Identification of Rare Recurrent Copy Number Variants in High-Risk Autism Families and Their Prevalence in a Large ASD Population

Abstract

Structural variation is thought to play a major etiological role in the development of autism spectrum disorders (ASDs), and numerous studies documenting the relevance of copy number variants (CNVs) in ASD have been published since 2006. To determine if large ASD families harbor high-impact CNVs that may have broader impact in the general ASD population, we used the Affymetrix genome-wide human SNP array 6.0 to identify 153 putative autism-specific CNVs present in 55 individuals with ASD from 9 multiplex ASD pedigrees. To evaluate the actual prevalence of these CNVs as well as 185 CNVs reportedly associated with ASD from published studies many of which are insufficiently powered, we designed a custom Illumina array and used it to interrogate these CNVs in 3,000 ASD cases and 6,000 controls. Additional single nucleotide variants (SNVs) on the array identified 25 CNVs that we did not detect in our family studies at the standard SNP array resolution. After molecular validation, our results demonstrated that 15 CNVs identified in high-risk ASD families also were found in two or more ASD cases with odds ratios greater than 2.0, strengthening their support as ASD risk variants. In addition, of the 25 CNVs identified using SNV probes on our custom array, 9 also had odds ratios greater than 2.0, suggesting that these CNVs also are ASD risk variants. Eighteen of the validated CNVs have not been reported previously in individuals with ASD and three have only been observed once. Finally, we confirmed the association of 31 of 185 published ASD-associated CNVs in our dataset with odds ratios greater than 2.0, suggesting they may be of clinical relevance in the evaluation of children with ASDs. Taken together, these data provide strong support for the existence and application of high-impact CNVs in the clinical genetic evaluation of children with ASD.

Eye Tracking Reveals Abnormal Visual Preference for Geometric Images as an Early Biomarker of an Autism Spectrum Disorder Subtype Associated With Increased Symptom Severity

“…With specificity levels as high as 98%, the GeoPref test was able to signify ASD status in a subset of individual toddlers with very high accuracy and as such may be more powerful than other biomarker attempts including those at the behavioral (29–31), genetic (32–34), and neuroimaging levels (35–37). Eye-tracking technology is attractive as a potential tool in early identification and clinical evaluation efforts because patterns of eye gaze are objective, quantifiable behaviors based on neural systems known to be abnormal in ASD, such as the visual attention system (38–40).…”

Clinical Performance of an Ultrahigh Resolution Chromosomal Microarray Optimized for Neurodevelopmental Disorders

“…Additional probe enrichment targeted genomic regions identified by our prior studies and identified elsewhere in the medical literature. These regions included published copy number variants and individual genes associated with DD/ID/ASD [20–29]. The increase in analytical sensitivity resulting from this additional 3.3% probe content has been calculated to be 2.6% [19].…”

Identification of rare DNA sequence variants in high-risk autism families and their prevalence in a large case/control population

“…The custom iSelect array was processed on 3,000 case and 6,000 control samples at the Center for Applied Genomics at The Children’s Hospital of Philadelphia (CHOP) [27]. The same array was also used to analyze DNA from 196 Utah discovery cohort family members at the University of Utah Genomics Core facility for variant validation and analysis of SNP segregation in families.…”