Deep exon resequencing of DLGAP2 as a candidate gene of autism spectrum disorders

Abstract

Background: We 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.

Methods: We 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.

Results: We 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.

Conclusions: We 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 registration: ClinicalTrial.gov, NCT00494754.

Figure 1

(A) Schematic genomic structure of the DLGAP2, and locations of the common single nucleotide polymorphisms (SNPs) and rare variants identified in this study. (B) Linkage disequlibrium (LD) analysis of nine common SNPs identified in this study.

Figure 2

(A) Pedigree of S15F mutation, (B) Pedigree of R93S mutation, (C) Pedigree of R182Q mutation. (D) Pedigree of A192S mutation. (E,F) Pedigrees of P281A mutation. (G) Pedigree of R324W mutation. (H) Pedigree of C506R mutation. (I) Pedigree of T712M mutation. (J) Pedigree of E798Q mutation. (K) Pedigree of P917L mutation.