BackgroundComparative gene expression profiling analysis is useful in discovering differentially expressed genes associated with various diseases, including mental disorders. Autism spectrum disorders (ASD) are a group of complex childhood-onset neurodevelopmental and genetic disorders characterized by deficits in language development and verbal communication, impaired reciprocal social interaction, and the presence of repetitive behaviors or restricted interests. The study aimed to identify novel genes associated with the pathogenesis of ASD.MethodsWe conducted comparative total gene expression profiling analysis of lymphoblastoid cell lines (LCL) between 16 male patients with ASD and 16 male control subjects to screen differentially expressed genes associated with ASD. We verified one of the differentially expressed genes, FOXP1, using real-time quantitative PCR (RT-qPCR) in a sample of 83 male patients and 83 male controls that included the initial 16 male patients and male controls, respectively.ResultsA total of 252 differentially expressed probe sets representing 202 genes were detected between the two groups, including 89 up- and 113 downregulated genes in the ASD group. RT-qPCR verified significant elevation of the FOXP1 gene transcript of LCL in a sample of 83 male patients (10.46 ± 11.34) compared with 83 male controls (5.17 ± 8.20, P = 0.001).ConclusionsComparative gene expression profiling analysis of LCL is useful in discovering novel genetic markers associated with ASD. Elevated gene expression of FOXP1 might contribute to the pathogenesis of ASD.Clinical trial registrationIdentifier: NCT00494754

BackgroundWe recently reported a terminal deletion of approximately 2.4 Mb at chromosome 8p23.2-pter in a boy with autism. The deleted region contained the DLGAP2 gene that encodes the neuronal post-synaptic density protein, discs, large (Drosophila) homolog-associated protein 2. The study aimed to investigate whether DLGAP2 is genetically associated with autism spectrum disorders (ASD) in general.MethodsWe re-sequenced all the exons of DLGPA2 in 515 patients with ASD and 596 control subjects from Taiwan. We also conducted bioinformatic analysis and family study of variants identified in this study.ResultsWe detected nine common single nucleotide polymorphisms (SNPs) and sixteen novel missense rare variants in this sample. We found that AA homozygotes of rs2906569 (minor allele G, alternate allele A) at intron 1 (P = 0.003) and CC homozygotes of rs2301963 (minor allele A, alternate allele C) at exon 3 (P = 0.0003) were significantly over-represented in the patient group compared to the controls. We also found no differences in the combined frequency of rare missense variants between the two groups. Some of these rare variants were predicted to have an impact on the function of DLGAP2 using informatics analysis, and the family study revealed most of the rare missense mutations in patients were inherited from their unaffected parents.ConclusionsWe detected some common and rare genetic variants of DLGAP2 that might have implication in the pathogenesis of ASD, but they alone may not be sufficient to lead to clinical phenotypes. We suggest that further genetic or environmental factors in affected patients may be present and determine the clinical manifestations.Trial registrationClinicalTrial.gov, NCT00494754

Evidence suggests an association between autism and immune dysfunction. The associations between human lymphocyte antigen (HLA)-A2, B44, DRβ1*04 (DR4), C4B, and haplotype B44-SC30-DR4 and autism have been reported in western countries but there is a lack of such information in Asian population. This study aimed to assess the association between HLA-DRB1 allele frequencies and the clinical phenomenology of autism. The sample included 141 participants (male, 87.2%), who were diagnosed with autistic disorder based on clinical assessments and structured interviews using the Chinese version of the Autism Diagnostic Interview-Revised, and 156 healthy controls (male, 38.6%). The HLA-DRB1 alleles were determined by sequencing-based typing method. A subsample of patients (n=39) were assessed for intelligence and neuropsychological functions. The results showed that the pattern of DRB1 allele frequencies was significantly different between patients with autism and the controls (P=0.047). After adjusting for sex by haplotype regression, the frequencies of DR4, DR11, and DR14 were significantly different between patients with autism and healthy controls. In addition, patients with autism and DR4, DR11, or DR14 had different performance on intelligence and neuropsychology tests. Despite a relatively small sample size and a case-control association design, the findings suggest HLA-DRB1 gene might be associated with autism in Han Chinese. The true functional variants associated with autism in our samples remain to be further clarified. It warrants a replication study of a larger family sample and to validate the HLA genetic association with autism and its influence on neuropsychological function.

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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.