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Congenital Central Hypothyroidism due to Homozygous Thyrotropin ß 313T Mutation Is Caused by a Founder Effect

Department of Pediatric Endocrinology (H.Br., H.Bi., D.S., D.D., A.G.), Charité, Humboldt University Berlin, D-13353 Berlin; Institute of Human Genetics (A.P.), Technical University Munich, D-81675 Munich; and Institute of Human Genetics (A.P.), GSF National Research Center, D-85764 Neuherberg, Germany

Address all correspondence and requests for reprints to: Arne Pfeufer, M.D., M.Sc., Institute of Human Genetics, Technical University Munich, Klinikum Rechts der Isar, and GSF Federal Research Center, Neuherberg, Trogerstr. 32, 81675 München, Germany. E-mail: arne.pfeufer{at}web.de.

Abstract

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 TSHß-subunit gene have been recognized as a cause of central hypothyroidism with isolated TSH deficiency. The most frequent TSHß mutation 313T (C105V) has been described in six apparently unrelated families. We investigated the frequency and possible monophyletic origin of the different TSHß 313T alleles of the three affected families. Haplotype analysis of five polymorphic single-nucleotide polymorphism loci in the TSHß 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 TSHß 313T 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 TSHß 313T 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.

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