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°Cobb angle) from large multiplex families were identified. A curve of 15°, 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.