GENETIC ANALYSIS OF FAMILIAL IDIOPATHIC SCOLIOSIS

描述（由申请人提供）：家族性特发性脊柱侧凸是一种复杂的遗传疾病，治疗选择有限。当进展时，可导致明显的畸形和手术脊柱融合。据估计，每年在青少年中进行15-20,000例脊柱融合术，费用约为14亿美元。这项研究的目的是确定负责这种疾病的基因从一个大的，明确的家庭样本至少有两个一级亲属与脊柱侧凸。这一策略是基于该疾病在一般人群中的高患病率（2- 3%）和疾病表现的广泛变异性。

DESCRIPTION (provided by applicant): Familial idiopathic scoliosis is a complex genetic disorder that has limited treatment options. When progressive, marked deformity and operative spinal fusion can result. An estimated 15-20,000 spinal fusions are performed in adolescents each year with an approximate cost of $1.4 billion. The goal of this research is to define the genes responsible for this disorder from a large, well-defined sample of families with at least two first-degree relatives with scoliosis. This strategy is based on the high prevalence of the disorder within the general population (2-3 percent), and the wide variability of disease presentation. A genomic-wide scan of the identified study sample (202 families, 1208 individuals) was completed by the Center of Inherited Disease Research. Model independent and dependent linkage analyses have suggested primary and secondary candidate regions on multiple chromosomes with a potential significant relationship to the observed phenotype. To date, fine mapping efforts have verified areas on chromosomes 6, 9, and 16 and have narrowed the intervals to 4-8 centimorgans. Stratification of the sample by mode of inheritance and additional phenotypic criteria has resulted in areas on chromosomes X, 5, and 13 to be potentially significant within subgroups of families. Finemapping has again verified and narrowed these areas to 2.5 -8 centimorgans. To narrow further the critical regions, an approach utilizing high-density biallelic markers (SNPs) will be combined with locus-specific association studies. The chances of observing linkage disequilibrium with the disease alleles are markedly improved through the pooling of adjacent SNP loci and marker loci for statistical association studies. Lastly, candidate genes or ESTs that have been mapped to the regions will be scrutinized on the basis of the known biology of the encoded proteins, their homology to proteins of known function, and on the basis of a positive statistical linkage to the observed phenotype. Analysis of these genes will include screening methodologies followed by direct mutational analyses. The rationale of this effort is to be able to identify at-risk individuals prior to the onset of curvature. Secondarily, specific genetic groups of individuals may be stratified earlier into therapeutic protocols. This may allow for earlier limited surgical intervention and avoid long-term bracing which, in many cases, results in an extensive surgical intervention once initial treatment has failed.