GENE DOSAGE IMBALANCE IN NEURODEVELOPMENTAL DISORDERS

描述（由申请人提供）：神经发育障碍，包括智力障碍（发育迟缓，智力迟钝）和自闭症谱系障碍（ASDs），是非常常见的，影响约3%的人口。最近的证据揭示了这些疾病中显著的遗传异质性，其中主要作用是罕见的、新生拷贝数变异（CNVs）或单个基因突变，这表明数百种不同的基因参与了这些疾病。需要替代全基因组关联研究（GWAS）的补充方法来鉴定这种罕见的新生突变，以鉴定大量涉及的基因。在神经发育障碍儿童的临床检测中，全基因组细胞基因组阵列正迅速取代核型，并为检测含有少量候选基因的亚显微镜下致病性CNVs（缺失和重复）提供了前所未有的分辨率。在美国，数以万计的细胞基因组阵列正在临床基础上进行。我们建议利用这一庞大的临床数据集来鉴定与神经发育障碍（以下简称IDD/ asd）相关的罕见CNVs，开发用于人类发育的基因剂量图，并鉴定与这些疾病相关的新CNVs和候选基因，具体目标如下：1)来自IDD/ asd患者大队列的高通量CNV和表型数据挖掘。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，已经建立起来，在一个集中的公共数据库（dbGaP， NCBI）中共享细胞基因组学阵列数据，保守估计为每年50-100,000例患者样本。大多数患者有智力障碍，约20%有泛自闭症障碍。2)致病性CNVs的机制和后果分析。来自致病性CNV+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用于开发发育障碍的人类基因剂量图。3)与IDD/ asd相关的新CNV疾病的鉴定。我们将进一步研究两类致病性CNVs，以确定新的IDD/ASD疾病：a)具有相似表型发现的复发性微缺失/重复区域（例如，我们最近发现del（17q12）是自闭症的一个原因，特别是在男性中），b)非复发性致病性CNVs将用于绘制具有相似独特表型的重叠病例（例如，自闭症，癫痫）。4) IDD/ asd的CNV定向基因发现。Aim 3的数据将产生许多致病CNV区域，其中包含有限数量的IDD/ASD表型候选基因（1-15）。为了确定具体的致病基因，将从公开来源（例如Simons Simplex Collection，自闭症遗传资源交换和NIMH知识库）对表型良好的患者（没有致病性CNVs）进行全面的突变分析。

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.