Association and mutation analyses of 16p11.2 autism candidate genes

Ravinesh A. Kumar, Christian R. Marshall, Judith A. Badner, Timothy D. Babatz, Zohar Mukamel, Kimberly A. Aldinger, Jyotsna Sudi, Camille W. Brune, Gerald Goh, Samer KaraMohamed, James S. Sutcliffe, Edwin H. Cook, Daniel H. Geschwind, William B. Dobyns, Stephen W. Scherer, Susan L. Christian

Research output: Contribution to journalArticlepeer-review

71 Scopus citations


Background: Autism is a complex childhood neurodevelopmental disorder with a strong genetic basis. Microdeletion or duplication of a ∼500-700-kb genomic rearrangement on 16p11.2 that contains 24 genes represents the second most frequent chromosomal disorder associated with autism. The role of common and rare 16p11.2 sequence variants in autism etiology is unknown. Methodology/Principal Findings: To identify common 16p11.2 variants with a potential role in autism, we performed association studies using existing data generated from three microarray platforms: Affymetrix 5.0 (777 families), Illumina 550 K (943 families), and Affymetrix 500 K (60 families). No common variants were identified that were significantly associated with autism. To look for rare variants, we performed resequencing of coding and promoter regions for eight candidate genes selected based on their known expression patterns and functions. In total, we identified 26 novel variants in autism: 13 exonic (nine non-synonymous, three synonymous, and one untranslated region) and 13 promoter variants. We found a significant association between autism and a coding variant in the seizure-related gene SEZ6L2 (12/1106 autism vs. 3/1161 controls; p = 0.018). Sez6l2 expression in mouse embryos was restricted to the spinal cord and brain. SEZ6L2 expression in human fetal brain was highest in post-mitotic cortical layers, hippocampus, amygdala, and thalamus. Association analysis of SEZ6L2 in an independent sample set failed to replicate our initial findings. Conclusions/Significance: We have identified sequence variation in at least one candidate gene in 16p11.2 that may represent a novel genetic risk factor for autism. However, further studies are required to substantiate these preliminary findings.

Original languageEnglish (US)
Article numbere4582
JournalPloS one
Issue number2
StatePublished - 2009
Externally publishedYes

Bibliographical note

Funding Information:
Funding: This work was supported in part by grants to Susan L. Christian from the National Alliance for Autism Research and the National Institute of Neurological Diseases and Stroke (1R01 NS51812), as well as to Daniel H. Geschwind (PI) from the National Institute of Mental Health (MH64547), National Institute of Mental Health (MH081754) and the Method to Extend Research in Time (MERIT) from the National Institute of Mental Health (MH60233). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Publisher Copyright:
© 2009 Kumar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


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