Novel Homozygous Na+/I- Symporter (NIS) Gene Variants of Unknown Clinical Significance Associated with Dyshormonogenetic Congenital Hypothyroidism

NICOLA JP; SIGNORINO M; TESTA G; SOBRERO GM; MUÑOZ L; MIRAS MB; MASINI - REPISO AM

Rio de Janeiro

Congreso; XVI Latin American Thyroid Congress (LATS); 2017

Latin American Thyroid Society (LATS)

Introduction: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)-codinggene. Clinical manifestations include low to absent iodide accumulationin the thyroid tissue and, if untreated, the patients develop a variable degree of hypothyroidism, goiter, and even mental retardation.Objectives:The objective of this work was to investigate the presence of inactivating mutations in the gene encoding NISin two unrelated pediatric patients with a clinical phenotype of ITD.Methods: The genomic DNA encoding all fifteenNIS-codinggene exons werePCR-amplified and further subjected to Sanger sequencing. Moreover, bioinformatics analysis of the newly identified NIS variants was performed using the software Alamut.Results andconclusions: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 but 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 enhancerlocated in exon 11 and retention of intron 11, originatingthe putative mutant p.P443fsX86 NIS.Whereas c.1973C>T would result in a novel splicing silencer in exon 13 and retention of intron 13, originating the putative mutant T550fsX3 NIS.Future experiments using functional in vivomini-gene splicing assays are required to fully characterize the impact of the variants on splicing defects.In conclusion, we identified two novel NIS variants of unknown clinical significance associated with dyshormonogenetic congenital hypothyroidism. These variants may lead to potential mis-splicingdefects causing structural changes in NIS molecules that impair its normal biogenesis and activity, thus leading to congenital hypothyroidism.