Impact of the mutational landscape of the sodium/iodide symporter in congenital hypothyroidism

MARTÍN, MARIANO; NICOLA, JUAN PABLO

THYROID

MARY ANN LIEBERT INC

Año: 2021

1050-7256

ackground. Iodide transport defect (ITD) is an uncommon cause of dyshormonogenic congenital hypothyroidism due to homozygous or compound heterozygous pathogenic variants in the SLC5A5 gene, which encodes the sodium/iodide symporter (NIS), causing deficient iodide accumulation in thyroid follicular cells, thus impairing thyroid hormonogenesis. Methods. SLC5A5 gene variants were compiled from public databases and research articles exploring the molecular bases of congenital hypothyroidism. Using a dataset of 198 missense NIS variants classified as either benign or pathogenic, we developed and validated a machine learning-based NIS-specific variant classifier to predict the impact of missense NIS variants. Results. We generated a manually-curated dataset containing 7,793 unique SLC5A5 variants. As most databases compiled exome sequencing data, variant mapping revealed an increased density of variants in SLC5A5 coding exons. Based on allele frequency analysis, we established an allele fr