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

基本信息

批准号：
8628195
负责人：
JOHN E LANDERS
金额：
$ 32.39万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-15 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8628195
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 Series Solutions Technology Variant cohort cost exome exome sequencing genetic pedigree genome-wide late disease onset member motor neuron degeneration novel rare variant screening

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 Series Solutions Technology Variant cohort cost exome exome sequencing genetic pedigree genome-wide late disease onset member motor neuron degeneration novel rare variant screening

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项目摘要

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）是一种成人发作，是由运动神经元选择性丧失引起的迅速进行性的，最终是致命的神经退行性疾病。尽管大多数ALS病例都是零星的（萨尔），但约有10％是家族性的（伪造）。迄今为止，在所有伪造案件中，只有约35％的35％确定了根本原因：20％是由SOD1突变引起的，tardbp中的5％和FUS中的5％引起。在较小程度上，在其他几个基因中发现了其他几个基因的变体。遗传研究提供了宝贵的信息，以了解伪造和萨尔的发病机理。毫无疑问，新型伪造基因的发现将大大进一步进一步了解导致运动神经元变性的细胞途径。到目前为止，在受疾病影响的样本中以全基因组范围内的稀有变体进行筛查在经济上是不可行的。然而，自动化的，短阅读的DNA测序的最新进展为此问题提供了新的解决方案：现在只能对基因组（EXOMES）的蛋白质编码区进行测序，以降低成本，同时富集了高度渗透变体。该提案的目的是使用外显捕捉的方法鉴定出伪造的新型病因基因，然后是简短读取测序。该提案的具体目的是：（1）执行外显子捕获和对选定样品的短阅读测序以识别特定于候选的特定变体。将对10名ALS折磨家庭（20个fals）的2个远距离影响的成员进行外显群捕获和短阅读测序。然后，将使用一系列生物信息学滤波步骤创建候选变异的主要列表。（2）确定从外显子组测序中得出的变体。候选变体将通过基因分型来询问〜1,100个对照样本的面板以及〜200 fals的附加面板。在伪造中检测到的变体（但不在对照人群内）强烈暗示了病因的变化。（3）确定候选基因是否在其他fals家族中显示出不同的突变。携带FALS特异性变体的候选基因将在约200个fals样品中进行测序，以鉴定其他变体。在对照群体中未观察到的fal中有多次改变的基因将被视为因果关系。我们提出的研究将确定其突变引起伪造的新型候选基因。从长远来看，了解ALS的遗传原因将有助于我们对所有形式的ALS的理解，并有助于开发诊断和疗法，以延长ALS患者的寿命。