Positional Cloning of Candidate Genes for Familial Idiopathic Scoliosis

¹Dallas, Texas; ²St Louis, MO, USA

Familial idiopathic scoliosis (IS) is a complex disorder, although some families with a Mendelian pattern of inheritance have been described. We have previously reported a strategy to positionally clone genes predisposing to IS. In this approach multiplex kindreds meeting stringent diagnostic criteria are ascertained through probands having clinically relevant idiopathic scoliosis (50° Cobb angle or greater). Affecteds are confirmed on the basis of a Cobb angle measurement of greater than or equal to 15°, made from standing posteroanterior radiographs. Genome-wide scans are performed, and conservative methods of analysis are applied to the data to localize IS susceptibility genes. Here we report results of such an analysis in an extended family (10 affected in a total of 38 family members sampled). Comprehensive health histories, physical examinations, and blood samples were obtained at a family reunion. The presence of IS was assessed in two independent tests from new or existing standing posteroanterior (PA) radiographs by an orthopedic surgeon who was blinded to identities and previous diagnoses. In this family the disease ranged from 15° to 70°. Genome-wide scans were performed with polymorphic microsatellites at a resolution of 10-15 cM, and both a dominant model of inheritance and model-free methods of analysis were applied to the data. Maximum evidence of linkage was detected at loci on chromosome 15 (Zmax = 3.22, qmax=0.0). A gene map of this region of the genome was constructed from available databases and analysis of genomic sequence data to identify candidates for IS susceptibility in this family. We have also initiated genome-wide scans in additional collected kindreds to confirm results and identify new loci encoding IS susceptibility genes. Genes from the identified candidate region(s) will be screened for mutations in affected members of the linked families. The identification of novel genes for idiopathic scoliosis by this approach will provide insights into the etiology of the disease.