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Author Notes:

Author correspondence: Michael E. Zwick, Department of Human Genetics, Emory University, Whitehead Biomedical Research Building, Suite 301, Atlanta, GA 30322, USA. Phone: 1-404-727-9924; Fax: 1-404-727-3949; Email: mzwick@emory.edu

The Emory Custom Cloning Core facility generated constructs to our specifications for our expression analysis.

We thank members of the Cutler and Zwick labs for comments on the manuscript, Jennifer Mulle and Stephen T. Warren for discussion, Cheryl T. Strauss for editing and the Emory-Georgia Research Alliance Genome Center (EGC), supported in part by PHS Grant UL1 RR025008 from the Clinical and Translational Science Award program, National Institutes of Health, National Center for Research Resources, for performing the Illumina sequencing runs.

The ELLIPSE Emory High Performance Computing Cluster was used for this project.

The authors would like to thank the NHLBI GO Exome Sequencing Project and its ongoing studies, which produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the WHI Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926), and the Heart GO Sequencing Project (HL-103010).

Conflict of Interest Statement: None declared.


Research Funding:

This work was supported by the National Institutes of Health/National Institutes of Mental Health (NIH/NIMH) and Gift Fund (grant number: MH076439, M.E.Z.); the Simons Foundation Autism Research Initiative (M.E.Z.); and the Training Program in Human Disease Genetics (grant number: 1T32MH087977, D.R.).

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


Journal Title:

Human Molecular Genetics


Volume 21, Number 19


, Pages 4356-4364

Type of Work:

Article | Post-print: After Peer Review


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.

Copyright information:

© The Author 2012. Published by Oxford University Press. All rights reserved.

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