title: Excess variants in AFF2 detected by massively parallel sequencing of males with autism spectrum disorder.
abstract: Autism spectrum disorder (ASD) is a heterogeneous disorder with substantial heritability, most of which is unexplained. ASD has a population prevalence of one percent and affects four times as many males as females. Patients with fragile X E (FRAXE) intellectual disability, which is caused by a silencing of the X-linked gene AFF2, display a number of ASD-like phenotypes. Duplications and deletions at the AFF2 locus have also been reported in cases with moderate intellectual disability and ASD. We hypothesized that other rare X-linked sequence variants at the AFF2 locus might contribute to ASD. We sequenced the AFF2 genomic region in 202 male ASD probands and found that 2.5% of males sequenced had missense mutations at highly conserved evolutionary sites. When compared with the frequency of missense mutations in 5545 X chromosomes from unaffected controls, we saw a statistically significant enrichment in patients with ASD (OR: 4.9; P < 0.014). In addition, we identified rare AFF2 3' UTR variants at conserved sites which alter gene expression in a luciferase assay. These data suggest that rare variation in AFF2 may be a previously unrecognized ASD susceptibility locus and may help explain some of the male excess of ASD.
authors: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Kajari
authors: K
authors: Mondal
authors: Dhanya
authors: D
authors: Ramachandran
authors: Viren C
authors: VC
authors: Patel
authors: Katie R
authors: KR
authors: Hagen
authors: Promita
authors: P
authors: Bose
authors: David J
authors: DJ
authors: Cutler
authors: Michael E
authors: ME
authors: Zwick
mesh_terms: D020413:3' Untranslated Regions; D001483:Base Sequence; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000235:genetics*; D002675:Child, Preschool; D041321:Chromosomes, Human, X / Q000235:genetics; D014644:Genetic Variation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; C099930:AFF2 protein, human; D009687:Nuclear Proteins