AUTHOR=Geysels Romina Celeste , Bernal Barquero Carlos Eduardo , Martín Mariano , Peyret Victoria , Nocent Martina , Sobrero Gabriela , Muñoz Liliana , Signorino Malvina , Testa Graciela , Castro Ricardo Belisario , Masini-Repiso Ana María , Miras Mirta Beatriz , Nicola Juan Pablo 

TITLE=Silent but Not Harmless: A Synonymous SLC5A5 Gene Variant Leading to Dyshormonogenic Congenital Hypothyroidism

JOURNAL=Frontiers in Endocrinology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2022.868891

DOI=10.3389/fendo.2022.868891

ISSN=1664-2392

ABSTRACT=<sec><title>Background</title><p>Congenital iodide transport defect (ITD) is an uncommon cause of dyshormonogenic congenital hypothyroidism characterized by the absence of active iodide accumulation in the thyroid gland. ITD is an autosomal recessive disorder caused by loss-of-function variants in the sodium/iodide symporter (NIS)-coding <italic>SLC5A5</italic> gene.</p></sec><sec><title>Objective</title><p>We aimed to identify, and if so to functionally characterize, novel ITD-causing <italic>SLC5A5</italic> gene variants in a cohort of five unrelated pediatric patients diagnosed with dyshormonogenic congenital hypothyroidism with minimal to absent <sup>99m</sup>Tc-pertechnetate accumulation in the thyroid gland.</p></sec><sec><title>Methods</title><p>The coding region of the <italic>SLC5A5</italic> gene was sequenced using Sanger sequencing. <italic>In silico</italic> analysis and functional <italic>in vitro</italic> characterization of a novel synonymous variant were performed.</p></sec><sec><title>Results</title><p>Sanger sequencing revealed a novel homozygous synonymous <italic>SLC5A5</italic> gene variant (c.1326A&gt;C in exon 11). <italic>In silico</italic> analysis revealed that the c.1326A&gt;C variant is potentially deleterious for NIS pre-mRNA splicing. The c.1326A&gt;C variant was predicted to lie within a putative exonic splicing enhancer reducing the binding of splicing regulatory trans-acting protein SRSF5. Splicing minigene reporter assay revealed that c.1326A&gt;C causes exon 11 or exon 11 and 12 skipping during NIS pre-mRNA splicing leading to the NIS pathogenic variants p.G415_P443del and p.G415L<italic>fs</italic>*32, respectively. Significantly, the frameshift variant p.G415L<italic>fs</italic>*32 is predicted to be subjected to degradation by nonsense-mediated decay.</p></sec><sec><title>Conclusions</title><p>We identified the first exonic synonymous <italic>SLC5A5</italic> gene variant causing aberrant NIS pre-mRNA splicing, thus expanding the mutational landscape of the <italic>SLC5A5</italic> gene leading to dyshormonogenic congenital hypothyroidism.</p></sec>