Silent but not harmless: A synonymous SLC5A5 gene variant leading to dyshormonogenic congenital hypothyroidism

GEYSELS, RC; BERNAL BARQUERO, CE; MARTIN, M; PEYRET, V; SOBRERO, G; MUÑOZ, L; SIGNORINO, M; TESTA, G; CASTRO, RB; MASINI-REPISO AM; MIRAS, M; NICOLA, JP

FRONTIERS IN ENDOCRINOLOGY

Frontiers Media

Año: 2022

1664-2392

Background: Congenital iodide transportdefect (ITD) is an uncommon cause of dyshormonogenic congenital hypothyroidismcharacterized by the absence of active iodide accumulation in the thyroidgland. ITD is an autosomal recessive disorder caused by loss-of-functionvariants in the sodium iodide symporter (NIS)-coding SLC5A5 gene. Objective: We aimed to identify, and if soto functionally characterize, novel ITD-causing SLC5A5 gene variants in a cohort of five unrelated pediatricpatients diagnosed with dyshormonogenic congenital hypothyroidism with minimalto absent 99mTc-pertechnetate accumulation in the thyroid gland. Methods: The coding region of the SLC5A5 gene was sequenced using Sangersequencing. In silico analysis and functional in vitro characterization of anovel synonymous variant were performed. Results: Sanger sequencing revealed anovel homozygous synonymous SLC5A5gene variant (c.1326A>C in exon 11). In silico analysis revealed that thec.1326A>C variant is potentially deleterious for NIS pre-mRNA splicing. Thec.1326A>C variant was predicted to lie within a putative exonic splicingenhancer reducing the binding of splicing regulatory trans-acting proteinSRSF5. Splicing minigene reporter assay revealed that c.1326A>C causes exon11 or exon 11 and 12 skipping during NIS pre-mRNA splicing leading to the NISpathogenic variants p.G415_P443del and p.G415Lfs*32, respectively. Significantly, the frameshift variant p.G415Lfs*32 is predicted to be subjected todegradation by nonsense-mediated decay. Conclusions: Weidentified the first exonic synonymous SLC5A5gene variant causing aberrant NIS pre-mRNA splicing, thus expanding themutational landscape of the SLC5A5gene leading to dyshormonogenic congenital hypothyroidism.