Abstract
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
Highlights
We recently reported a terminal deletion of approximately 2.4 Mb at chromosome 8p23.2-pter in a boy with autism
In haplotype-based association analysis derived from nine Single nucleotide polymorphism (SNP), we found significant difference in the haplotype distribution of ACACAAGGT and CCACCAACT between the autism spectrum disorders (ASD) patients and controls, but only haplotype CCA CCAACT was sustained after correction for multiple comparisons (Table 3)
In this study, we found that rs2906569 at intron 1 and rs2301963 (P384Q) at exon 3 of DLGAP2 were associated with ASD
Summary
We recently reported a terminal deletion of approximately 2.4 Mb at chromosome 8p23.2-pter in a boy with autism. Traditional cytogenetic studies [6,7,8,9] and the recent array-based comparative genomic hybridization (array CGH) analysis have shown that chromosome abnormalities and rare copy number variants [10,11] are associated with ASD. Various chromosome abnormalities such as deletion, duplication, inversion, and translocation were identified in ASD patients. It is likely that haploinsufficiency of one or several of these genes might result in the clinical phenotypes of the affected patients. These genes might be considered as candidate genes of ASD patients in general
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