De novo hotspot variants in CYFIP2 cause early‐onset epileptic encephalopathy
Abstract
Objective: The cytoplasmic fragile X mental retardation 1 interacting proteins 2 (CYFIP2) is a component of the WASP‐family verprolin‐homologous protein (WAVE) regulatory complex, which is involved in actin dynamics. An obvious association of CYFIP2 variants with human neurological disorders has never been reported. Here, we identified de novo hotspot CYFIP2 variants in neurodevelopmental disorders and explore the possible involvement of the CYFIP2 mutants in the WAVE signaling pathway. Methods: We performed trio‐based whole‐exome sequencing (WES) in 210 families and case‐only WES in 489 individuals with epileptic encephalopathies. The functional effect of CYFIP2 variants on WAVE signaling was evaluated by computational structural analysis and in vitro transfection experiments. Results: We identified three de novo CYFIP2 variants at the Arg87 residue in 4 unrelated individuals with early‐onset epileptic encephalopathy. Structural analysis indicated that the Arg87 residue is buried at an interface between CYFIP2 and WAVE1, and the Arg87 variant may disrupt hydrogen bonding, leading to structural instability and aberrant activation of the WAVE regulatory complex. All mutant CYFIP2 showed comparatively weaker interactions to the VCA domain than wild‐type CYFIP2. Immunofluorescence revealed that ectopic speckled accumulation of actin and CYFIP2 was significantly increased in cells transfected with mutant CYFIP2. Interpretation: Our findings suggest that de novo Arg87 variants in CYFIP2 have gain‐of‐function effects on the WAVE signaling pathway and are associated with severe neurological disorders. Ann Neurol 2018;83:794–806
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Three de novo heterozygous missense variants in CYFIP2 were identified in four unrelated individuals diagnosed with early-onset epileptic encephalopathy through trio whole-exome sequencing, suggesting an association of this gene with neurodevelopmental disorders.
“Three de novo heterozygous missense variants in CYFIP2 were identified in four unrelated individuals diagnosed with early-onset epileptic encephalopathy through trio whole-exome sequencing (WES), suggesting the association of this gene with NDDs.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [118]
The accompanying phenotypes of these CYFIP2 variants include severe psychomotor delay, intellectual disability, craniofacial anomalies, and hypotonia.
“The accompanying phenotypes include severe psychomotor delay, ID, craniofacial anomalies, and hypotonia118.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [118]
Protein modeling and functional analyses suggest a model of sustained activation of the WAVE complex by Arg87 variants of CYFIP2.
“Based on the LoF intolerance score (pLI = 1) of CYFIP2, the authors initially assumed that variants in Arg87 might lead to impaired WAVE-mediated actin dynamics through an LoF mechanism, but subsequent protein modeling and functional analyses suggest a model of sustained activation of the WAVE complex by Arg87 variants118.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [118]
West syndrome was diagnosed in two individuals with CYFIP2 variants, similar to the reported patient with a CYFIP1 variant.
“Interestingly, West syndrome was diagnosed in two individuals118, similar to the reported patient with a CYFIP1 variant116.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [118]
All three CYFIP2 variants affect Arg87 (p.Arg87Cys, p.Arg87Leu, and p.Arg87Pro), suggesting that it represents a hotspot for these mutations.
“All three variants affect Arg87—p.Arg87Cys, p.Arg87Leu, and p.Arg87Pro—suggesting that it represents a hotspot for these mutations (Table 2p).”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [118]
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“This prediction was supported by the FoldX calculation of free energy change for each mutation (Fig 4E).(34) Tyr151 in WAVE1 is a highly conserved residue located in the meander regions of WAVE1 and is important for WRC activation.”
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CYFIP family proteins between autism and intellectual disability: links with Fragile X syndrome
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Davenport, E. C., Szulc, B. R., Drew, J., Taylor, J., Morgan, T., Higgs, N. F., López-Doménech, G., & Kittler, J. T. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.01.092 · Cited by 125 · see citing works
The WAVE complex in developmental and adulthood brain disorders
Kim, H.-G., Berdasco, C., Nairn, A. C., & Kim, Y. (2025) · Experimental & Molecular Medicine · doi:10.1038/s12276-024-01386-w · Cited by 8 · see citing works
- Authors
- Nakashima, M., Kato, M., Aoto, K., Shiina, M., Belal, H., Mukaida, S., Kumada, S., Sato, A., Zerem, A., Lerman‐Sagie, T., Lev, D., Leong, H. Y., Tsurusaki, Y., Mizuguchi, T., Miyatake, S., Miyake, N., Ogata, K., Saitsu, H., & Matsumoto, N.
- Affiliations
- Hamamatsu University (JP)
- Yamagata University (JP)
- Yokohama City University (JP)
- National Hospital Organization (JP)
- Tokyo Metropolitan Neurological Hospital (JP)
- University of Tokyo Hospital (JP)
- Tel Aviv University (IL)
- Hospital Kuala Lumpur (MY)
- Corresponding author
- Saitsu, Hirotomo
- Matsumoto, Naomichi
- ORCID
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2018-04
- Volume
- 83
- Issue
- 4
- Pages
- 794-806
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- OpenAlex
- W2792298997
- Cited by
- 80
- References
- 6
- Citations by year
- 2026: 5 · 2025: 15 · 2024: 7 · 2023: 7 · 2022: 14 · 2021: 9 · 2020: 10 · 2019: 12 · 2018: 1
- FWCI
- 4.83
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science
- Japan Science and Technology Agency
- Takeda Science Foundation
- Hayashi Memorial Foundation for Female Natural Scientists
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- CYFIP2, de novo mutations, early-onset epileptic encephalopathy, WAVE regulatory complex, WAVE1, actin dynamics, neurodevelopmental disorders, gain-of-function mutations, protein-protein interaction
- MeSH terms
- Exome Sequencing, Animals, Arginine, Brain, Cell Line, Transformed, Child, Child, Preschool, Electroencephalography, Female, Humans, Infant, Magnetic Resonance Imaging, Male, Models, Molecular, Mutation, Pedigree, Spasms, Infantile, Transfection, Gene Expression Regulation, Developmental, Adaptor Proteins, Signal Transducing, Green Fluorescent Proteins, Mice, HEK293 Cells
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