, T. and Abali, S. and Biebermann, H. and Bereket, A. and Grueters, A. and Chen, W. and Krude, H.
Abstract:Context: Congenital hypothyroidism (CH), the most frequent endocrine congenital disease, can occur either based on a thyroid hormone biosynthesis defect or can predominantly be due to thyroid dysgenesis. However, a genetic cause could so far only be identified in less than 10% of patients with a thyroid dysgenesis. Objectives: Exome-sequencing was used for the first time to find additional genetic defects in thyroid dysgenesis. Patients and Methods: In a consanguineous family with thyroid dysgenesis exome-sequencing was applied and findings were further validated by Sanger sequencing in a cohort of 94 patients with thyroid dysgenesis. Results: By exome-sequencing we identified a homozygous missense mutation (p.Leu597Ser) in the SLC26A4 gene of a patient with hypoplastic thyroid tissue, who was otherwise healthy. In the cohort of patients with thyroid dysgenesis we observed a second case with a homozygous missense mutation (p.Gln413Arg) in the SLC26A4 gene, who was additionally affected by severe hearing problems. Both mutations were previously described as loss-of-function mutations in patients with Pendred syndrome and nonsyndromic EVA (enlarged vestibular aqueduct). Conclusion: We identified unexpectedly SLC26A4 mutations, that were hitherto diagnosed in thyroid dyshormonogenesis patients, now for the first time in patients with structural thyroid defects. This result resembles the historic description of thyroid atrophy in patients with the so-called myxedematous form of cretinism following severe iodine deficiency. Most likely, the thyroid defect of the two homozygous SLC26A4 gene mutation carriers represents a kind of secondary thyroid "atrophy", rather than a primary defect of thyroid development in the sense of thyroid "agenesis". Our study extends the variable clinical spectrum of patients with SLC26A4 mutations and points out the necessity to analyze the SLC26A4 gene in patients with "apparent" thyroid dysgenesis in addition to the known candidate genes TSHR, PAX8, NKX2.1, NKX2.5 and FOXE1.
Keywords:Case-Control Studies, Cohort Studies, Congenital Hypothyroidism, DNA Mutational Analysis, Genetic Association Studies, Membrane Transport Proteins, Mutation, Pedigree, Thyroid Dysgenesis, Turkey
Source:Journal of Clinical Endocrinology and Metabolism
Publisher:Endocrine Society
Page Range:E169-E176
Date:January 2014
Official Publication:https://doi.org/10.1210/jc.2013-2619
PubMed:View item in PubMed

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