Abstract
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.
Highlights
Autism spectrum disorder (ASD) is an early-onset neurodevelopmental disorder with complex genetic underpinning in its etiology
Case-specific copy number variations (CNV) loci The present study focused on the case-specific CNV segments, which were detected in at least one case but none in healthy controls from the screening stage (Additional file 1: Figure S2)
In addition to the known CNV loci associated with ASD, we identified 17 marginally significant case-specific CNV loci at which duplication and deletion were detected in at least four cases (patient frequency (Fpatient) > 1 %; P < 0.01) (Table 1)
Summary
Autism spectrum disorder (ASD) is an early-onset neurodevelopmental disorder with complex genetic underpinning in its etiology. Sander et al reported that duplications of 7q11.23, the region of Williams Syndrome, were strongly associated with ASD and that large de novo CNVs encompassing multiple genes were more pathogenic in ASD (OR = 5.6, CI = 2.6–12.0, P = 2.4 × 10−7) [9]. Many of these loci/genes are relevant to the process of neurotransmission [10,11,12], synapse formation [10, 11], or protein ubiquitination [12]. Functional levels of genes change with CNV (termed dosage sensors) may contribute to the etiology of ASD [10,11,12]
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