Genetics and phenomics of hypothyroidism and goiter due to NIS mutations

Molecular cloning of the NIS gene in 1996 allowed examination of the molecular basis of congenital hypothyroidism due to iodide transport defect (ITD) many years after the first case was described by Federman et al. in 1958. Since 1997, when the first NIS mutation causing ITD was identified and characterized, 12 different NIS molecular defects have been described in 31 ITD patients. Interestingly, marked clinical heterogeneity between patients with the same NIS mutation and in patients with different mutations in the NIS gene without a clear genotype–phenotype correlation has been observed. The study of NIS mutations as the molecular basis of ITD has not only yielded extremely valuable structure/function information on NIS, but has also provided an important tool for preclinical diagnosis and genetic counseling of ITD patients.