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

BERNAL BARQUERO, CARLOS EDUARDO; GEYSELS, ROMINA CELESTE; JACQUES, VIRGINIE; CARRO, GERARDO HERNÁN; MARTÍN, MARIANO; PEYRET, VICTORIA; ABREGÚ, MARÍA CELESTE; PAPENDIECK, PATRICIA; MASINI-REPISO, ANA MARÍA; SAVAGNER, FRÉDÉRIQUE; CHIESA, ANA ELENA; CITTERIO, CINTIA E.; NICOLA, JUAN PABLO

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES

MDPI

Año: 2022 vol. 23

1661-6596

ongenital iodide transport defect is an uncommon autosomal recessive disorder caused by loss-of-function variants in the sodium iodide symporter (NIS)-coding SLC5A5 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 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>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>C affected normal TG pre-mRNA splicing, leading to the frameshift variant p