BackgroundAutism spectrum disorder (ASD) is an early-onset neurodevelopmental disorder with complex genetic underpinning in its etiology. Copy number variations (CNVs) as one of the genetic factors associated with ASD have been addressed in recent genome-wide association studies (GWAS). However, the significance of CNV has not been well investigated in non-Caucasian ASD population.MethodsTo identify the pathogenic CNVs responsible for ASD in Han Chinese, we performed a segment-based GWAS of CNV in 335 ASD cases and 1093 healthy controls using Affymetrix single nucleotide polymorphism (SNP) array by focusing on case-specific CNVs. PARK2 was one of the important genes with several case-specific regions overlapped on it. The findings were validated in the initial screen sample set and replicated in another sample set by real-time quantitative PCR (qPCR).ResultsA total of six CNVs at 6q26 that spanned different exons of PARK2 were identified. The PARK2 expression level was down-regulated at exon-dependent manner in cases with either deletion or duplication. The result revealed that the gene function might be disrupted by exonic deletion and duplication. We also observed that the ASD case with exonic duplication demonstrated a more severe interference of PARK2 expression and the clinical feature than the ones with deletion at the exons 2–4 of the PARK2 gene.ConclusionsOur finding provides evidence to support that CNVs affecting PARK2 function might contribute to genetic etiology of a proportion of cases with ASD. The intriguing results of this work warrant further study on characterizing the functional impact of various exonic CNVs on the PARK2 gene.Trial registrationClinicalTrials.gov NCT00494754Electronic supplementary materialThe online version of this article (doi:10.1186/s13229-016-0087-7) contains supplementary material, which is available to authorized users.

Rare genomic copy number variations (CNVs) (frequency <1%) contribute a part to the genetic underpinnings of autism spectrum disorders (ASD). The study aimed to understand the scope of rare CNV in Taiwanese patients with ASD. We conducted a genome-wide CNV screening of 335 ASD patients (299 males, 36 females) from Taiwan using Affymetrix Genome-Wide Human SNP Array 6.0 and compared the incidence of rare CNV with that of 1093 control subjects (525 males, 568 females). We found a significantly increased global burden of rare CNVs in the ASD group compared to the controls as a whole or when the rare CNVs were classified by the size and types of CNV. Further analysis confirmed the presence of several rare CNVs at regions strongly associated with ASD as reported in the literature in our sample. Additionally, we detected several new private pathogenic CNVs in our samples and five patients carrying two pathogenic CNVs. Our data indicate that rare genomic CNVs contribute a part to the genetic landscape of our ASD patients. These CNVs are highly heterogeneous, and the clinical interpretation of the pathogenic CNVs of ASD is not straightforward in consideration of the incomplete penetrance, varied expressivity, and individual genetic background.

No abstract

Microdeletion at 22q11.2, a common copy number variation (CNV) noted in neurodevelopmental disorders, may be associated with cognitive impairment. However, cognitive function in individuals with microduplication remains unclear. This work presents the genetic, clinical, and brain structural data of two men out of 335 probands with autistic spectrum disorder (ASD) who had different CNV dosages at 22q11.2, and comparison with their siblings, 55 ASD probands, and 73 controls. Both showed severe autistic symptoms, but the proband with microduplication demonstrated better cognitive functions. Furthermore, different cingulate gyrus volume changes were noted, indicating that the proband with 22q11.2 microduplication had a different pattern of cingulate gyrus structure. Our comprehensive characterization of the behavioral, cognitive, and imaging phenotypes of ASD probands with different CNV dosage at 22q11.2 contribute to how copy number changes at 22q11.2 mediate the phenotypes in ASD, and pave the way for future clinical and functional study on these variants.