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.
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Authors | Xudong Liu, Patrick Malenfant, Chelsea Reesor, Alana Lee, Melissa L Hudson, Chansonette Harvard, Ying Qiao, Antonio M Persico, Ira L Cohen, Albert E Chudley, Cynthia Forster-Gibson, Evica Rajcan-Separovic, M E Suzanne Lewis, Jeanette J A Holden |
Journal | European journal of human genetics : EJHG
(Eur J Hum Genet)
Vol. 19
Issue 12
Pg. 1264-70
(Dec 2011)
ISSN: 1476-5438 [Electronic] England |
PMID | 21750575
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Karyopherins
- OTX1 protein, human
- Otx Transcription Factors
- Receptors, Cytoplasmic and Nuclear
- exportin 1 protein
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Topics |
- Alleles
- Child
- Child Development Disorders, Pervasive
(genetics)
- Child, Preschool
- Chromosome Breakpoints
- Chromosome Deletion
- Chromosomes, Human, Pair 2
- Gene Order
- Genetic Association Studies
- Genetic Predisposition to Disease
- Haplotypes
- Humans
- Karyopherins
(genetics)
- Otx Transcription Factors
(genetics)
- Polymorphism, Single Nucleotide
- Receptors, Cytoplasmic and Nuclear
(genetics)
- Syndrome
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