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Here, we conducted a targeted next-generation sequencing assessment of congenital hypothyroidism-causative genes in a cohort of nine unrelated pediatric patients suspected of having a congenital iodide transport defect based on the absence of 99mTc-pertechnetate accumulation in a eutopic thyroid gland. Although, unexpectedly, we could not detect pathogenic SLC5A5 gene variants, we identified two novel compound heterozygous TG gene variants (p.Q29* and c.177-2A&gt;C), three novel heterozygous TG gene variants (p.F1542Vfs*20, p.Y2563C, and p.S523P), and a novel heterozygous DUOX2 gene variant (p.E1496Dfs*51). Splicing minigene reporter-based in vitro assays revealed that the variant c.177-2A&gt;C affected normal TG pre-mRNA splicing, leading to the frameshift variant p.T59Sfs*17. The frameshift TG variants p.T59Sfs*17 and p.F1542Vfs*20, but not the DUOX2 variant p.E1496Dfs*51, were predicted to undergo nonsense-mediated decay. Moreover, functional in vitro expression assays revealed that the variant p.Y2563C reduced the secretion of the TG protein. Our investigation revealed unexpected findings regarding the genetics of congenital iodide transport defects, supporting the existence of yet to be discovered mechanisms involved in thyroid hormonogenesis.<\/jats:p>","DOI":"10.3390\/ijms23169251","type":"journal-article","created":{"date-parts":[[2022,8,17]],"date-time":"2022-08-17T21:23:56Z","timestamp":1660771436000},"page":"9251","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Targeted Next-Generation Sequencing of Congenital Hypothyroidism-Causative Genes Reveals Unexpected Thyroglobulin Gene Variants in Patients with Iodide Transport Defect"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7166-2210","authenticated-orcid":false,"given":"Carlos Eduardo","family":"Bernal Barquero","sequence":"first","affiliation":[{"name":"Departamento de Bioqu\u00edmica Cl\u00ednica, Facultad de Ciencias Qu\u00edmicas, Universidad 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31300 Toulouse, France"},{"name":"Institut des Maladies M\u00e9taboliques et Cardiovasculaires (I2MC), Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM) UMR 1297, 31432 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9221-9573","authenticated-orcid":false,"given":"Gerardo Hern\u00e1n","family":"Carro","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica Cl\u00ednica, Facultad de Ciencias Qu\u00edmicas, Universidad Nacional de C\u00f3rdoba, Cordoba 5000, Argentina"},{"name":"Centro de Investigaciones en Bioqu\u00edmica Cl\u00ednica e Inmunolog\u00eda, Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CIBICI-CONICET), Cordoba 5000, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariano","family":"Mart\u00edn","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica Cl\u00ednica, Facultad de Ciencias 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Mol. Genet. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1007\/s12020-021-02646-9","article-title":"New genetics in congenital hypothyroidism","volume":"71","author":"Stoupa","year":"2021","journal-title":"Endocrine"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1089\/thy.2020.0333","article-title":"Congenital hypothyroidism: A 2020\u20132021 consensus guidelines update\u2014An ENDO-European Reference Network initiative endorsed by the European Society for Pediatric Endocrinology and the European Society for Endocrinology","volume":"31","author":"Stoupa","year":"2021","journal-title":"Thyroid"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"620117","DOI":"10.3389\/fendo.2021.620117","article-title":"Novel Compound Heterozygous Pathogenic Mutations of SLC5A5 in a Chinese Patient with Congenital Hypothyroidism","volume":"12","author":"Zhang","year":"2021","journal-title":"Front. Endocrinol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1089\/thy.2021.0478","article-title":"Brief Report: A Novel Sodium\/Iodide Symporter Mutation, S356F, Causing Congenital Hypothyroidism","volume":"32","author":"Durgia","year":"2022","journal-title":"Thyroid"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"E1100","DOI":"10.1210\/jc.2011-0349","article-title":"Iodide transport defect: Functional characterization of a novel mutation in the Na+\/I\u2212 symporter 5\u2032-untranslated region in a patient with congenital hypothyroidism","volume":"96","author":"Nicola","year":"2011","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"E1353","DOI":"10.1210\/jc.2015-1824","article-title":"Sodium\/Iodide Symporter Mutant V270E Causes Stunted Growth but No Cognitive Deficiency","volume":"100","author":"Nicola","year":"2015","journal-title":"J. Clin. Endocrinol. 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