Localization of susceptibility to familial idiopathic scoliosis.

STUDY DESIGN: Genome-wide linkage surveys in large multiplex families with apparent inherited idiopathic scoliosis.

OBJECTIVE: To identify chromosomal loci encoding genes involved in susceptibility to idiopathic scoliosis by positional cloning.

SUMMARY OF BACKGROUND DATA: Although the inheritance of idiopathic scoliosis most often exhibits a complex pattern, autosomal dominant inheritance can be identified in some families. Families exhibiting such an inheritance pattern present an opportunity to identify the predisposing gene(s) by positional cloning.

METHODS: Probands having clinically relevant idiopathic scoliosis (50 degrees Cobb angle) from large multiplex families were identified. A curve of 15 degrees, made from standing posteroanterior radiographs, was required for a positive diagnosis. A genome-wide search in one large family (seven affected members) was conducted with 385 polymorphic microsatellite markers spaced at an approximate 10-cM resolution. Hot spots identified in this family were subsequently tested in a second large kindred.

RESULTS: Maximum evidence of allele-sharing in affected individuals from the first family was detected for three loci on chromosomes 6p, distal 10q, and 18q with nonparametric lod scores of 1.42 (P = 0.020), 1.60 (P = 0.019), and 8.26 (P = 0.002), respectively. Evidence of allele-sharing was also detected in the second family at distal chromosome 10q (nonparametric lod score = 2.02; P = 0.033).

CONCLUSIONS: These data indicate a limited number of genetic loci predisposing to idiopathic scoliosis.