Association and mutation analyses of 16p11.2 autism candidate genes
Open accessAbstract
BACKGROUND: Autism is a complex childhood neurodevelopmental disorder with a strong genetic basis. Microdeletion or duplication of a approximately 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.
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CHD8 mutation frequency is the highest of all genes screened and nearly matches the frequency of CNVs at 16p11.2, the most frequent recurrent deletion or duplication locus in sporadic ASD.
“The frequency of mutations in this gene is the highest of all genes screened thus far and nearly matches that of CNVs at 16p11.2, which is the most frequent recurrently deleted (0.5%) or duplicated (0.3%) locus in sporadic ASD [50,51].”
From A de novo convergence of autism genetics and molecular neuroscience (2014) · cites this paper as [50]
Genetic mutations identified in small numbers of people with autism have been generated in mice.
“To incorporate construct validity for the various genetic mutations identified in small numbers of people with autism (12–21), these mutations have been generated in mice (22, 23).”
From Negative allosteric modulation of the mGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism (2012) · cites this paper as [19]
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Cites
PLINK: a tool set for whole-genome association and population-based linkage analyses.
Purcell, S., Neale, B., Todd-Brown, K., Thomas, L., Ferreira, M. A. R., Bender, D., Maller, J., Sklar, P., de Bakker, P. I. W., Daly, M. J., et al. (2007) · The American Journal of Human Genetics · doi:10.1086/519795 · Cited by 34,089 · see citing works
Spielman, R. S., McGinnis, R. E., & Ewens, W. J. (1993) · PubMed · Cited by 3,679 · see citing works
Strong association of de novo copy number mutations with autism
Sebat, J., Lakshmi, B., Malhotra, D., Troge, J., Lese-Martin, C., Walsh, T., Yamrom, B., Yoon, S., Krasnitz, A., Kendall, J., et al. (2007) · Science · doi:10.1126/science.1138659 · Cited by 2,795 · see citing works
Self-citationAutism as a strongly genetic disorder: evidence from a British twin study
Bailey, A., Le Couteur, A., Gottesman, I., Bolton, P., Simonoff, E., Yuzda, E., & Rutter, M. (1995) · Psychological Medicine · doi:10.1017/s0033291700028099 · Cited by 2,461 · see citing works
Advances in autism genetics: on the threshold of a new neurobiology
Abrahams, B. S., & Geschwind, D. H. (2008) · Nature Reviews Genetics · doi:10.1038/nrg2346 · Cited by 1,866 · see citing works
Self-citationMutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism
Study, P. A. R. I. S., Jamain, S., Quach, H., Betancur, C., Råstam, M., Colineaux, C., Gillberg, I. C., Soderstrom, H., Giros, B., Leboyer, M., et al. (2003) · Nature Genetics · doi:10.1038/ng1136 · Cited by 1,851 · see citing works
Structural Variation of Chromosomes in Autism Spectrum Disorder
Marshall, C. R., Noor, A., Vincent, J. B., Lionel, A. C., Feuk, L., Skaug, J., Shago, M., Moessner, R., Pinto, D., Ren, Y., et al. (2008) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2007.12.009 · Cited by 1,815 · see citing works
Self-citationRare Structural Variants Disrupt Multiple Genes in Neurodevelopmental Pathways in Schizophrenia
Walsh, T., McClellan, J. M., McCarthy, S. E., Addington, A. M., Pierce, S. B., Cooper, G. M., Nord, A. S., Kusenda, M., Malhotra, D., Bhandari, A., et al. (2008) · Science · doi:10.1126/science.1155174 · Cited by 1,800 · see citing works
Association between Microdeletion and Microduplication at 16p11.2 and Autism
Weiss, L. A., Shen, Y., Korn, J. M., Arking, D. E., Miller, D. T., Fossdal, R., Saemundsen, E., Stefansson, H., Ferreira, M. A. R., Green, T., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa075974 · Cited by 1,666 · see citing works
Durand, C. M., Betancur, C., Boeckers, T. M., Bockmann, J., Chaste, P., Fauchereau, F., Nygren, G., Rastam, M., Gillberg, I. C., Anckarsäter, H., et al. (2007) · Nature Genetics · doi:10.1038/ng1933 · Cited by 1,602 · see citing works
Amaral, D. G., Schumann, C. M., & Nordahl, C. W. (2008) · Trends in Neurosciences · doi:10.1016/j.tins.2007.12.005 · Cited by 1,492 · see citing works
Autism spectrum disorders: developmental disconnection syndromes
Geschwind, D. H., & Levitt, P. (2007) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2007.01.009 · Cited by 1,411 · see citing works
Self-citationMapping autism risk loci using genetic linkage and chromosomal rearrangements
The Autism Genome Project Consortium (2007) · Nature Genetics · doi:10.1038/ng1985 · Cited by 1,402 · see citing works
Prevalence of Autism in a US Metropolitan Area
Yeargin-Allsopp, M., Rice, C., Karapurkar, T., Doernberg, N., Boyle, C., & Murphy, C. (2003) · JAMA · doi:10.1001/jama.289.1.49 · Cited by 1,248 · see citing works
On the allelic spectrum of human disease
Reich, D. E., & Lander, E. S. (2001) · Trends in Genetics · doi:10.1016/s0168-9525(01)02410-6 · Cited by 1,185 · see citing works
Common and rare variants in multifactorial susceptibility to common diseases
Bodmer, W., & Bonilla, C. (2008) · Nature Genetics · doi:10.1038/ng.f.136 · Cited by 1,131 · see citing works
Duan, J. (2003) · Human Molecular Genetics · doi:10.1093/hmg/ddg055 · Cited by 916 · see citing works
Mapping early brain development in autism
Courchesne, E., Pierce, K., Schumann, C. M., Redcay, E., Buckwalter, J. A., Kennedy, D. P., & Morgan, J. (2007) · Neuron · doi:10.1016/j.neuron.2007.10.016 · Cited by 860 · see citing works
Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene
Alarcón, M., Abrahams, B. S., Stone, J. L., Duvall, J. A., Perederiy, J. V., Bomar, J. M., Sebat, J., Wigler, M., Martin, C. L., Ledbetter, D. H., et al. (2008) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2007.09.005 · Cited by 818 · see citing works
Self-citationA Twin Study of Autism in Denmark, Finland, Iceland, Norway and Sweden
Steffenburg, S., Gillberg, C., Hellgren, L., Andersson, L., Gillberg, I. C., Jakobsson, G., & Bohman, M. (1989) · Journal of Child Psychology and Psychiatry · doi:10.1111/j.1469-7610.1989.tb00254.x · Cited by 780 · see citing works
Recurrent 16p11.2 microdeletions in autism
Kumar, R. A., KaraMohamed, S., Sudi, J., Conrad, D. F., Brune, C., Badner, J. A., Gilliam, T. C., Nowak, N. J., Cook, E. H., Dobyns, W. B., et al. (2007) · Human Molecular Genetics · doi:10.1093/hmg/ddm376 · Cited by 731 · see citing works
Self-citationContribution of SHANK3 Mutations to Autism Spectrum Disorder
Moessner, R., Marshall, C. R., Sutcliffe, J. S., Skaug, J., Pinto, D., Vincent, J., Zwaigenbaum, L., Fernandez, B., Roberts, W., Szatmari, P., et al. (2007) · The American Journal of Human Genetics · doi:10.1086/522590 · Cited by 681 · see citing works
Self-citationA Sibship Test for Linkage in the Presence of Association: The Sib Transmission/Disequilibrium Test
Spielman, R. S., & Ewens, W. J. (1998) · The American Journal of Human Genetics · doi:10.1086/301714 · Cited by 666 · see citing works
Arking, D. E., Cutler, D. J., Brune, C. W., Teslovich, T. M., West, K., Ikeda, M., Rea, A., Guy, M., Lin, S., Cook, E. H., et al. (2008) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2007.09.015 · Cited by 590 · see citing works
Self-citationPeer Bork, B., & Beckmann, G. (1993) · Journal of Molecular Biology · doi:10.1006/jmbi.1993.1305 · Cited by 582 · see citing works
Lecavalier, L. (2006) · Journal of Autism and Developmental Disorders · doi:10.1007/s10803-006-0147-5 · Cited by 569 · see citing works
Bakkaloglu, B., O'Roak, B. J., Louvi, A., Gupta, A. R., Abelson, J. F., Morgan, T. M., Chawarska, K., Klin, A., Ercan-Sencicek, A. G., Stillman, A. A., et al. (2008) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2007.09.017 · Cited by 537 · see citing works
Self-citationWilson, H. L., Wong, A. C. C., Shaw, S. R., Tse, W.-Y., Stapleton, G. A., Phelan, M. C., Hu, S., Marshall, J., & McDermid, H. E. (2003) · Journal of Medical Genetics · doi:10.1136/jmg.40.8.575 · Cited by 377 · see citing works
Vorstman, J. A. S., Staal, W. G., van Daalen, E., van Engeland, H., Hochstenbach, P. F. R., & Franke, L. (2006) · Molecular Psychiatry · doi:10.1038/sj.mp.4001757 · Cited by 353 · cited 1× · see citing works
“The frequency of microscopically visible structural chromosomal imbalances in autism is high and estimated at ,7% [11,12].”
BackgroundJacquemont, M.-L., Sanlaville, D., Redon, R., Raoul, O., Cormier-Daire, V, Lyonnet, S., Amiel, J., Le Merrer, M., Heron, D., de Blois, M.-C., et al. (2006) · Journal of Medical Genetics · doi:10.1136/jmg.2006.043166 · Cited by 305 · see citing works
Novel submicroscopic chromosomal abnormalities detected in autism spectrum disorder.
Christian, S. L., Brune, C. W., Sudi, J., Kumar, R. A., Liu, S., Karamohamed, S., Badner, J. A., Matsui, S., Conroy, J., McQuaid, D., et al. (2008) · Biological Psychiatry · doi:10.1016/j.biopsych.2008.01.009 · Cited by 299 · see citing works
Self-citationAUTISM AS A PARADIGMATIC COMPLEX GENETIC DISORDER
Veenstra-VanderWeele, J. M., Christian, S. L., & Cook, E. H. (2004) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev.genom.5.061903.180050 · Cited by 271 · see citing works
Self-citationHigh frequency of neurexin 1β signal peptide structural variants in patients with autism
Feng, J., Schroer, R. J., Jin, Y., Song, W., Yang, C., Bockholt, A., Cook, E. H., Skinner, C. D., Schwartz, C. E., & Sommer, S. S. (2006) · Neuroscience Letters · doi:10.1016/j.neulet.2006.08.017 · Cited by 271 · see citing works
Self-citationChildhood autism and associated comorbidities
Zafeiriou, D., Ververi, A., & Vargìami, E. (2006) · Brain and Development · doi:10.1016/j.braindev.2006.09.003 · Cited by 221 · see citing works
(2006) · CRC Press eBooks · doi:10.1201/9781420004205 · Cited by 171 · see citing works
The autism‐epilepsy connection
Levisohn, P. M. (2007) · Epilepsia · doi:10.1111/j.1528-1167.2007.01399.x · Cited by 146 · see citing works
Doc2: A Novel Brain Protein Having Two Repeated C2-like Domains
Orita, S., Sasaki, T., Naito, A., Komuro, R., Ohtsuka, T., Maeda, M., Suzuki, H., Igarashi, H., & Takai, Y. (1995) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1995.1062 · Cited by 122 · see citing works
Groffen, A. J. A., Friedrich, R., Brian, E. C., Ashery, U., & Verhage, M. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.03755.x · Cited by 102 · see citing works
Molecular Cytogenetics of Autism
Xu, J., Zwaigenbaum, L., Szatmari, P., & Scherer, S. (2004) · Current Genomics · doi:10.2174/1389202043349246 · Cited by 95 · see citing works
Self-citationAbu‐Khalil, A., Fu, L., Grove, E. A., Zečević, N., & Geschwind, D. H. (2004) · The Journal of Comparative Neurology · doi:10.1002/cne.20112 · Cited by 88 · see citing works
Self-citationMiyazaki, T., Hashimoto, K., Uda, A., Sakagami, H., Nakamura, Y., Saito, S., Nishi, M., Kume, H., Tohgo, A., Kaneko, I., et al. (2006) · FEBS Letters · doi:10.1016/j.febslet.2006.06.043 · Cited by 81 · see citing works
CDC: Autism Spectrum Disorders Common
Kuehn, B. M. (2007) · JAMA · doi:10.1001/jama.297.9.940 · Cited by 72 · see citing works
Control of Roof Plate Development and Signaling by Lmx1b in the Caudal Vertebrate CNS
Chizhikov, V. V., & Millen, K. J. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.0758-04.2004 · Cited by 72 · see citing works
Past and Future Perspectives on Autism Epidemiology
Fombonne, E. J. (2006) · CRC Press eBooks · doi:10.1201/9781420004205.ch2 · Cited by 71 · see citing works
Doc2α is an activity‐dependent modulator of excitatory synaptic transmission
Sakaguchi, G., Manabe, T., Kobayashi, K., Orita, S., Sasaki, T., Naito, A., Maeda, M. H., Igarashi, H., Katsuura, G., Nishioka, H., et al. (1999) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.1999.00855.x · Cited by 68 · see citing works
Peer Bork, B. (1991) · FEBS Letters · doi:10.1016/0014-5793(91)80433-4 · Cited by 48 · see citing works
Cloning and Characterization of Seizure-Related Gene, SEZ-6
Shimizu‐Nishikawa, K., Kajiwara, K., & Sugaya, E. (1995) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1995.2635 · Cited by 43 · see citing works
Autism and cytogenetic abnormalities: Solving autism one chromosome at a time
Martin, C. L., & Ledbetter, D. H. (2007) · Current Psychiatry Reports · doi:10.1007/s11920-007-0084-9 · Cited by 27 · see citing works
Use of ‘Omic’ Approaches in Unraveling Mechanisms of Gene-Environment Interactions
Olden, K. (2004) · Current Genomics · doi:10.2174/1389202043489980 · Cited by 11 · see citing works
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Silverman, J. L., Yang, M., Lord, C., & Crawley, J. N. (2010) · Nature Reviews Neuroscience · doi:10.1038/nrn2851 · Cited by 1,462 · see citing works
Shinawi, M., Liu, P., Kang, S.-H. L., Shen, J., Belmont, J. W., Scott, D. A., Probst, F. J., Craigen, W. J., Graham, B. H., Pursley, A., et al. (2010) · Journal of Medical Genetics · doi:10.1136/jmg.2009.073015 · Cited by 580 · see citing works
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Fernandez, B. A., Roberts, W., Chung, B., Weksberg, R., Meyn, S., Szatmari, P., Joseph-George, A. M., MacKay, S., Whitten, K., Noble, B., et al. (2010) · Journal of Medical Genetics · doi:10.1136/jmg.2009.069369 · Cited by 335 · see citing works
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Silverman, J. L., Smith, D. G., Rizzo, S. J. S., Karras, M. N., Turner, S. M., Tolu, S. S., Bryce, D. K., Smith, D. L., Fonseca, K., Ring, R. H., et al. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3003501 · Cited by 251 · see citing works
Yang, M., Mahrt, E. J., Lewis, F., Foley, G., Portmann, T., Dolmetsch, R. E., Portfors, C. V., & Crawley, J. N. (2015) · Autism Research · doi:10.1002/aur.1465 · Cited by 96 · see citing works
Autism spectrum disorder, developmental and psychiatric features in 16p11.2 duplication
on behalf of the Simons VIP consortium, Green Snyder, L., D’Angelo, D., Chen, Q., Bernier, R., Goin-Kochel, R. P., Wallace, A. S., Gerdts, J., Kanne, S., Berry, L., et al. (2016) · Journal of Autism and Developmental Disorders · doi:10.1007/s10803-016-2807-4 · Cited by 61 · see citing works
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- Authors
- Kumar, R. A., Marshall, C. R., Badner, J. A., Babatz, T. D., Mukamel, Z., Aldinger, K. A., Sudi, J., Brune, C. W., Goh, G., KaraMohamed, S., Sutcliffe, J. S., Cook, E. H., Geschwind, D. H., Dobyns, W. B., Scherer, S. W., & Christian, S. L.
- Affiliations
- University of Chicago (US)
- University of Toronto (CA)
- University of California, Los Angeles (US)
- University of Illinois Chicago (US)
- Vanderbilt University (US)
- Corresponding author
- Kumar, Ravinesh A.
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2009-02-26
- Volume
- 4
- Issue
- 2
- Pages
- e4582
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC2644762
- OpenAlex
- W1984939227
- Cited by
- 95
- References
- 49
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 3 · 2023: 1 · 2022: 5 · 2021: 2 · 2020: 7 · 2019: 3 · 2018: 1 · 2017: 5 · 2016: 5 · 2015: 9 · 2014: 6 · 2013: 8 · 2012: 10
- FWCI
- 5.26
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Knowledge@UChicago (University of Chicago) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Figshare (submittedVersion, cc-by)
- University of Chicago (cc-by)
- Funders
- Autism Speaks (AS1583)
- National Institute of Mental Health (MH-60233, MH 64547, R01MH060233, MH081754, R01MH081754, R56MH060233, R37MH060233, R01MH064547)
- National Institute of Neurological Disorders and Stroke (R01NS051812)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- autism spectrum disorder, 16p11.2, candidate genes, genetic association, rare variants, microdeletion, microduplication, promoter polymorphism, coding variants, genetic risk factors, neurodevelopmental disorders
- MeSH terms
- Animals, Autistic Disorder, Chromosomes, Human, Pair 16, DNA Mutational Analysis, Embryo, Mammalian, Exons, Family Health, Humans, Membrane Proteins, Promoter Regions, Genetic, Genetic Variation, Genetic Predisposition to Disease, Mice
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