Identification and Analysis of Candidate Genes for Familial Idiopathic Scoliosis

Results of population surveys and family studies have supported the conclusion that there is a significant genetic contribution to the pathogenesis of idiopathic scoliosis (IS). We have hypothesized that analysis of genes contributing to familial IS cases will reveal insights not only into the more common sporadic forms of IS, but also will contribute fundamentally to an understanding of human spinal growth and development. Genes contributing to both simple Mendelian and complex human diseases may be identified in three steps. First, chromosomal loci potentially encoding disease genes are identified by genome wide linkage scans of family DNA collections. Second, a map of candidate genes encoded by each locus is constructed by a variety of techniques. Third, each candidate gene is screened for disease-causing sequence variations (mutations) in affected family members. We have previously reported evidence of linkage to loci on chromosome 15q (Zmax = 3.15, max=0.0) in an extended family. In this kindred physical examination plus standing posteroanterior (PA) radiographs were obtained for 38 members, of which 10 were found to be affected with IS. We now report construction of a detailed gene map of this region of chromosome 15. Known genes were identified within public databases such as GeneMap 99; novel genes were predicted by application of gene prediction algorithms to available genomic sequence. Sequence variants in affected individuals are currently being screened in selected genes by denaturing high performance chromatography (DHPLC) and/or automated DNA sequencing. We have also initiated collection of DNA samples from families exhibiting complex inheritance of IS. A mechanism has been established for systematically ascertaining appropriate families from all orthopaedic clinics within Texas Scottish Rite Hospital for Children, a regional referral center for the treatment of IS. This growing repository will be used for en masse identification of additional genes contributing to disease susceptibility.