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

BERNAL BARQUERO, CE; GEYSELS, RC; JACQUES, V; CARRO, GH; MARTIN, M; PEYRET, V; ABREGÚ, MC; PAPENDIECK, P; MASINI-REPISO, AM; SAVAGNER, F; CHIESA, AE; CITTERIO, CE; NICOLA, JP

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES

MOLECULAR DIVERSITY PRESERVATION INTERNATIONAL-MDPI

Lugar: Basel; Año: 2022 vol. 23

1422-0067

Congenital iodide transportdefect is an uncommon autosomal recessive disorder caused by loss-of-functionvariants in the sodium iodide symporter (NIS)-coding SLC5A5 gene, and leading to dyshormonogenic congenital hypothyroidism.Here, we conducted a targeted next-generation sequencing assessment ofcongenital hypothyroidism-causative genes, in a cohort of nine unrelatedpediatric patients suspectedof having a congenital iodide transport defect based on the absence of 99mTc-pertechnetateaccumulation in an eutopic thyroid gland. Although, unexpectedly, we could notdetect pathogenic SLC5A5 genevariants, we identified two novel compound heterozygous TG gene variants (p.Q29* and c.177-2A>C), three novelheterozygous TG gene variants(p.F1542Vfs*2, p.Y2563C, andp.S523P), and a novel heterozygous DUOX2gene variant (p.E1496Dfs*51).Splicing minigene reporter-based in vitroassays revealed that the variant c.177-2A>C affected normal TG pre-mRNAsplicing, leading to the frameshift variant p.T59Sfs*17. The frameshift TGvariants p.T59Sfs*17 and p.F1542Vfs*2, but not the DUOX2 variant p.E1496Dfs*51, were predicted to undergononsense-mediated decay. Moreover, functional in vitro expression assays revealed that the variant p.Y2563C reducedthe secretion of the TG protein. Our investigation revealed unexpected findingsregarding the genetics of congenital iodide transport defects, supporting theexistence of yet to be discoverednovelmechanisms being involved in thyroid hormonogenesis.