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

MARTIN, M; NICOLA, JP

Congreso; XVIII Latin American Thyroid Congress; 2021

Latin American Thyroid Society

Iodide transport defect 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. Objective: To uncover novel SLC5A5
gene variants involved in the pathogenesis of dyshormonogenic congenital hypothyroidism. Methods: SLC5A5 gene variants were
compiled from public databases and research articles assessing the molecular bases of congenital hypothyroidism. Using a set 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. Most pathogenic NIS variants were located in the protein-coding region as most patients were genetically
diagnosed using a candidate gene strategy limited to this region. Significantly, we evidenced that 94.5% of missense NIS variants were
classified as of uncertain significance. Therefore, we developed a machine learning-based NIS-specific variant classifier to improve the
prediction of pathogenicity of missense variants. Our classifier allowed us to predict the clinical outcome of missense variants with
high accuracy (90%), outperforming state-of-the-art pathogenicity predictors (REVEL, PolyPhen-2 and SIFT). Based on the excellent
predictive performance of our classifier, we predicted the mutational landscape of NIS, revealing that most missense variants located
in transmembrane segments are frequently pathogenic. Moreover, we predicted that ~17% of all single-nucleotide variants that could
cause missense NIS variants are pathogenic and thus, putatively leading to congenital hypothyroidism if present in homozygous or
compound heterozygous state. Conclusions: We reported the first NIS-specific variant classifier aiming to improve the interpretation of
missense NIS variants in clinical practice. Deciphering the mutational landscape for every protein involved in thyroid hormonogenesis
is a relevant task for a deep understanding of the molecular mechanisms causing dyshormonogenic congenital hypothyroidism.