A method for rapid, targeted CNV genotyping identifies rare variants associated with neurocognitive disease

Abstract

Copy-number variants (CNVs) are substantial contributors to human disease A central challenge in CNV-disease association studies is to characterize the pathogenicity of rare and possibly incompletely penetrant events - a task that requires the accurate detection of rare CNVs in large numbers of cases and controls. The high cost, low throughput, and inflexibility of currently available technologies limit our ability to perform these studies. We have adapted the Illumina BeadXpress SNP genotyping assay and developed an algorithm, Snp-Conditional OUTlier detection (SCOUT), to rapidly and accurately detect both rare and common CNVs in large sample collections. This approach is customizable, cost-effective, highly parallelized, and largely automated. We applied this method to screen 69 loci in 1,105 children with unexplained intellectual disability, identifying variants known to be pathogenic in 3.1% of these individuals and potentially pathogenic rearrangements in an additional 2.3%. We identified 7 individuals (0.7%) with a deletion of 16p11.2. The same deletion has been reported in individuals with autism, but our results widen the phenotypic spectrum to include intellectual disability without autism. We also detected a 1.65-3.4 Mbp region of 16p13.11 duplicated in 1.1% of affected individuals and a 350 kbp deletion of 15q11.2, near the Prader-Willi/Angelman syndrome critical region, in 0.8% of the tested individuals. Compared to published CNVs in control cohorts they are significantly (p = 4.7 × 10^-5 and 0.003, respectively) enriched in this series of children, supporting previously published hypotheses that they are risk factors for neurocognitive illness. More generally, this approach offers a previously unavailable balance between customization, cost, and throughput for accurate analysis of both rare and common CNVs, and should prove valuable for targeted CNV detection in both research and diagnostic settings.