Congenital hypothyroidism (CH) with multinodular goiter (MNG) is uncommonly seen in children. However, CH associated with goiter is often caused by defectiveThyroid peroxidase(TPO) gene. In this study, we screened for mutation(s) in theTPOgene in two siblings with CH and MNG and their healthy family members. The two sisters, born to consanguineous parents, were diagnosed with CH during infancy and received treatment since then. They developed MNG during childhood despite adequate L-thyroxine replacement and negative thyroid antibody screening. PCR-amplification of all exons using flanking primers followed by DNA sequencing revealed that the two sisters were homozygous for a novel c.1502T>G mutation. The mutation is predicted to substitute valine for glycine at a highly conserved amino acid residue 501 (p.Val501Gly). Other healthy family members were either heterozygotes or mutation-free. The mutation was not detected in 50 healthy unrelated individuals.In silicoanalyses using PolyPhen-2 and SIFT predicted that the p.Val501Gly mutation is functionally “damaging.” Tertiary modeling showed structural alterations in the active site of the mutant TPO. In conclusion, a novel mutation, p.Val501Gly, in theTPOgene was detected expanding the mutation spectrum ofTPOassociated with CH and MNG.
Sotos syndrome with a novel mutation in the NSD1 gene associated with congenital hypothyroidism