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, which requires the accurate detection of rare CNVs in large numbers of individuals. Cost and throughput issues 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 cohorts. This approach is customizable, cost effective, highly parallelized, and largely automated. We applied this method to screen 69 loci in 1105 children with unexplained intellectual disability, identifying pathogenic variants in 3.1% of these individuals and potentially pathogenic variants in an additional 2.3%. We identified seven individuals (0.7%) with a deletion of 16p11.2, which has been previously associated with autism. Our results widen the phenotypic spectrum of these deletions to include intellectual disability without autism. We also detected 1.65-3.4 Mbp duplications at 16p13.11 in 1.1% of affected individuals and 350 kbp deletions at 15q11.2, near the Prader-Willi/Angelman syndrome critical region, in 0.8% of affected individuals. Compared to published CNVs in controls they are significantly (P = 4.7 3 10 À5 and 0.003, respectively) enriched in these children, supporting previously published hypotheses that they are neurocognitive disease risk factors. More generally, this approach offers a previously unavailable balance between customization, cost, and throughput for analysis of CNVs and should prove valuable for targeted CNV detection in both research and diagnostic settings.

NF1 microduplications: identification of seven nonrelated individuals provides further characterization of the phenotype

“…It has been hypothesized that this deletion can predispose individuals to a variety of neurocognitive disabilities, including the developmental delay and seizures present in this subject. 27,29,30 This deletion may contribute to the resulting phenotype in this proband along with the duplication of NF1, consistent with a "two-hit" model recently proposed to explain phenotypic variability and reduced penetrance with recurrent 16p12.1 microdeletions 41 and hypothesized to hold true for other genomic disorders. 42 In other individuals, the phenotype may be impacted by environmental, genetic, or epigenetic variants that are undetectable by aCGH.…”

“…This deletion has been implicated as a risk factor for a variety of neurocognitive disorders including behavioral problems and idiopathic generalized epilepsy. [27][28][29][30][31] It is often inherited from a normal or mildly affected parent and has also been seen in normal control individuals. 27,28,30,31 Additional clinically significant copy-number alterations were not identified in any of the remaining subjects.…”

Rare copy number variation in cerebral palsy

“…Microdeletions of 15q11.2 region have also been reported in cases with delayed motor and speech development, autism, obsessive-compulsive disorder, and dysmorphic features without Prader-Willi/Angelman syndrome, suggesting HI for TUBGCP5, CYFIP1, NIPA2, and NIPA1. 35 Although observed in control individuals, the role of 15q11.2 duplications is yet to be unravelled. (iv) CTNND2 446 bp duplication in case P036.…”

Cyclin D1 rare variants in UK multiple adenoma and early-onset colorectal cancer patients

“…[38][39][40][41] More recent studies have demonstrated additional rare variant influences on the pathogenesis of a variety of complex diseases and traits such as type 1 diabetes, colorectal cancer, plasma lipoprotein levels and neurological disorders. [42][43][44][45][46][47][48][49] Screening candidate genes in groups of patients for germline variation is the first step in unraveling rare variation, a step that is already being made much easier by the increasing accessibility of nextgeneration sequencing technologies. However, functional studies of the most interesting variants must follow closely.…”