Congenital Central Hypothyroidism due to Homozygous Thyrotropin β 313ΔT Mutation Is Caused by a Founder Effect

Neonatal TSH screening has been a major achievement for the early detection and treatment of primary congenital hypothyroidism. It nevertheless fails to reveal cases of central hypothyroidism caused by TSH levels in the low normal range. In the last 10 yr, homozygous mutations in the TSHβ-subunit gene have been recognized as a cause of central hypothyroidism with isolated TSH deficiency. The most frequent TSHβ mutation 313ΔT (C105V) has been described in six apparently unrelated families. We investigated the frequency and possible monophyletic origin of the different TSHβ 313ΔT alleles of the three affected families. Haplotype analysis of five polymorphic single-nucleotide polymorphism loci in the TSHβ region revealed the presence of seven different haplotypes in the general population. In all six parental lines, the mutation occurred on the same haplotype. Extending the haplotype by two flanking microsatellite markers led to a mutational age estimate of about 150 generations. In 500 unrelated individuals from the general population, we did not detect any TSHβ 313ΔT allele, suggesting a population heterozygote carrier frequency less than 1:170 with more than 95% probability. Accordingly, the disease risk in the general population because of homozygosity is low. Our data suggest a monophyletic origin of the TSHβ 313ΔT mutation from a common ancestor and no significant population prevalence. Therefore, identification and genetic counseling of heterozygous carriers in affected families seems to be more advisable than population-wide neonatal T4 screening programs for an early detection of this rare condition.