Reports of unrelated individuals with autism spectrum disorder (ASD) and similar clinical features having overlapping de novo interstitial deletions at 2p15-p16.1 suggest that this region harbors a gene(s) important to the development of autism. We molecularly characterized two such deletions, selecting two genes in this region, exportin 1 (XPO1) and orthodenticle homolog 1 (OTX1) for association studies in three North American cohorts (Autism Spectrum Disorder - Canadian American Research Consortium (ASD-CARC), New York, and Autism Genetic Resource Exchange (AGRE)) and one Italian cohort (Societ Italiana per la Ricerca e la Formazione sullAutismo (SIRFA)) of families with ASD. In XPO1, rs6735330 was associated with autism in all four cohorts (P0.05), being significant in ASD-CARC cohorts (P-value following false discovery rate correction for multiple testing (P FDR)1.29 × 10 5), the AGRE cohort (P FDR 0.0011) and the combined families (P FDR 2.34 × 10 9). Similarly, in OTX1, rs2018650 and rs13000344 were associated with autism in ASD-CARC cohorts (P FDR 8.65 × 10 7 and 6.07 × 10 5, respectively), AGRE cohort (P FDR 0.0034 and 0.015, respectively) and the combined families (P FDR 2.34 × 10 9 and 0.00017, respectively); associations were marginal or insignificant in the New York and SIRFA cohorts. A significant association (P FDR 2.63 × 10 11) was found for the rs2018650G-rs13000344C haplotype. The above three SNPs were associated with severity of social interaction and verbal communication deficits and repetitive behaviors (P-values 0.01). No additional deletions were identified following screening of 798 ASD individuals. Our results indicate that deletion 2p15-p16.1 is not commonly associated with idiopathic ASD, but represents a novel contiguous gene syndrome associated with a constellation of phenotypic features (autism, intellectual disability, craniofacial/CNS dysmorphology), and that XPO1 and OXT1 may contribute to ASD in 2p15-p16.1 deletion cases and non-deletion cases of ASD mapping to this chromosome region.
- array comparative genomic hybridization
- exportin 1 gene
- orthodenticle homolog 1 gene
- real-time quantitative PCR
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