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性疾病，治疗选择有限。当进行性时，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例脊柱融合手术，费用约为14亿美元。这项研究的目的是从一个至少有两个一级亲属患有脊柱侧凸的大的、明确的家庭样本中确定导致这种疾病的基因。这一策略是基于一般人群中这种疾病的高患病率（2- 3%）和疾病表现的广泛变异性。 遗传疾病研究中心完成了对确定的研究样本（202个家庭，1208个个体）的全基因组扫描。模型独立和依赖的连锁分析表明，多个染色体上的主要和次要候选区域与观察到的表型有潜在的显着关系。到目前为止，精细的绘图工作已经验证了6号、9号和16号染色体上的区域，并将间隔缩小到4-8厘摩。根据遗传模式和额外的表型标准对样本进行分层，导致X、5和13号染色体上的区域在家族亚组中具有潜在的显著性。精细制图再次验证并将这些区域缩小到2.5 - 8厘摩。 为了进一步缩小关键区域，利用高密度双等位基因标记（SNP）的方法将与基因座特异性关联研究相结合。通过将相邻的SNP位点和标记位点合并用于统计关联研究，观察与疾病等位基因的连锁不平衡的机会显著提高。最后，将根据编码蛋白的已知生物学特性、它们与已知功能蛋白的同源性以及与观察到的表型的正统计学联系，对已经定位到这些区域的候选基因或EST进行仔细检查。这些基因的分析将包括筛选方法，然后进行直接突变分析。这项工作的基本原理是能够在曲率开始之前识别出有风险的个体。其次，个体的特定遗传群体可以更早地分层到治疗方案中。这可能允许早期有限的手术干预，并避免长期支具，在许多情况下，一旦初始治疗失败，就会导致广泛的手术干预。

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.