GENE DOSAGE IMBALANCE IN NEURODEVELOPMENTAL DISORDERS

描述(由申请人提供)：神经发育障碍，包括智力残疾(发育迟缓、精神发育迟缓)和自闭症谱系障碍(ASDS)非常常见，影响到约3%的人口。最近的证据表明，这些疾病具有显著的遗传异质性，其中罕见的从头拷贝数变异(CNV)或单基因突变起着重要作用，表明数百个不同的基因参与了这些疾病的发生。为了识别这种罕见的从头开始的突变，需要替代的、互补的全基因组关联研究(GWAS)方法来识别所涉及的大量基因。全基因组细胞基因组阵列正在迅速取代核型用于神经发育障碍儿童的临床测试，并提供前所未有的分辨率来检测包含少量候选基因的亚微观致病CNV(缺失和复制)。数以万计的细胞基因组阵列正在美国的临床基础上进行。我们建议利用这个庞大的临床数据集来识别与神经发育障碍(以下称为IDD/ASD)相关的罕见CNV，开发人类发育的基因剂量图，并识别新的CNV和导致这些疾病的候选基因，具体目标如下：1)从大量IDD/ASD患者队列中高通量挖掘CNV和表型数据。一个由临床细胞遗传学实验室组成的大型联盟--国际标准细胞基因组学阵列(ISCA)联盟已经成立，以便在一个集中的公共数据库(DBGaP，NCBI)中共享细胞基因组阵列数据，保守地估计每年有50-100,000个患者样本。大多数患者有智力障碍，约20%有自闭症。2)病理性CNV发病机制及后果分析。来自致病性CNV阳性患者(占总数的20%)的数据将用于研究CNV形成的分子机制及其表型后果。ISCA数据库与正常CNV数据库中重叠区域的比较将被用于开发发育障碍的人类基因剂量图。3)发现与IDD/ASDS相关的新的CNV疾病。将进一步研究两类致病CNV，以确定新的IDD/ASD疾病：a)具有类似表型发现的反复微缺失/重复区域(例如，我们最近发现del(17q12)是自闭症的原因，尤其是在男性中)；b)非复发性致病CNV将用于定位具有相似、独特表型的重叠病例(例如自闭症、癫痫)。4)CNV导向的IDD/ASD基因发现。来自AIM 3的数据将产生一些致病CNV区域，其中包含IDD/ASD表型的有限数量的候选基因(1-15)。为了确定具体的致病基因，将对表型良好的患者(没有致病的CNV)进行全面的突变分析，这些患者来自可公开获得的来源(例如，Simons Simplex Collection、自闭症遗传学资源交换和NIMH储存库)。 公共卫生相关性：神经发育障碍，包括智力残疾和自闭症谱系障碍(ASDS)，非常常见，影响到约3%的人口。最近的证据表明，在这些疾病的病因中存在显著的遗传异质性，其中罕见的拷贝数变异或CNV(亚显微缺失或复制)起主要作用。我们提出了一种新的、具有成本效益的策略，利用每年在美国对患有神经发育障碍的儿童进行的数万项临床诊断测试的CNV和表型数据，以确定导致这些智力障碍、自闭症和自闭症的基因组关键区域和单个基因。

DESCRIPTION (provided by applicant): Neurodevelopmental disorders, including intellectual disabilities (developmental delay, mental retardation) and autism spectrum disorders (ASDs), are very common, affecting ~3% of the population. Recent evidence has revealed remarkable genetic heterogeneity in these disorders, with a major role for rare, de novo copy number variations (CNVs) or mutations in single genes, suggesting that hundreds of different genes are involved in these disorders. Alternative, complementary approaches to genome-wide association studies (GWAS) are needed for the identification of such rare, de novo mutations to identify the large number of genes implicated. Whole genome cytogenomic arrays are rapidly replacing the karyotype in clinical testing of children with neurodevelopmental disorders, and provide unprecedented resolution to detect submicroscopic, pathogenic CNVs (deletions and duplications) containing small numbers of candidate genes. Tens of thousands of cytogenomic arrays are being done on a clinical basis in the U.S. We propose to leverage this large clinical dataset for identification of rare CNVs associated with neurodevelopmental disorders (hereafter referred to as IDD/ASDs), to develop a Gene Dosage Map for human development and to identify new CNVs and candidate genes responsible for these disorders with the following specific aims: 1) High-throughput CNV and phenotype data mining from large cohorts of patients with IDD/ASDs. A large consortium of clinical cytogenetics laboratories, the International Standard Cytogenomics Array (ISCA) consortium, has been established to share cytogenomic array data in a centralized, public database (dbGaP, NCBI), conservatively estimated at 50-100,000 patient samples/year. Most patients have intellectual disability and ~20% have ASDs. 2) Analysis of the mechanisms and consequences of pathogenic CNVs. Data from pathogenic CNV+ patients (20% of total) will be used to investigate the molecular mechanisms of CNV formation and their phenotypic consequence. Comparison of overlapping regions in the ISCA database vs. normal CNV databases will be used to develop a Human Gene Dosage Map for developmental disorders. 3) Identification of new CNV disorders associated with IDD/ASDs. Two classes of pathogenic CNVs will be investigated further to identify new IDD/ASD disorders: a) recurrent microdeletion/duplication regions with similar phenotypic findings (e.g., our recent discovery that del(17q12) is a cause of autism, especially in males), b) Non-recurrent, pathogenic CNVs will be used for mapping of overlapping cases with similar, distinctive phenotypes (e.g., autism, epilepsy). 4) CNV directed gene discovery for IDD/ASDs. Data from Aim 3 will generate a number of pathogenic CNV regions containing a limited number of candidate genes (1-15) for the IDD/ASD phenotype. To identify the specific genes responsible, comprehensive mutation analysis will be performed in well-phenotyped patients (without pathogenic CNVs) from publicly available sources (e.g., Simons Simplex Collection, Autism Genetics Resource Exchange and the NIMH repositories). PUBLIC HEALTH RELEVANCE: Neurodevelopmental disorders, including intellectual disabilities and autism spectrum disorders (ASDs), are very common, affecting ~3% of the population. Recent evidence indicates remarkable genetic heterogeneity in the etiology of these disorders with a major role for rare copy number variations or CNVs (submicroscopic deletions or duplications). We propose a novel, cost-effective strategy to leverage the CNV and phenotype data from tens of thousands of clinical diagnostic tests performed on children with neurodevelopmental disorders each year in the United States to identify the critical regions of the genome and individual genes responsible for these intellectual disabilities, autism and ASDs.