Identification of a locus for nongoitrous congenital hypothyroidism on chromosome 15q25.3-26.1

Helmut Grasberger, Martine Vaxillaire, Silvana Pannain, John C. Beck, Aviva Mimouni-Bloch, Vincent Vatin, Gilbert Vassart, Philippe Froguel, Samuel Refetoff*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Permanent congenital hypothyroidism is the most prevalent inborn endocrine disorder, and principally due to developmental defects leading to absent, ectopic or hypoplastic thyroid gland. Although commonly regarded as sporadic disease, nonsyndromic thyroid hypoplasia has, in rare cases, been attributed to inherited defects in PAX8 and the TSHR gene. The shared clinical picture caused by these defects is a variable degree of thyrotropin resistance (RTSH [MIM 275200]), accompanied in its severe form by thyroid gland hypoplasia. We recently identified six extended kindreds with autosomal dominant RTSH, only one of which was linked to a mutation in the PAX8 candidate gene. Genome wide scans conducted in two of the remaining five families revealed independently significant linkage to chromosome 15q25.3-26.1, with maximum multipoint LOD scores of 8.51 and 4.31. Linkage to this novel locus was replicated (P<0.01) in each of the three remaining kindreds. Fine mapping of key recombinants in the largest family localized the causative gene within a 3 cM/2.9 Mb interval. Thus, we report the first locus for congenital nongoitrous hypothyroidism identified by a genome wide screening approach.

Original languageEnglish
Pages (from-to)348-355
Number of pages8
JournalHuman Genetics
Issue number3-4
StatePublished - Dec 2005
Externally publishedYes


  • Genetic linkage
  • Hypothyroidism
  • Thyroid stimulating hormone
  • Thyrotropin


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