dentification of novel missense mutations of the tsh-β subunit gene in pediatric patients with congenital central hypothyroidism

Background: congenital central hypothyroidism (cch) is a rare autosomal recessive disease caused by mutations in the thyroid-stimulating hormone β subunit (tshβ) gene. since patients with cch do not experience increased serum levels of tsh, the diagnosis is usually delayed, which leads to negative consequences in the neonatal tsh screening. genetic diagnostic studies enable us to identify affected relatives at high risk for rapid diagnosis and treatment of the disorder. objectives: this study aimed to investigate genetic variations in the tshβ gene for the first time in iranian patients with cch. methods: seven children affected by congenital tsh-deficient hypothyroidism were investigated for mutations in tshβ. variable tsh levels in these patients ranged from low values for diagnosis to significant values, so central hypothyroidism was assumed due to mutations in the tshβ gene. results: we identified two novel heterozygous (f11y and g106r) and one homozygous (t14a) missense mutations in the coding sequence of exons 2 and 3. one of the new heterozygous mutations (f11y) and a homozygous (t14a) missense mutation were found in exon 2 of the tshß-subunit gene. the novel mutation g106r in exon 3 was found in three pediatric patients with congenital hypothyroidism. c.40a>g (t14a, rs10776792) appears to be the most common genetic variation associated with tsh deficiency. the others were c.32t>a in exon 2 and c.316g>c in exon 3, which resulted in a change from phenylalanine to tyrosine (p.f11y) and glycine to arginine (g106r), respectively. conclusions: the identification of these mutations for the first time in iranian patients suggests that cch is more common than previously recognized, and the tshβ gene may be the mutational hot spot.