Identification of genes causative for familial ALS gene using exome sequencing

使用外显子组测序鉴定导致家族性 ALS 基因的基因

• 批准号: 8296297
• 负责人: JOHN E LANDERS
• 金额: $ 35.98万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8296297
• 关键词: Adopted; Adult; Affect; Amyotrophic Lateral Sclerosis; Bioinformatics; Candidate Disease Gene; DNA Sequence; Data; Defect; Development; Diagnostic; Disease; Exons; Familial Amyotrophic Lateral Sclerosis; Family; Genes; Genetic; Genome; Genotype; Knowledge; Lead; Longevity; Motor Neurons; Mutation; Nature; Neurodegenerative Disorders; Open Reading Frames; Pathogenesis; Pathway interactions; Patients; Population Control; Publishing; Reading; Sampling; Screening procedure; Series; Solutions; Technology; Variant; cohort; cost; exome; genetic pedigree; genome-wide; late disease onset; member; motor neuron degeneration; novel

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is an adult-onset, rapidly progressive and ultimately fatal neurodegenerative disease caused by the selective loss of motor neurons. Although most ALS cases are sporadic (SALS), ~10% are familial (FALS). To date, the underlying cause has been identified in only ~35% of all FALS cases: 20% are caused by mutations in SOD1, 5% in TARDBP and 5% in FUS. Variants in several other genes have been found in additional families to a lesser degree. Genetic studies have provided invaluable information for understanding of the pathogenesis of both FALS and SALS. Undoubtedly, the discovery of novel FALS- associated genes will dramatically further our knowledge of the cellular pathways that lead to motor neuron degeneration. Until now, it was not economically feasible to screen for rare variants at a genome-wide scale within disease-affected samples. However, the recent advances in automated, short-read DNA sequencing offer new solutions to this problem: it is now possible to sequence only protein-coding regions of the genome (exomes) to reduce costs while enriching for the discovery of highly penetrant variants. The purpose of this proposal is to identify novel causative genes for FALS using the approach of exome capture followed by short- read sequencing. The Specific Aims of this proposal are to: (1) Perform exon capture and short-read sequencing of selected samples to identify candidate FALS-specific variants. Exome capture and short-read sequencing will be performed for 2 distantly-related affected members of 10 ALS afflicted families (20 FALS). A primary list of candidate variants causative for ALS will then be created using a series of bioinformatic filtering steps. (2) Identify the variants derived from exome sequencing that are specific for FALS. Candidate variants will be interrogated by genotyping a panel of ~1,100 control samples as well as an additional panel of ~200 FALS. Variants detected in FALS, but not within the control population, are highly suggestive of a causative change. (3) Determine if candidate FALS genes show different mutations in additional FALS families. Candidate genes harboring FALS-specific variants will be sequenced in ~200 FALS samples to identify additional variants. Genes with multiple alterations in FALS not observed in control populations will be considered causal. Our proposed studies will identify novel candidate genes whose mutations cause FALS. In the long term, understanding the genetic causes of ALS will facilitate our understanding of all forms of ALS as well as assisting in the development of diagnostics and therapies to extend the lifespan of ALS patients.

描述（由申请人提供）：肌萎缩性侧索硬化症（ALS）是一种由运动神经元选择性丧失引起的成人发病、快速进展和最终致命的神经退行性疾病。虽然大多数ALS病例是散发的（SALS），但约10%是家族性的（FALS）。迄今为止，仅在35%的FALS病例中确定了潜在原因：20%是由SOD1突变引起的，5%是由TARDBP突变引起的，5%是由FUS突变引起的。其他几个基因的变异也在其他家庭中被发现，但程度较低。遗传研究为了解FALS和SALS的发病机制提供了宝贵的信息。毫无疑问，新的FALS相关基因的发现将极大地促进我们对导致运动神经元退化的细胞途径的认识。到目前为止，在受疾病影响的样本中筛查全基因组范围内的罕见变异在经济上是不可行的。然而，自动化短读DNA测序的最新进展为这一问题提供了新的解决方案：现在可以只对基因组的蛋白质编码区域（外显子组）进行测序，以降低成本，同时丰富了高渗透变异的发现。本建议的目的是利用外显子组捕获和短读测序的方法来鉴定FALS的新致病基因。本提案的具体目的是：(1)对选定的样品进行外显子捕获和短读测序，以确定候选的fals特异性变体。外显子组捕获和短读测序将对10个ALS患者家庭（20个FALS）的2个远亲受影响成员进行。然后将使用一系列生物信息学过滤步骤创建导致ALS的候选变异的主要列表。(2)鉴定FALS特异性外显子组测序衍生的变异。候选变异将通过约1100个对照样本和约200个FALS样本进行基因分型。在FALS中检测到的变异，而不是在对照人群中检测到的变异，高度提示有致病变化。(3)确定候选FALS基因是否在其他FALS家族中表现出不同的突变。将在约200个FALS样本中对含有FALS特异性变异的候选基因进行测序，以确定其他变异。在对照人群中未观察到的FALS中具有多重改变的基因将被认为是因果关系。我们提出的研究将确定突变导致FALS的新的候选基因。从长远来看，了解ALS的遗传原因将有助于我们了解各种形式的ALS，并有助于开发诊断和治疗方法，以延长ALS患者的寿命。