Journal Article

Excess variants in AFF2 detected by massively parallel sequencing of males with autism spectrum disorder

Kajari Mondal, Dhanya Ramachandran, Viren C. Patel, Katie R. Hagen, Promita Bose, David J. Cutler and Michael E. Zwick

in Human Molecular Genetics

Volume 21, issue 19, pages 4356-4364
Published in print October 2012 | ISSN: 0964-6906
Published online July 2012 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/dds267
Excess variants in AFF2 detected by massively parallel sequencing of males with autism spectrum disorder

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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.

Journal Article.  6185 words.  Illustrated.

Subjects: Genetics and Genomics

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