SLC5A5 encodes the sodium-iodide symporter (NIS), a transmembrane glycoprotein that mediates active transport of iodide from blood into thyroid follicular cells, essential for thyroid hormone synthesis 1. Beyond iodide, NIS can transport chlorate, thiocyanate, nitrate, and selenocyanate. The protein functions as a sodium:iodide cotransporter located on the plasma membrane and is regulated by thyroid-stimulating hormone signaling. Loss-of-function variants in SLC5A5 cause congenital iodide transport defect (ITD), an autosomal recessive form of dyshormonogenic congenital hypothyroidism characterized by absent or minimal iodide accumulation in the thyroid gland 2. SLC5A5 mutations account for approximately 0.06% carrier frequency in general populations, with higher prevalence in East Asian populations 3. Mutations identified include nonsense variants, frameshifts, and notably, synonymous variants affecting pre-mRNA splicing 2. SLC5A5 variants are detected in 30-72% of congenital hypothyroidism patients, though less frequently than DUOX2 or TPO mutations 4. Beyond thyroid disease, SLC5A5 is expressed in reproductive tissues during development 5, and genetic variants influence breast milk iodine transfer and thyroid cancer risk in genotype-dependent manners 67. The rs77277498 polymorphism shows protective associations with thyroid cancer when combined with high dietary iodine intake 7.