Determining the genetic basis of autism by hi-resolution analysis of copy number

通过高分辨率拷贝数分析确定自闭症的遗传基础

• 批准号: 7127603
• 负责人: Jonathan Sebat
• 金额: $ 41.53万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7127603
• 关键词: autism; clinical research; cognition; disease /disorder etiology; family genetics; gene expression; genetic mapping; genetic markers; genetic polymorphism; genetic registry /resource /referral center; genetic screening; genome; high throughput technology; human genetic material tag; human tissue; microarray technology

DESCRIPTION (provided by applicant): Autism is a neuropsychiatric disorder characterized by deficits in social interaction and communication, and unusual and repetitive behavior. The causes of autism are poorly understood. It has been clearly determined that genes play a major role in the etiology of the disease, and autism has been linked to a few rare single gene mutations, as well as many visible chromosomal abnormalties resulting in changes in gene copy number; however, the majority causes of autism remain undetermined. We hypothesize that alterations in gene dosage including heritable copy number polymorphisms (CNPs) are an underlying basis for autism. We have developed a powerful approach for identifying CNPs: Representational Oligonucleotide Microarray Analysis (ROMA). By whole-genome ROMA scans of patients from the Autism Genetic Resource Exchange (AGRE), we previously identified familial copy number variants that are significantly more frequent in autism than in controls. We propose to determine the role of CNPs in autism by determining disease association of CNPs in concordant sibling pairs. Using a "candidate chip" approach, we will screen the entire AGRE sample by ROMA (500 families) using an array that targets 200 candidate CNPs at a resolution 6 kb. We will determine the association of CNPs by the proportion of allele-sharing in siblings; in addition, we will examine CNPs for parent-of-origin effects. The relevance of specific CNPs to autism will be further evaluated by examining the genomic position of autism CNPs with respect to candidate regions from previous linkage and cytogenetic studies. We will determine the exact gene content of CNPs and examine the potential role of individual genes in cognitive function and disease. Lastly, we will investigate a link between individual structural variants and subtypes of autism with distinguishable clinical profiles such as specific cognitive and motor defects, brain abnormalities, craniofacial dysmorphism and comorbidity with other disorders. The results of this study will make substantial contributions to our knowledge of the causes of autism and the role of specific genes in cognitive development. Recognition of specific disorders of the autism spectrum caused by small copy number polymorphisms will improve treatment and prognosis, as well as genetic counseling for families with autism.

描述（由申请人提供）：自闭症是一种神经精神疾病，其特征是社会互动和沟通中的缺陷以及异常和重复的行为。自闭症的原因知之甚少。已经清楚地确定基因在疾病的病因中起主要作用，自闭症与一些罕见的单基因突变以及许多可见的染色体异常有关，导致基因拷贝数变化。但是，自闭症的多数原因仍未确定。我们假设基因剂量的改变，包括可遗传的拷贝数多态性（CNP）是自闭症的基础。我们已经开发了一种强大的方法来识别CNP：代表性寡核苷酸微阵列分析（ROMA）。通过对自闭症遗传资源交换（CLES）患者的全基因组ROMA扫描，我们先前确定了自闭症中比对照组明显更频繁的家族拷贝数变异。我们建议通过确定CNP在一致的兄弟姐妹对中的疾病关联来确定CNP在自闭症中的作用。使用“候选芯片”方法，我们将使用Roma（500个家庭）的整个同意样本，使用以6 KB的分辨率针对200个候选CNP的阵列。我们将通过兄弟姐妹中等位基因共享的比例来确定CNP的关联；此外，我们将检查CNP是否有原始效应。特定CNP与自闭症的相关性将通过检查自闭症CNP的基因组位置在先前的链接和细胞遗传学研究中的候选区域。我们将确定CNP的确切基因含量，并检查单个基因在认知功能和疾病中的潜在作用。最后，我们将研究自闭症的单个结构变异和亚型之间的联系，以及可区分的临床特征，例如特定的认知和运动缺陷，大脑异常，颅面畸形和合并症与其他疾病。这项研究的结果将对我们对自闭症原因的了解以及特定基因在认知发展中的作用做出重大贡献。识别由小拷贝数多态性引起的自闭症谱系的特定疾病的认识将改善治疗和预后，以及对自闭症家庭的遗传咨询。