Genome Studies in Hereditary Spastic Paraplegia

遗传性痉挛性截瘫的基因组研究

• 批准号: 8448439
• 负责人: Stephan Zuchner
• 金额: $ 5.05万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8448439
• 关键词: Abbreviations; Affect; Bioinformatics; Candidate Disease Gene; Clinical; Clinical Data; Code; Computer Simulation; Copy Number Polymorphism; Custom; Data; Detection; Dideoxy Chain Termination DNA Sequencing; Disease; Europe; Exclusion; Exons; Face; Family; Family Study; Family member; Genes; Genetic; Genetic Variation; Genome; Genomics; Genotype; Goals; Haplotypes; Hereditary Spastic Paraplegia; Human; Individual; Institutes; Life; Maps; Medical; Methods; Neurodegenerative Disorders; Patients; Population; Process; Publishing; Quality Control; RNA Splicing; Recording of previous events; Reporting; Research; Sampling; Set protein; Site; Technology; Testing; Universities; Variant; abstracting; base; density; exome; genetic linkage analysis; genetic pedigree; genome sequencing; improved; indexing; innovation; nervous system disorder; next generation; novel; public health relevance; sample collection; segregation; tool

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. PUBLIC HEALTH RELEVANCE: The sequencing of the complete set of coding variation in an individual (the "exome") is now feasible as recently shown by others and us. We propose to study well defined relatively small Mendelian families with Hereditary Spastic Paraplegia (HSP), a disabling neurodegenerative disease. The goal is to accelerate the identification of still missing genes in HSP.

描述（由申请人提供）：下一代测序技术正在开辟新的机会，重新思考我们识别导致遗传变异的疾病的方式。一个早期的应用，全外显子组测序，现在已经建立了一个小的研究实验室，包括我们。外显子组测序允许在单个个体中以低于5，000美元的价格获得一套接近完整的蛋白质编码基因组变异。外显子组测序研究的有希望的目标是孟德尔疾病，例如遗传性痉挛性截瘫（HSP）。HSP包括一组遗传上非常异质的神经系统疾病，目前报道了39个不同的HSP染色体位点;然而，所鉴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，但对于罕见的HSP形式来说，鉴定这种扩展的家系越来越困难。然而，本申请中描述的创新方法将克服这些限制中的一些，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，这将表征一个家族中两个个体的所有编码变化和侧翼外显子变异。我们已经开发了一种多层次的策略，以减少在单个家族中发现的新变异的数量。我们建议研究至少60个HSP家族，这些家族太小，无法用连锁分析得出结论性结果。如果发展中的技术允许，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，这将有利于大量其他疾病的研究。 公共卫生关系：正如最近其他人和我们所展示的那样，个体中编码变异的完整集合（“外显子组”）的测序现在是可行的。我们建议研究定义明确的相对较小的孟德尔家族遗传性痉挛性截瘫（HSP），致残性神经退行性疾病。我们的目标是加速HSP中仍然缺失的基因的鉴定。