Novel homozygous sodium/iodide symporter (NIS) gene variants of unknown clinical significance associated with dyshormonogenetic congenital hypothyroidism

MASINI-REPISO, AM; SIGNORINO, M; MUÑOZ, L; NICOLA, JP; MIRAS, M; TESTA, G

Washington

Congreso; 10th International Meeting of Pediatric Endocrinology; 2018

Pediatric Endocrine Society

Objectives: Iodide transport defect (ITD) is an autosomal recessive disorder whose hallmark is the inability of the thyroid follicular cell to actively accumulate iodide. ITD is an uncommon cause of dyshormonogenetic congenital hypothyroidism that results from inactivating mutations in the sodium iodide symporter (NIS)-coding gene. Clinical manifestations include low to absent thyroid iodide accumulation and, if untreated, variable degrees of hypothyroidism, goiter, and even mental retardation.The objective of this work was to investigate the presence of inactivating mutations in NIS-coding gene in two unrelated pediatric patients with a clinical ITD phenotype.Methods: The genomic DNA encoding all fifteen NIS-coding gene exons were PCR-amplified and further subjected to Sanger sequencing. Moreover, bioinformatics analysis of the newly identified NIS variants was performed using Alamut software.Results: We identify two homozygous variants in the DNA sequence encoding NIS in two unrelated pediatric patients with dyshormonogenetic congenital hypothyroidism. The patients were homozygous for the variants c.1673A>C in exon 11 and c.1973C>T in exon 13, respectively. Significantly, both variants were silent, not observed in the genome of 50 healthy controls, and therefore classified as variants of unknown clinical significance.Bioinformatics analysis revealed that both variants are potentially deleterious for normal NIS mRNA splicing to maintain the open reading frame. The variant c.1673A>C would result in the disruption of a splicing enhancer located in exon 11?retention of intron 11?originating the putative mutant p.P443fsX86 NIS, whereas c.1973C>T would result in a novel splicing silencer in exon 13?retention of intron 13?originating the putative mutant T550fsX3 NIS. Future experiments using functional in vivo mini-gene splicing assays are required to fully characterize splicing defects.Conclusions: In conclusion, we identified two novel NIS variants of unknown clinical significance associated with dyshormonogenetic congenital hypothyroidism. These variants lead to potential mis-splicing defects causing structural changes in NIS molecules that impair its normal biogenesis and function.