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，精神发育迟滞）和自闭症谱系障碍（ASD），非常常见，影响约3%的人口。最近的证据表明，这些疾病中存在显着的遗传异质性，其中罕见的从头拷贝数变异（CNVs）或单个基因突变起着重要作用，这表明数百种不同的基因参与了这些疾病。全基因组关联研究（GWAS）的替代，互补的方法是必要的，以确定这种罕见的，从头突变，以确定大量的基因牵连。全基因组细胞基因组阵列在神经发育障碍儿童的临床检测中正在迅速取代核型，并提供前所未有的分辨率来检测含有少量候选基因的亚显微、致病性CNV（缺失和重复）。在美国，数以万计的细胞基因组阵列正在临床基础上进行。我们建议利用这一大型临床数据集来鉴定与神经发育障碍相关的罕见CNV（以下称为IDD/ASD），以开发用于人类发育的基因剂量图，并鉴定负责这些疾病的新CNV和候选基因，具体目标如下：1）来自IDD/ASD患者的大队列的高通量CNV和表型数据挖掘。已经建立了一个大型临床细胞遗传学实验室联盟，即国际标准细胞基因组学阵列（ISCA）联盟，以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，保守估计每年有50- 100，000例患者样本。大多数患者患有智力残疾，约20%患有ASD。2)致病性CNV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谱。3)与IDD/ASD相关的新CNV疾病的鉴定将进一步研究两类致病性CNV以鉴定新的IDD/ASD病症：我们最近发现del（17 q12）是孤独症的原因，尤其是在男性中），B）非复发性、致病性CNV将用于具有相似、独特表型的重叠病例的作图（例如，自闭症、癫痫）。4)CNV指导IDD/ASD的基因发现。来自目标3的数据将产生许多致病性CNV区域，其含有IDD/ASD表型的有限数目的候选基因（1-15）。为了鉴定负责的特定基因，将在来自公开来源（例如，Simons Simplex Collection，Autism Genetics Resource Exchange和NIMH repositories）。 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（ASD），非常常见，影响约3%的人口。最近的证据表明，这些疾病的病因学具有显着的遗传异质性，其中罕见的拷贝数变异或CNV（亚显微缺失或重复）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CNV和表型数据，每年在美国对神经发育障碍儿童进行数以万计的临床诊断测试，以确定基因组的关键区域和负责这些智力残疾，自闭症和ASD的个体基因。

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.