The genetic basis underlying the phenotype heterogeneity of the 16p11.2 CNV

说明书(申请人提供)：拷贝数变异体(CNV)是由于高度相同的基因组区域之间的不等交换而产生的，导致插入序列的缺失或复制。其中一个这样的CNV发生在16p11.2位点，与自闭症谱系障碍和其他神经认知表型有关。尽管有相同的遗传异常，携带16p11.2CNV的个体在疾病严重程度和表型上表现出广泛的异质性。在过去的三年里，作为西蒙斯个体变异项目(VIP)的一部分，收集了大量16p11.2 CNV患者(&gt；200)以及完整的表型和临床信息。我们的假设是，遗传修饰者解释了在这个群体中观察到的表型变异的很大一部分。我们将表征16p11.2 CNV的全局和局部遗传修饰物，并将这些与表型相关联。对于全球修饰基因，我们将使用高密度、商业上可用的单核苷酸多态(SNP)微阵列来评估这些基因组中额外的CNV负担。我们将确定聚集体上的CNV负荷是否与表型严重程度相关。我们将确定正在进行的外显子组测序工作中出现的候选自闭症基因中是否存在突变，并将使用分子反转探针(MIP)技术对前25个候选基因进行重新排序。对于局部修饰，我们将使用MIP技术对位于16p11.2关键区的基因及其调节区进行重新测序。我们推测这些基因是由16p11.2的缺失或复制引起的剂量敏感性。这有可能将特定的基因与特定的表型联系起来。最后，我们将使用MIP和允许在高度相同的序列之间进行区分的标记来评估16p11.2 CNV的断裂点。有三个基因位于假定的断裂点，这些基因的缺失或复制可能会影响疾病的严重程度。这项工作将为16p11.2患者及其家属的咨询提供与现有表型数据相称的基因信息以及有价值的即时信息。

DESCRIPTION (provided by applicant): Copy number variants (CNVs) arise due to unequal crossing over between highly identical genomic regions, leading to deletion or duplication of the intervening sequence. One such CNV occurs at the locus 16p11.2 and is associated with autism spectrum disorder and other neurocognitive phenotypes. Despite having the same genetic aberration, individuals with the 16p11.2 CNV display a wide heterogeneity of disease severity and phenotype. Over the past three years, a large cohort of patients (>200) with the 16p11.2 CNV has been collected as part of the Simons Variation in Individuals Project (VIP) along with full phenotype and clinical information. Our hypothesis is that genetic modifiers explain a large fraction of the observed phenotypic variation in this population. We will characterize genetic modifiers global and local to the 16p11.2 CNV and correlate these to phenotype. For global modifiers we will assess the additional CNV burden in these genomes using high-density, commercially available Single Nucleotide Polymorphism (SNP) microarrays. We will determine if CNV burden on aggregate correlates with phenotype severity. We will determine if mutations exist in candidate autism genes emerging from ongoing exome sequencing efforts and will resequence the top 25 candidates using molecular inversion probe (MIP) technology. For local modifiers we will resequence the genes and their regulatory regions lying in the 16p11.2 critical region using MIP technology. We hypothesize that these genes are dosage sensitized by the deletion or duplication occurring at 16p11.2. This has the potential to link particular genes to specific phenotypes. Finally, we will assess the breakpoint of the 16p11.2 CNV using MIPs and markers that allow differentiation between highly identical sequences. Three genes lie at the putative breakpoint, and deletion or duplication of these genes may affect disease severity. This work will provide genotypic information commensurate with the available phenotypic data as well as valuable and immediate information for the counseling of 16p11.2 patients and their families.