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

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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.