Copy-number variation (CNV) is the most prevalent type of structural variation in the human genome. Studies of CNVs in neuropsychiatric disorders, including Autism Spectrum Disorders (ASD) have demonstrated the potential promise of CNVs as a window into their genetic susceptibility. These structural anomalies, including inversions, translocations, duplications and deletions have been identified as being associated with ASD in numerous studies. Some research has proposed a strong association of de novo copy number mutations with autism, whereas other studies have addressed the overall CNV burden in cases when compared to control subjects, and still other research has implicated CNVs at specific cytoband locations (e.g. deletions at 16p11.2 and 22q11.2 and duplications at 15q13) as being associated with ASD. Moreover, the evidence suggests that recurrent CNVs have impact on broader phenotypic manifestations such as learning disability, physical characteristics, and seizures as opposed to the strict autism phenotype.
The primary object of this study was to investigate the phenotypic outcome of CNVs. We hypothesized that individuals carrying CNVs with prior evidence of aetiological significance would be more likely to present with general developmental anomalies that might aid in the description of associated syndromes.
All subjects were diagnosed with the Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Schedule (ADOS). Singletons derived from simplex and multiplex families were included. Subjects with known karyotypic abnormalities or genetic disorders were excluded. Genotyping of DNA was completed on the Illumina Infinium 1M SNP microarray. CNVs were called using combinations of the QuantiSNP, iPattern and PennCNV calling algorithms, and stringent quality control criteria were applied. As data relating to early development and physical features was not obtained systematically in this cohort, items in the ADI-R reflecting developmental delay were selected. Where available, IQ data, parental age and body measurement data were also included in the analysis.
Prevalence of developmental anomalies, IQ categorization and parental age in the group with aetiologically significant CNVs compared with those without known aetiologically significant CNVs will be presented.
The association of broader phenotypic manifestations such as learning disability, physical characteristics, and seizures with ASD and specific genetic variants may provide additional support in elucidating the aetiology of this highly heritable and complex disorder. The results of this study may also suggest new targets for candidate region genetic studies and future research.