Athanasia Stoupa1,2,3, Ghada Al Hage Chehade3, Rim Chaabane4, Dulanjalee Kariyawasam3, Gabor Szinnai5,6, Sylvain Hanein7, Christine Bole-Feysot8, Cécile Fourrage9, Patrick Nitschke9, Caroline Thalassinos3, Graziella Pinto3, Mouna Mnif10, Sabine Baron11, Marc De Kerdanet12, Rachel Reynaud13, Pascal Barat14, Mongia Hachicha15, Neila Belguith4,16, Michel Polak1,2,3,17,18, Aurore Carré1,2. 1. INSERM U1016, Cochin Institute, Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. 2. IMAGINE Institute affiliate, Paris, France. 3. Pediatric Endocrinology, Gynecology and Diabetology Unit, Hôpital Universitaire Necker-Enfants Malades, AP-HP, Paris, France. 4. Laboratory of Human Molecular Genetics, Medicine School, University of Sfax, Sfax, Tunisia. 5. Pediatric Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland. 6. Pediatric Endocrinology, University Children's Hospital Basel, University of Basel, Basel, Switzerland. 7. INSERM U1163, IMAGINE Institute, Translational Genetics, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. 8. Genomics Platform, INSERM UMR 1163, Paris Descartes Sorbonne Paris Cite University, Imagine Institute, Paris, France. 9. Bioinformatics Platform, Paris Descartes University, IMAGINE Institute, Paris, France. 10. Endocrinology Department, CHU Hedi Chaker, Sfax, Tunisia. 11. Pediatrics Department, CHU Nantes, Nantes, France. 12. Pediatrics Department, CHU Rennes, Rennes, France. 13. Pediatrics Department, CHU La Timone, Marseille, France. 14. CHU de Bordeaux, Pediatric Endocrinology, Bordeaux, France. 15. Pediatrics Department, CHU Hedi Chaker, Sfax, Tunisia. 16. Medical Genetics Department, CHU Hedi Chaker, Sfax, Tunisia. 17. Centre de Référence des Maladies Endocriniennes Rares de la Croissance et du Développement, Necker-Enfants Malades University Hospital, Paris, France. 18. Centre Régional de Dépistage Néonatal (CRDN) Ile de France, Paris, France.
Abstract
Objective: To elucidate the molecular cause in a well-characterized cohort of patients with Congenital Hypothyroidism (CH) and Dyshormonogenesis (DH) by using targeted next-generation sequencing (TNGS). Study design: We studied 19 well-characterized patients diagnosed with CH and DH by targeted NGS including genes involved in thyroid hormone production. The pathogenicity of novel mutations was assessed based on in silico prediction tool results, functional studies when possible, variant location in important protein domains, and a review of the recent literature. Results: TNGS with variant prioritization and detailed assessment identified likely disease-causing mutations in 10 patients (53%). Monogenic defects most often involved TG, followed by DUOXA2, DUOX2, and NIS and were usually homozygous or compound heterozygous. Our review shows the importance of the detailed phenotypic description of patients and accurate analysis of variants to provide a molecular diagnosis. Conclusions: In a clinically well-characterized cohort, TNGS had a diagnostic yield of 53%, in accordance with previous studies using a similar strategy. TG mutations were the most common genetic defect. TNGS identified gene mutations causing DH, thereby providing a rapid and cost-effective genetic diagnosis in patients with CH due to DH.
Objective: To elucidate the molecular cause in a well-characterized cohort of patients with Congenital Hypothyroidism (CH) and Dyshormonogenesis (DH) by using targeted next-generation sequencing (TNGS). Study design: We studied 19 well-characterized patients diagnosed with CH and DH by targeted NGS including genes involved in thyroid hormone production. The pathogenicity of novel mutations was assessed based on in silico prediction tool results, functional studies when possible, variant location in important protein domains, and a review of the recent literature. Results:TNGS with variant prioritization and detailed assessment identified likely disease-causing mutations in 10 patients (53%). Monogenic defects most often involved TG, followed by DUOXA2, DUOX2, and NIS and were usually homozygous or compound heterozygous. Our review shows the importance of the detailed phenotypic description of patients and accurate analysis of variants to provide a molecular diagnosis. Conclusions: In a clinically well-characterized cohort, TNGS had a diagnostic yield of 53%, in accordance with previous studies using a similar strategy. TG mutations were the most common genetic defect. TNGS identified gene mutations causing DH, thereby providing a rapid and cost-effective genetic diagnosis in patients with CH due to DH.
Authors: S A van de Graaf; C Ris-Stalpers; G J Veenboer; M Cammenga; C Santos; H M Targovnik; J J de Vijlder; G Medeiros-Neto Journal: J Clin Endocrinol Metab Date: 1999-07 Impact factor: 5.958
Authors: H M Targovnik; G Medeiros-Neto; V Varela; P Cochaux; B L Wajchenberg; G Vassart Journal: J Clin Endocrinol Metab Date: 1993-07 Impact factor: 5.958
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