De novo copy number variation and gene discovery in human brain malformations

人脑畸形中的从头拷贝数变异和基因发现

• 批准号: 7778246
• 负责人: William B. Dobyns
• 金额: $ 22.85万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2010-08-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7778246
• 关键词: Affect; Animal Model; Asthma; Behavioral; Bioinformatics; Biological Assay; Biology; Brain; Brain imaging; Candidate Disease Gene; Caring; Cell Line; Cells; Cerebellar vermis structure; Child; Chromosome Deletion; Chromosome Mapping; Chromosome abnormality; Chromosomes; Classification; Clinical; Cognitive; Collaborations; Congenital Abnormality; Copy Number Polymorphism; Corpus Callosum; Counseling; Cytogenetic Analysis; Cytogenetics; DNA; Dandy-Walker Syndrome; Data; Databases; Detection; Development; Developmental Disabilities; Diabetes Mellitus; Diagnosis; Diagnostic tests; Diffuse; Disease; Disease model; Embryo; Emerging Technologies; Epilepsy; Exons; Family; Fluorescent in Situ Hybridization; Follow-Up Studies; Future; Gene Dosage; Gene Expression; Genes; Genetic; Genetic Counseling; Genetic Polymorphism; Genome; Genomics; Gestational Age; Goals; Grant; Human; Human Genome; Hybridization Array; Incidence; Individual; Laboratories; Lead; Literature; Medical; Mental Retardation; Microgyria; Microsatellite Repeats; Molecular; Mus; Mutation; Mutation Analysis; Nature; Outcome; Parents; Patient Selection; Patients; Pattern; Phenotype; Population; Publishing; Recurrence; Relative (related person); Reporting; Research; Research Personnel; Resolution; Risk; Sampling; Seizures; Signal Transduction; Syndrome; Testing; Triage; Variant; Vertical Disease Transmission; Work; base; brain malformation; comparative genomic hybridization; developmental disease; disability; effective therapy; experience; fitness; gene discovery; improved; interest; lymphoblast; malformation; mouse model; outcome forecast; proband; reproductive; sex

DESCRIPTION (provided by applicant): The number of recognized brain malformations and syndromes has grown rapidly during the past several decades, yet relatively few causative genes have been identified, especially for three common malformations that have been associated with numerous cytogenetically visible chromosome deletions and duplications, and that often occur together: agenesis of the corpus callosum (ACC), cerebellar vermis hypoplasia (CVH) including Dandy-Walker malformation (DWM), and polymicrogyria (PMG). We propose to perform high-resolution array comparative genome hybridization (aCGH), emerging technology able to detect small copy number variants (CNV), in 700 probands with one or more of these three malformations. Our central hypothesis states that more than 10% of patients with ACC, CVH or PMG will have de novo CNV below the resolution of routine cytogenetic analysis, but detectable by current array platforms. We therefore expect to identify 70-100 patients with small CNV. We will distinguish CNV found in normal individuals from potentially disease-associated changes, and will confirm CNV using fluorescence in situ hybridization (FISH) and microsatellite (STRP) analysis. We will give highest priority to CNV that are de novo and involve 2 or more BACs, and secondary priority to familial and smaller CNV excluding known polymorphisms. After that, we will evaluate and rank candidate genes in the critical regions using information from public databases and our own expression studies, and perform mutation analysis of the best candidate genes from well-defined critical regions by sequencing in a large panel of subjects with phenotypes that match the phenotypes of the patients whose CNV define the critical regions. Here, we will use more refined criteria to supplement our clinical classification, such as the developmental level and presence of epilepsy or other birth defects. Any abnormalities found will be analyzed using existing data regarding polymorphisms (i.e. dbSNP), cross-species comparisons, and functional assays appropriate for the specific sequence change. We expect our focus on small chromosome imbalances to efficiently lead to discovery of new genes that cause these three focus malformations. These discoveries will lead directly to improved care for affected children and families consisting of more accurate diagnosis and outcome counseling, which will include specific diagnostic testing, as well as improved genetic counseling. Relevance: The work proposed in this grant will lead to lead to the discovery of many of the genes that cause of birth defects of the brain and related - but often less severe - developmental disorders. These results will prove immediately helpful in providing better information regarding diagnosis and prognosis to the families of affected children, and will also lead to better understanding of the underlying biology and in some cases to more effective treatment.

描述（由申请人提供）：在过去的几十年中，公认的脑畸形和综合征的数量迅速增长，但已确定的致病基因相对较少，尤其是与大量细胞遗传学可见的染色体缺失和重复相关的三种常见畸形，并且经常同时发生：胼胝体发育不全 (ACC)、小脑蚓部发育不全 (CVH)，包括 Dandy-Walker 畸形 (DWM) 和多小脑回（PMG）。我们建议对 700 名患有这三种畸形中的一种或多种的先证者进行高分辨率阵列比较基因组杂交 (aCGH)，这是一种能够检测小拷贝数​​变异 (CNV) 的新兴技术。我们的中心假设指出，超过 10% 的 ACC、CVH 或 PMG 患者的从头 CNV 低于常规细胞遗传学分析的分辨率，但可以通过当前的阵列平台检测到。因此，我们预计会识别出 70-100 名患有小 CNV 的患者。我们将区分正常个体中发现的 CNV 与潜在的疾病相关变化，并将使用荧光原位杂交 (FISH) 和微卫星 (STRP) 分析来确认 CNV。我们将最高优先考虑从头开始并涉及 2 个或更多 BAC 的 CNV，其次优先考虑家族性和较小的 CNV（不包括已知的多态性）。之后，我们将使用公共数据库和我们自己的表达研究中的信息对关键区域中的候选基因进行评估和排名，并通过在大量具有表型的受试者中进行测序，对明确定义的关键区域中的最佳候选基因进行突变分析与 CNV 定义关键区域的患者表型相匹配。在这里，我们将使用更精细的标准来补充我们的临床分类，例如发育水平以及是否存在癫痫或其他出生缺陷。发现的任何异常都将使用有关多态性（即 dbSNP）、跨物种比较和适合特定序列变化的功能测定的现有数据进行分析。我们期望对小的染色体不平衡的关注能够有效地发现导致这三种焦点畸形的新基因。这些发现将直接改善对受影响儿童和家庭的护理，包括更准确的诊断和结果咨询，其中包括具体的诊断测试以及改进的遗传咨询。相关性：这项资助中提出的工作将导致发现许多导致大脑出生缺陷和相关（但通常不太严重）发育障碍的基因。这些结果将立即证明有助于为受影响儿童的家庭提供有关诊断和预后的更好信息，并且还将导致更好地了解基础生物学，并在某些情况下导致更有效的治疗。