Disruption of the ASTN2/TRIM32 locus at 9q33.1 is a risk factor in males for autism spectrum disorders, ADHD and other neurodevelopmental phenotypes
Open accessAbstract
Rare copy number variants (CNVs) disrupting ASTN2 or both ASTN2 and TRIM32 have been reported at 9q33.1 by genome-wide studies in a few individuals with neurodevelopmental disorders (NDDs). The vertebrate-specific astrotactins, ASTN2 and its paralog ASTN1, have key roles in glial-guided neuronal migration during brain development. To determine the prevalence of astrotactin mutations and delineate their associated phenotypic spectrum, we screened ASTN2/TRIM32 and ASTN1 (1q25.2) for exonic CNVs in clinical microarray data from 89 985 individuals across 10 sites, including 64 114 NDD subjects. In this clinical dataset, we identified 46 deletions and 12 duplications affecting ASTN2. Deletions of ASTN1 were much rarer. Deletions near the 3' terminus of ASTN2, which would disrupt all transcript isoforms (a subset of these deletions also included TRIM32), were significantly enriched in the NDD subjects (P = 0.002) compared with 44 085 population-based controls. Frequent phenotypes observed in individuals with such deletions include autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), speech delay, anxiety and obsessive compulsive disorder (OCD). The 3'-terminal ASTN2 deletions were significantly enriched compared with controls in males with NDDs, but not in females. Upon quantifying ASTN2 human brain RNA, we observed shorter isoforms expressed from an alternative transcription start site of recent evolutionary origin near the 3' end. Spatiotemporal expression profiling in the human brain revealed consistently high ASTN1 expression while ASTN2 expression peaked in the early embryonic neocortex and postnatal cerebellar cortex. Our findings shed new light on the role of the astrotactins in psychopathology and their interplay in human neurodevelopment.
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In a recent study of 89,985 individuals, 46 deletions and 12 duplication mutations were observed in the ASTN2 gene.
“In a recent study of 89,985 individuals, approximately 71% of whom were reported to have a neurodevelopmental disorder (NDD), a total of 46 deletions and 12 duplication mutations were observed in the ASTN2 gene [58].”
The peak of the association signal at 9q33.1 extends over the 3' end of ASTN2, corresponding to a region encoding the C terminus of the protein, a region with cross-species sequence conservation and strong enrichment of exonic deletions in male NDD cases.
“The peak of our association signal at 9q33.1 extends over the 3’ end of ASTN2 corresponding to a region of the gene that encodes the C terminus of the protein, a region with cross-species sequence conservation and strong enrichment of exonic deletions in male NDD cases [58].”
Exonic deletions in ASTN2 were significantly enriched in the NDD cohort (OR = 2.69, 95% CI 1.13-7.77; P = 0.01).
“Exonic deletions were significantly enriched in the NDD cohort (OR = 2.69 (95% CI 1.13–7.77); P = 0.01).”
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- Authors
- Lionel, A. C., Tammimies, K., Vaags, A. K., Rosenfeld, J. A., Ahn, J. W., Merico, D., Noor, A., Runke, C. K., Pillalamarri, V. K., Carter, M. T., Gazzellone, M. J., Thiruvahindrapuram, B., Fagerberg, C., Laulund, L. W., Pellecchia, G., Lamoureux, S., Deshpande, C., Clayton-Smith, J., White, A. C., Leather, S., Trounce, J., Melanie Bedford, H., Hatchwell, E., Eis, P. S., Yuen, R. K. C., Walker, S., Uddin, M., Geraghty, M. T., Nikkel, S. M., Tomiak, E. M., Fernandez, B. A., Soreni, N., Crosbie, J., Arnold, P. D., Schachar, R. J., Roberts, W., Paterson, A. D., So, J., Szatmari, P., Chrysler, C., Woodbury-Smith, M., Brian Lowry, R., Zwaigenbaum, L., Mandyam, D., Wei, J., MacDonald, J. R., Howe, J. L., Nalpathamkalam, T., Wang, Z., Tolson, D., Cobb, D. S., Wilks, T. M., Sorensen, M. J., Bader, P. I., An, Y., Wu, B.-L., Musumeci, S. A., Romano, C., Postorivo, D., Nardone, A. M., Monica, M. D., Scarano, G., Zoccante, L., Novara, F., Zuffardi, O., Ciccone, R., Antona, V., Carella, M., Zelante, L., Cavalli, P., Poggiani, C., Cavallari, U., Argiropoulos, B., Chernos, J., Brasch-Andersen, C., Speevak, M., Fichera, M., Ogilvie, C. M., Shen, Y., Hodge, J. C., Talkowski, M. E., Stavropoulos, D. J., Marshall, C. R., & Scherer, S. W.
- Affiliations
- University of Toronto (CA)
- Karolinska Institutet (SE)
- Alberta Health Services (CA)
- Guy's Hospital (GB)
- Centre for Applied Genomics (CA)
- Hospital for Sick Children (CA)
- Mayo Clinic (US)
- Harvard University (US)
- Odense University Hospital (DK)
- Brighton General Hospital (GB)
- Brighton and Sussex University Hospitals NHS Trust (GB)
- University of Ottawa (CA)
- Children's Hospital of Eastern Ontario (CA)
- Memorial University of Newfoundland (CA)
- St. Joseph’s Healthcare Hamilton (CA)
- Centre for Addiction and Mental Health (CA)
- McMaster University (CA)
- University of Alberta (CA)
- Madigan Army Medical Center (US)
- Kalispell Regional Medical Center (US)
- Fudan University (CN)
- Boston Children's Hospital (US)
- University of Rome Tor Vergata (IT)
- Azienda Ospedaliera G.Rummo (IT)
- University of Verona (IT)
- University of Pavia (IT)
- University of Palermo (IT)
- Casa Sollievo della Sofferenza (IT)
- Istituti Ospitalieri di Cremona (IT)
- Trillium Health Centre (CA)
- University of Catania (IT)
- Corresponding author
- Scherer, S. W.
- ORCID
- Lionel, A. C.
- Tammimies, K.
- Rosenfeld, J. A.
- Ahn, J. W.
- Merico, D.
- Noor, A.
- Runke, C. K.
- Pillalamarri, V. K.
- Thiruvahindrapuram, B.
- Fagerberg, C.
- Laulund, L. W.
- Pellecchia, G.
- Deshpande, C.
- Hatchwell, E.
- Eis, P. S.
- Yuen, R. K. C.
- Uddin, M.
- Geraghty, M. T.
- Nikkel, S. M.
- Tomiak, E. M.
- Fernandez, B. A.
- Soreni, N.
- Crosbie, J.
- Arnold, P. D.
- Schachar, R. J.
- Paterson, A. D.
- So, J.
- Zwaigenbaum, L.
- Wei, J.
- Nalpathamkalam, T.
- An, Y.
- Musumeci, S. A.
- Romano, C.
- Postorivo, D.
- Monica, M. D.
- Scarano, G.
- Zoccante, L.
- Novara, F.
- Zuffardi, O.
- Ciccone, R.
- Antona, V.
- Carella, M.
- Cavallari, U.
- Argiropoulos, B.
- Speevak, M.
- Fichera, M.
- Ogilvie, C. M.
- Hodge, J. C.
- Talkowski, M. E.
- Stavropoulos, D. J.
- Marshall, C. R.
- Scherer, S. W.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-12-30
- Volume
- 23
- Issue
- 10
- Pages
- 2752-2768
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC3990173
- OpenAlex
- W2155294359
- Cited by
- 163
- References
- 19
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 14 · 2023: 10 · 2022: 19 · 2021: 17 · 2020: 16 · 2019: 10 · 2018: 15 · 2017: 14 · 2016: 18 · 2015: 12 · 2014: 7
- FWCI
- 8.17
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- public-domain
- Locations
- Human Molecular Genetics (publishedVersion, public-domain)
- Europe PMC (PubMed Central) (publishedVersion, public-domain)
- PubMed Central (publishedVersion, public-domain)
- PubMed (publishedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- U.S. Department of Defense
- Autism Speaks
- GlaxoSmithKline
- Canadian Institute for Advanced Research
- Genome Canada
- Ontario Genomics
- Broad Institute (U01HG004424)
- Government of Ontario
- Ontario Genomics Institute
- Sick Kids Foundation
- University of Toronto
- Vetenskapsrådet
- Hospital for Sick Children
- National Institutes of Health (CA87969, CA55075, CA 87969, CA55075)
- U.S. Navy
- Canadian Institutes of Health Research
- National Institute of Mental Health (MH095867)
- National Institute on Drug Abuse (P50DA019706)
- National Human Genome Research Institute (U01HG004399, U01HG004446, U01HG004424)
- National Cancer Institute (CA-87969, CA-55075, P01CA087969, P01CA089392, P01CA055075, P50CA084724)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK058845, DK58845)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Keywords
- ASTN2, TRIM32, copy number variation, neurodevelopmental disorders, autism spectrum disorder, attention deficit hyperactivity disorder, sex differences, alternative transcription start sites, speech delay, anxiety, obsessive-compulsive disorder
- MeSH terms
- Tripartite Motif Proteins, Adolescent, Adult, Attention Deficit Disorder with Hyperactivity, Child, Child Development Disorders, Pervasive, Child, Preschool, Chromosomes, Human, Pair 9, Exons, Female, Glycoproteins, Humans, Infant, Infant, Newborn, Male, Nerve Tissue Proteins, Organ Specificity, Phenotype, Receptors, Cell Surface, Risk Factors, Transcription Factors, Gene Expression, Case-Control Studies, Sequence Deletion, Genetic Predisposition to Disease, Protein Isoforms, Polymorphism, Single Nucleotide, Transcription Initiation Site, Ubiquitin-Protein Ligases, Young Adult, Genetic Association Studies, DNA Copy Number Variations
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