title: Identification of a locus for nongoitrous congenital hypothyroidism on chromosome 15q25.3-26.1.
abstract: 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.
authors.affiliation: Department of Medicine, The University of Chicago, 5841 S. Maryland Avenue, MC3090, Chicago, IL, 60637, USA.
authors.forename: Helmut
authors.initials: H
authors.lastname: Grasberger
authors.forename: Martine
authors.initials: M
authors.lastname: Vaxillaire
authors.forename: Silvana
authors.initials: S
authors.lastname: Pannain
authors.forename: John C
authors.initials: JC
authors.lastname: Beck
authors.forename: Aviva
authors.initials: A
authors.lastname: Mimouni-Bloch
authors.forename: Vincent
authors.initials: V
authors.lastname: Vatin
authors.forename: Gilbert
authors.initials: G
authors.lastname: Vassart
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
authors.forename: Samuel
authors.initials: S
authors.lastname: Refetoff
mesh_terms: D002884:Chromosomes, Human, Pair 15; D003409:Congenital Hypothyroidism / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D040582:Inheritance Patterns; D008297:Male; D010375:Pedigree