title: 2p15-p16.1 microdeletion syndrome: molecular characterization and association of the OTX1 and XPO1 genes with autism spectrum disorders.
abstract: 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 (Società Italiana per la Ricerca e la Formazione sull'Autismo (SIRFA)) of families with ASD. In XPO1, rs6735330 was associated with autism in all four cohorts (P<0.05), 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.
authors.affiliation: Department of Psychiatry, Queen's University, Kingston, Ontario, Canada.
authors.forename: Xudong
authors.initials: X
authors.lastname: Liu
authors.forename: Patrick
authors.initials: P
authors.lastname: Malenfant
authors.forename: Chelsea
authors.initials: C
authors.lastname: Reesor
authors.forename: Alana
authors.initials: A
authors.lastname: Lee
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Hudson
authors.forename: Chansonette
authors.initials: C
authors.lastname: Harvard
authors.forename: Ying
authors.initials: Y
authors.lastname: Qiao
authors.forename: Antonio M
authors.initials: AM
authors.lastname: Persico
authors.forename: Ira L
authors.initials: IL
authors.lastname: Cohen
authors.forename: Albert E
authors.initials: AE
authors.lastname: Chudley
authors.forename: Cynthia
authors.initials: C
authors.lastname: Forster-Gibson
authors.forename: Evica
authors.initials: E
authors.lastname: Rajcan-Separovic
authors.forename: M E Suzanne
authors.initials: ME
authors.lastname: Lewis
authors.forename: Jeanette J A
authors.initials: JJ
authors.lastname: Holden
mesh_terms: D000483:Alleles; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000235:genetics*; D002675:Child, Preschool; D056905:Chromosome Breakpoints; D002872:Chromosome Deletion; D002889:Chromosomes, Human, Pair 2; D023061:Gene Order; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D028884:Karyopherins / Q000235:genetics*; D051857:Otx Transcription Factors / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D013577:Syndrome; D000097606:Exportin 1 Protein
chemical_list: D028884:Karyopherins; D051857:Otx Transcription Factors; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein; C497655:OTX1 protein, human