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 (Po0.05), being significant in ASD-CARC cohorts (P-value following false discovery rate correction for multiple testing (P FDR )¼1.29Â10 À5 ), the AGRE cohort (P FDR ¼0.0011) and the combined families (P FDR ¼2.34Â10 À9 ). Similarly, in OTX1, rs2018650 and rs13000344 were associated with autism in ASD-CARC cohorts (P FDR ¼8.65Â10 À7 and 6.07Â10 5 , respectively), AGRE cohort (P FDR ¼0.0034 and 0.015, respectively) and the combined families (P FDR ¼2.34Â10 À9 and 0.00017, respectively); associations were marginal or insignificant in the New York and SIRFA cohorts. A significant association (P FDR ¼2.63Â10 À11 ) 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 o0.01). 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.

Identifying candidate genes for 2p15p16.1 microdeletion syndrome using clinical, genomic, and functional analysis

“…The recurrence of deletions in the 2p15p16.1 region of variable size is intriguing, and we demonstrated the presence of different types of repeats at the breakpoints as well as an absence of low-copy repeats (LCRs) (40). Constitutional duplications in the region were also reported in 8 DECIPHER cases and 1 recently reported case (chr2:60150427-61816209, hg19) (52) that had no consistent abnormalities or evidence of a mirror image phenotype (e.g., macrocephaly).…”

“…21), neuronal positioning during brain development (20), and stabilization of centrosomes and mitotic spindles of the dividing cells (39). In humans, XPO1 SNPs were linked to autism (40), mutations with genomic instability in cancer (41), and overexpression in multiple sclerosis (MS) (42). To date, patients with isolated deletion of XPO1 were not reported, although 4 cases had a deletion containing only XPO1 and USP34 (subject 1 in Shimojima et al, ref.…”

Biological Significance of the Importin‐β Family‐Dependent Nucleocytoplasmic Transport Pathways

“…Interstitial deletions and SNPs in the CRM1 gene ( XPO1 ) and the nearby OTX1 gene are associated with autism spectrum disorders . Some SNPs in the RanBP5 locus ( KPNB3 ) are associated with schizophrenia .…”

Bio-collections in autism research

“…20 novel genes found putative non-coding regions associated with androgen sensitivity[225]AGREGenomic data1295 families (total)696 families (AGRE)GWASNoise reduction filter for GWAS leads to list of 830 candidate genes, where they impact dendrite and axon outgrowth and guidance[29]AGRE ATPBlood and brain133 sib pairs (total) 77 Sib pairs (AGRE) 17 brain tissue (ATP)Ogliogenic hypothesis studyEvidence of epigenetic and genetic factors possibly contributing to ASD and UBE3 having a possible role in ASD[179]AGREBlood and lymphoblasts192 subjects (AGRE)483 subjects (total)Association studyDisruptions in NRXN1 gene found to be associated with ASD[226]AGREGenomic data476 subjects (total)290 subjects (AGRE)Association studySuggestive association of parent and maternal origin effect on SLC6A4 promoter variant and ASD. Further testing required on biological model or larger cohort[26]AGREBlood and lymphoblasts1549 subjects410 subjects (AGRE)Mutation screeningRecurrent microdeletions in chromosome region 16p11.2 were observed in ASD patients and not in controls[227]AGREBlood and lymphoblasts974 subjects (total)512 subjects (AGRE)Mutation screening RIMS3 identified as a possible ASD susceptibility gene[228]AGREBlood33 families (AGRE)49 families (total)Association studyAssociation found for HLA-DR4 gene in higher frequency in geographically defined subtype, but not in controls or AGRE sample[229]AGREBlood508 families (total)139 families (AGRE)Association studyAnalysis of 2p15-16.1 microdeletions region identified two candidate genes; XPO1 and OXT1 [230]AGREBlood and lymphoblasts407 families (total)138 familiesAssociation analysisPolymorphisms found in or near DLX1 and DLX2 found to be associated with ASD[231]AGREBlood and lymphoblasts512 families (total) 138 families (AGRE)Association studyAssociation found between ASD and MTHFR gene in simplex families but not in multiplex families[37]AGREBlood and lymphoblasts219 families (total)98 families (AGRE)Association study…”