Genome Studies in Hereditary Spastic Paraplegia

描述（由申请人提供）：下一代测序技术为重新思考我们识别导致遗传变异的疾病的方式提供了新的机会。一个早期的应用，全外显子组测序，现在已经由少数研究实验室建立，包括我们的实验室。外显子组测序允许在单个个体中获得几乎完整的蛋白质编码基因组变异集，花费不到5000美元。外显子组测序研究的有希望的目标是孟德尔疾病，如遗传性痉挛性截瘫（HSP）。HSP包括一组遗传上非常异质性的神经系统疾病，目前报道了39种不同的HSP染色体位点；然而，已确定的基因最多只能解释60%的遗传效应。传统的基因鉴定方法需要对大家族进行连锁分析，但在鉴定罕见热sp的扩展谱系时面临越来越大的困难。然而，本应用程序中描述的创新方法将克服这些限制，并利用相对较小的谱系进行高效的基因鉴定。我们将应用外显子组测序，它将表征一个家庭中两个个体的所有编码变化和侧面外显子变化。我们已经开发了一种多层策略，以减少单个家庭中确定的新变异的数量。我们建议研究至少60个HSP家族，这些家族数量太少，无法用连锁分析得出结论性结果。如果发展技术允许，我们将考虑更大的样本或进行全基因组测序。除了对HSP遗传学的重要益处之外，这项研究将使我们能够进一步建立这种新方法，这将有利于大范围的其他疾病研究。

DESCRIPTION (provided by applicant): Next-generation sequencing technology is opening up new opportunities to rethink the way we identify disease causing genetic variation. An early application, whole exome sequencing, has now been established by a small number of research labs, including ours. Exome sequencing allows obtaining a near complete set of protein coding genomic variation in single individuals for less than $5,000. Promising targets for exome sequencing studies are Mendelian diseases, such as hereditary spastic paraplegias (HSP). HSP comprise a genetically very heterogeneous set of neurological disorders with currently 39 different HSP chromosomal loci being reported; yet, the identified genes explain only 60% of the genetic effect at best. Traditional methods of gene identification require linkage analysis of large families, but face increasing difficulties to identify such extended pedigrees for rare HSP forms. However, the innovative approach described in this application will overcome some of these limitations and utilize relatively small pedigrees for highly effective gene identification. We will apply exome sequencing, which will characterize all coding changes and flanking exonic variation in two individuals of a family. We have developed a multi-tiered strategy to reduce the number of identified novel variants to the very causative change in an individual family. We propose to study at least 60 HSP families, which are too small to yield conclusive results with linkage analysis. If the developing technology permits we will consider a larger sample or perform whole genome sequencing. Beyond the important benefit to genetics of HSP, this study will allow us to further establish this new method, which will benefit a large range of additional disease studies.