Targeted Next-Generation Sequencing of Congenital Hypothyroidism-Causative Genes Reveals Unexpected Thyroglobulin Gene Variants in Patients with Iodide Transport Defect

Targeted Next-Generation Sequencing of Congenital Hypothyroidism-Causative Genes Reveals Unexpected Thyroglobulin Gene Variants in Patients with Iodide Transport Defect

Congenital iodide transport defect is an uncommon autosomal recessive disorder caused by loss-of-function variants in the sodium iodide symporter (NIS)-coding <i>SLC5A5</i> gene and leading to dyshormonogenic congenital hypothyroidism. Here, we conducted a targeted next-generation sequen...

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Bibliographic Details
Main Authors: Carlos Eduardo Bernal Barquero, Romina Celeste Geysels, Virginie Jacques, Gerardo Hernán Carro, Mariano Martín, Victoria Peyret, María Celeste Abregú, Patricia Papendieck, Ana María Masini-Repiso, Frédérique Savagner, Ana Elena Chiesa, Cintia E. Citterio, Juan Pablo Nicola
Format: Article
Language:English
Published: MDPI AG 2022-08-01
Series:International Journal of Molecular Sciences
Subjects:
congenital hypothyroidism
thyroid dyshormonogenesis
iodide transport defect
sodium iodide symporter
thyroglobulin
Online Access:https://www.mdpi.com/1422-0067/23/16/9251
Description
Summary:Congenital iodide transport defect is an uncommon autosomal recessive disorder caused by loss-of-function variants in the sodium iodide symporter (NIS)-coding <i>SLC5A5</i> gene and leading to dyshormonogenic congenital hypothyroidism. 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 <sup>99m</sup>Tc-pertechnetate accumulation in a eutopic thyroid gland. Although, unexpectedly, we could not detect pathogenic <i>SLC5A5</i> gene variants, we identified two novel compound heterozygous <i>TG</i> gene variants (p.Q29* and c.177-2A>C), three novel heterozygous <i>TG</i> gene variants (p.F1542V<i>fs</i>*20, p.Y2563C, and p.S523P), and a novel heterozygous <i>DUOX2</i> gene variant (p.E1496D<i>fs</i>*51). Splicing minigene reporter-based in vitro assays revealed that the variant c.177-2A>C affected normal TG pre-mRNA splicing, leading to the frameshift variant p.T59S<i>fs</i>*17. The frameshift <i>TG</i> variants p.T59S<i>fs</i>*17 and p.F1542V<i>fs</i>*20, but not the DUOX2 variant p.E1496D<i>fs</i>*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.
ISSN:1661-6596
1422-0067

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