Common variants in genes of the postsynaptic FMRP signalling pathway are risk factors for autism spectrum disorders
Abstract
Autism spectrum disorders (ASD) are heterogeneous disorders with a high heritability and complex genetic architecture. Due to the central role of the fragile X mental retardation gene 1 protein (FMRP) pathway in ASD we investigated common functional variants of ASD risk genes regulating FMRP. We genotyped ten SNPs in two German patient sets (N = 192 and N = 254 families, respectively) and report association for rs7170637 (CYFIP1; set 1 and combined sets), rs6923492 (GRM1; combined sets), and rs25925 (CAMK4; combined sets). An additional risk score based on variants with an odds ratio (OR) >1.25 in set 1 and weighted by their respective log transmitted/untransmitted ratio revealed a significant effect (OR 1.30, 95 % CI 1.11-1.53; P = 0.0013) in the combined German sample. A subsequent meta-analysis including the two German samples, the "Strict/European" ASD subsample of the Autism Genome Project (1,466 families) and a French case/control (541/366) cohort showed again association of rs7170637-A (OR 0.85, 95 % CI 0.75-0.96; P = 0.007) and rs25925-G (OR 1.31, 95 % CI 1.04-1.64; P = 0.021) with ASD. Functional analyses revealed that these minor alleles predicted to alter splicing factor binding sites significantly increase levels of an alternative mRNA isoform of the respective gene while keeping the overall expression of the gene constant. These findings underpin the role of ASD candidate genes in postsynaptic FMRP regulation suggesting that an imbalance of specific isoforms of C…
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Four heterozygous missense CYFIP1 variants were identified in patients with autism spectrum disorder, including a common variant p.Gly820Ser and three rare variants p.Asp544Asn, p.Met956Arg, and p.Ala1025Thr.
“Four heterozygous missense CYFIP1 variants were identified in patients with ASD, including a common variant, p.Gly820Ser113 (Table 2l), and three rare variants, p.Asp544Asn, p.Met956Arg and p.Ala1025Thr114 (Table 2m).”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [113]
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“Further, associations between schizophrenia and mutations in CYFIP1 altering mRNA levels have also been reported (21–24).”
CYFIP1 governs the development of cortical axons by modulating calcium availability
Ricci, C., Midroit, M. J., Caicci, F., Achsel, T., Domínguez-Iturza, N., & Bagni, C. (2025) · Nature Communications · doi:10.1038/s41467-025-65801-0 · Cited by 1 · see citing works
“Genomic variations and point mutations identi fi ed CYFIP1 as the most likely gene from the region causally associated with SCZ 9 – 11 and ASDs 12,13 .”
- Authors
- Waltes, R., Duketis, E., Knapp, M., Anney, R. J. L., Huguet, G., Schlitt, S., Jarczok, T. A., Sachse, M., Kämpfer, L. M., Kleinböck, T., Poustka, F., Bölte, S., Schmötzer, G., Voran, A., Huy, E., Meyer, J., Bourgeron, T., Klauck, S. M., Freitag, C. M., & Chiocchetti, A. G.
- Affiliations
- Goethe University Frankfurt (DE)
- University of Bonn (DE)
- Trinity College Dublin (IE)
- Centre National de la Recherche Scientifique (FR)
- Universitätsklinikum des Saarlandes (DE)
- Universität Trier (DE)
- German Cancer Research Center (DE)
- Corresponding author
- Chiocchetti, Andreas G.
- ORCID
- Venue
- Human Genetics
- Published
- 2014-01-19
- Volume
- 133
- Issue
- 6
- Pages
- 781-792
- ISSN
- 0018-7348 (ISSN-L)
- 0340-6717
- 1432-1203
- OpenAlex
- W2041143775
- Cited by
- 71
- References
- 11
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 3 · 2023: 7 · 2022: 5 · 2021: 4 · 2020: 9 · 2019: 5 · 2018: 6 · 2017: 9 · 2016: 11 · 2015: 3 · 2014: 4
- FWCI
- 5.90
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Human Genetics (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- eSpace (Curtin University) (submittedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Funders
- World Health Organization
- Agence Nationale de la Recherche (ANR-10-NEUR-0003)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- autism spectrum disorder, FMRP, common genetic variants, CYFIP1, metabotropic glutamate receptor 1, CaMKIV, splice variants, risk score, synaptic plasticity, genetic association
- MeSH terms
- Adolescent, Alleles, Child, Child Development Disorders, Pervasive, Child, Preschool, Female, Gene Expression Regulation, Humans, Male, Neuronal Plasticity, Protein Binding, Risk Factors, Signal Transduction, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, White People, Adaptor Proteins, Signal Transducing, Fragile X Messenger Ribonucleoprotein 1, Calcium-Calmodulin-Dependent Protein Kinase Type 4, Genotyping Techniques
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