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 suscepti bility to idiopathic scoliosis by positional cloning. Summary of Background Data. Although the inheritance of idiopathic scoliosi s most often exhibits a complex pattern, autosomal dominant inheritance can be identified in some families. Families exhibiting such an inheritance pa ttern present an opportunity to identify the predisposing gene(s) by positi onal cloning. Methods. Probands having clinically relevant idiopathic scoliosis (50 degre es 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 affec ted members) was conducted with 385 polymorphic microsatellite markers spac ed 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 th e first family was detected for three loci on chromosomes 6p, distal 10q, a nd 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 de tected in the second family at distal chromosome 10q (nonparametric lod sco re = 2.02; P = 0.033). Conclusions. These data indicate a limited number of genetic loci predispos ing to idiopathic scoliosis.