A co-segregating microduplication of chromosome 15q11.2 pinpoints two risk genes for autism spectrum disorder.
Open accessAbstract
High resolution genomic copy‐number analysis has shown that inherited and de novo copy‐number variations contribute significantly to autism pathology, and that identification of small chromosomal aberrations related to autism will expedite the discovery of risk genes involved. Here, we report a microduplication of chromosome 15q11.2, spanning only four genes, co‐segregating with autism in a Dutch pedigree, identified by SNP microarray analysis, and independently confirmed by FISH and MLPA analysis. Quantitative RT‐PCR analysis revealed over 70% increase in peripheral blood mRNA levels for the four genes present in the duplicated region in patients, and RNA in situ hybridization on mouse embryonic and adult brain sections revealed that two of the four genes, CYFIP1 and NIPA1 , were highly expressed in the developing mouse brain. These findings point towards a contribution of microduplications at chromosome 15q11.2 to autism, and highlight CYFIP1 and NIPA1 as autism risk genes functioning in axonogenesis and synaptogenesis. Thereby, these findings further implicate defects in dosage‐sensitive molecular control of neuronal connectivity in autism. However, the prevalence of this microduplication in patient samples was statistically not significantly different from control samples (0.94% in patients vs. 0.42% controls, P = 0.247), which suggests that our findings should be interpreted with caution and indicates the need for studies that include large numbers of control subjects to ascertain the impact of these changes on a population scale. © 2009 Wiley‐Liss, Inc.
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Copy number variation at the 15q11.2 region is a significant risk locus for neurological and neuropsychiatric conditions such as schizophrenia and autism spectrum disorder.
“Copy number variation (CNV) at the 15q11.2 region has been identified as a significant risk locus for neurological and neuropsychiatric conditions such as schizophrenia (SCZ) and autism spectrum disorder (ASD).”
From The autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines (2014) · cites this paper as [1]
The indexed text reports a 15q11.2 microduplication co-segregating with autism in one family and describes the locus as a possible shared susceptibility region for ASD and schizophrenia. But it says the difference in duplication prevalence between ASD patients and controls was not statistically significant (p=0.247) and that its status as an autism risk factor remains under debate. It therefore does not establish 15q11.2 CNV as a significant risk locus for both conditions. (LLM, conf=0.90)
Experimental — accuracy not yet measuredCHRNA7 and CYFIP1 were already proposed as susceptibility genes for neuropsychiatric disorders, and our study provides additional support for this association.
“CHRNA7 and CYFIP1 were already proposed as susceptibility genes for neuropsychiatric disorders [43], [45], [49], [51], and our study provides additional support for this association.”
From Genetic and Functional Analyses of SHANK2 Mutations Suggest a Multiple Hit Model of Autism Spectrum Disorders (2012) · cites this paper as [45]
The most compelling candidate in the deleted region is CYFIP1, which codes for a binding partner of FMRP, the protein responsible for fragile X syndrome.
“However, the most compelling candidate in the deleted region is CYFIP1 [45], [53], which codes for a binding partner of FMRP, the protein responsible for fragile X syndrome.”
From Genetic and Functional Analyses of SHANK2 Mutations Suggest a Multiple Hit Model of Autism Spectrum Disorders (2012) · cites this paper as [45]
Dysregulation or mutations of FMRP-interacting proteins such as CYFIP1, eIF4E, and a subset of FMRP mRNA targets may contribute to the autism spectrum disorder phenotype observed in fragile X syndrome.
“Recent evidence indicates that dysregulation and or mutations of FMRP-interacting proteins, such as the cytoplasmic FMRP-interacting protein 1 (CYFIP1) (52-55), eukaryotic initiation factor 4 (eIF4E) (56,57), and a subset of FMRP mRNA targets (58), may contribute to the ASD phenotype observed in FXS.”
From Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics (2012) · cites this paper as [54]
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- Authors
- van der Zwaag, B., Staal, W. G., Hochstenbach, R., Poot, M., Spierenburg, H. A., de Jonge, M. V., Verbeek, N. E., van 't Slot, R., van Es, M. A., Staal, F. J., Freitag, C. M., Buizer‐Voskamp, J. E., Nelen, M. R., van den Berg, L. H., van Amstel, H. K. P., van Engeland, H., & Burbach, J. P. H.
- Affiliations
- University Medical Center Utrecht (NL)
- Erasmus MC (NL)
- Universitätsklinikum des Saarlandes (DE)
- Corresponding author
- Burbach, J. Peter H.
- ORCID
- Venue
- American Journal of Medical Genetics Part B: Neuropsychiatric Genetics
- Publisher
- Wiley
- Published
- 2010-05-17
- Volume
- 153B
- Issue
- 4
- Pages
- 960-966
- ISSN
- 1552-4841 (ISSN-L)
- 1552-485X
- PMC
- PMC2933514
- OpenAlex
- W2081989700
- Cited by
- 108
- References
- 29
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 2 · 2023: 5 · 2022: 2 · 2021: 11 · 2020: 11 · 2019: 6 · 2018: 4 · 2017: 5 · 2016: 4 · 2015: 7 · 2014: 13 · 2013: 7 · 2012: 10
- FWCI
- 4.46
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Medical Genetics Part B Neuropsychiatric Genetics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- RePub (Erasmus University Rotterdam) (submittedVersion)
- Funders
- Autism Speaks
- Universiteit Utrecht
- National Institutes of Health
- National Institute of Mental Health (U24MH081810)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- autism spectrum disorder, microduplication, copy number variation, co-segregation, CYFIP1, NIPA1, autism risk genes, dosage-sensitive genes, axonogenesis, synaptogenesis, neuronal connectivity
- MeSH terms
- Animals, Autistic Disorder, Child, Child Development Disorders, Pervasive, Chromosome Aberrations, Chromosomes, Chromosomes, Human, Pair 2, Female, Genes, Humans, Nucleic Acid Hybridization, Risk, Case-Control Studies, Reverse Transcriptase Polymerase Chain Reaction, Mice
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