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

描述（由申请人提供）：拷贝数变异（CNVs）是由于高度相同的基因组区域之间的不平等杂交而产生的，导致中间序列的缺失或重复。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。尽管具有相同的遗传畸变，但具有16p11.2 CNV的个体在疾病严重程度和表型上表现出广泛的异质性。在过去的三年中，作为Simons个体变异项目（VIP）的一部分，我们收集了大量携带16p11.2 CNV的患者（bbb200），并提供了完整的表型和临床信息。我们的假设是，遗传修饰因子解释了该人群中观察到的大部分表型变异。我们将描述16p11.2 CNV的全局和局部遗传修饰因子，并将它们与表型相关联。对于全局修饰子，我们将使用高密度、市售的单核苷酸多态性（SNP）微阵列来评估这些基因组中额外的CNV负担。我们将确定CNV总体负担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是否存在突变，并将使用分子倒置探针（MIP）技术对前25个候选基因进行重测序。对于局部修饰子，我们将使用MIP技术对位于16p11.2关键区域的基因及其调控区域进行重排序。我们假设这些基因是由发生在16p11.2的缺失或重复剂量致敏的。这有可能将特定基因与特定表型联系起来。最后，我们将使用允许高度相同序列之间区分的MIPs和标记来评估16p11.2 CNV的断点。三个基因处于假定的断点，这些基因的缺失或重复可能影响疾病的严重程度。这项工作将提供与现有表型数据相称的基因型信息，以及为16p11.2患者及其家属提供有价值的即时信息。

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.