CoChat
Sign Up
Cited by 61Genetics and Neurodevelopmental DisordersGenomics and Rare DiseasesFetal and Pediatric Neurological Disorders

New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental disorder and impairment of the WRC-mediated actin dynamics

Open access
Begemann, Anaïs, Sticht, Heinrich, Begtrup, Amber, Vitobello, Antonio, Faivre, Laurence, Banka, Siddharth, Alhaddad, Bader, Asadollahi, Reza +43 more·2021·Genetics in Medicine
DOI 10.1038/s41436-020-01011-xPMC PMC7935717
Open this paper in CoChat — free accountOpen PDF

Abstract

PURPOSE: A few de novo missense variants in the cytoplasmic FMRP-interacting protein 2 (CYFIP2) gene have recently been described as a novel cause of severe intellectual disability, seizures, and hypotonia in 18 individuals, with p.Arg87 substitutions in the majority. METHODS: We assembled data from 19 newly identified and all 18 previously published individuals with CYFIP2 variants. By structural modeling and investigation of WAVE-regulatory complex (WRC)-mediated actin polymerization in six patient fibroblast lines we assessed the impact of CYFIP2 variants on the WRC. RESULTS: Sixteen of 19 individuals harbor two previously described and 11 novel (likely) disease-associated missense variants. We report p.Asp724 as second mutational hotspot (4/19 cases). Genotype-phenotype correlation confirms a consistently severe phenotype in p.Arg87 patients but a more variable phenotype in p.Asp724 and other substitutions. Three individuals with milder phenotypes carry putative loss-of-function variants, which remain of unclear pathogenicity. Structural modeling predicted missense variants to disturb interactions within the WRC or impair CYFIP2 stability. Consistent with its role in WRC-mediated actin polymerization we substantiate aberrant regulation of the actin cytoskeleton in patient fibroblasts. CONCLUSION: Our study expands the clinical and molecular spectrum of CYFIP2-related neurodevelopmental disorder and provides evidence for aberrant WRC-mediated actin dynamics as contributing cellular pathomechanism.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41436-020-01011-x

Cites

3 of 3 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Three individuals harboring loss-of-function CYFIP2 variants (p.Lys501Ter, p.Ser258Glnfs2, and c.2058-1G > C) exhibited clinical features such as developmental delay, intellectual disability, ADHD, behavioral problems, seizures, craniofacial anomalies, and digital anomalies.

    “Among them, three individuals harboring LoF variants—p.Lys501Ter, p.Ser258Glnfs2, and c.2058-1G > C—exhibited clinical features such as DD, ID, attention-deficit/hyperactivity disorder (ADHD), behavioral problems, seizures, craniofacial anomalies, and digital anomalies.”

    From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [124]

    The Results section (‘No evidence that loss-of-function variants lead to a similarly severe phenotype’; page unavailable) identifies the three variants and reports mild intellectual disability and epilepsy in individual 19, and language delay and behavioral problems in individuals 17 and 18. It does not report ADHD, craniofacial anomalies, or digital anomalies for these three individuals; the facial features and tapered fingers described elsewhere in Results concern individuals with likely disease-associated missense variants. The authors also say the clinical significance of the three putative loss-of-function variants remains unclear. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Begemann et al. reported 19 additional individuals harboring CYFIP2 variants through exome sequencing, including 14 with novel variants.

    “Begemann et al. reported 19 additional individuals harboring CYFIP2 variants through exome sequencing, including 14 with novel variants (Table 2r).”

    From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [124]

    The Introduction reports 19 additional individuals, and the Results describe 11 novel missense substitutions plus three novel putative loss-of-function variants. But Materials and Methods (Patients) says exome sequencing identified variants in 17 individuals; the other two underwent targeted panel sequencing. Thus the claim overstates the use of exome sequencing across the cohort. (LLM, conf=0.92)

    Experimental — accuracy not yet measured

  • Disruption of CYFIP2 and its interaction with FMRP causes a neurodevelopmental disorder characterized by intellectual disability and seizures.

    “Disruption of CYFIP2 and its interaction with Fragile X Mental Retardation Protein (FMRP) is known to cause a neurodevelopmental disorder characterized by intellectual disability and seizures [49].”

    From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [49]

    The Introduction and Discussion link disease-associated CYFIP2 variants to a neurodevelopmental disorder involving intellectual disability and seizures. The Discussion says the variants disturb WRC-mediated actin regulation, but explicitly states that their effect on the CYFIP2–FMRP interaction has not been studied. The claimed disruption of that interaction as a cause is therefore unsupported. (LLM, conf=0.91)

    Experimental — accuracy not yet measured

  • Five individuals had two reported CYFIP2 variants, p.Arg87Cys and p.Asp724His, with p.Asp724 being the second mutational hotspot.

    “Five individuals had two reported variants, p.Arg87Cys and p.Asp724His, with p.Asp724 being the second mutational hotspot.”

    From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [124]

  • The phenotypes of individuals with missense CYFIP2 variants included developmental delay, intellectual disability, epilepsy, hypsarrhythmia, microcephaly, facial dysmorphism, dysphagia, visual problems, and sleep disturbances.

    “The phenotypes of individuals with missense variants included DD, ID, epilepsy, hypsarrhythmia, microcephaly, facial dysmorphism, dysphagia, visual problems, and sleep disturbances.”

    From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [124]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 37

  1. [1]Schenck A Bardoni B Langmann C CYFIP/Sra-1 controls neuronal connectivity in Drosophila and links the Rac1 GTPase pathway to the fragile X protein Neuron. 2003 38 887 898 10.1016/S0896-6273(03)00354-4 12818175 · DOI · Paper page
  2. [2]Chen Z Borek D Padrick SB Structure and control of the actin regulatory WAVE complex Nature. 2010 468 533 538 10.1038/nature09623 21107423 PMC3085272 · DOI · Paper page
  3. [3]Schenck A Qurashi A Carrera P WAVE/SCAR, a multifunctional complex coordinating different aspects of neuronal connectivity Dev Biol 2004 274 260 270 10.1016/j.ydbio.2004.07.009 15385157 · DOI · Paper page
  4. [4]Nakashima M Kato M Aoto K De novo hotspot variants in CYFIP2 cause early-onset epileptic encephalopathy Ann Neurol 2018 83 794 806 10.1002/ana.25208 29534297 · DOI · Paper page
  5. [5]Zweier M Begemann A McWalter K Spatially clustering de novo variants in CYFIP2, encoding the cytoplasmic FMRP interacting protein 2, cause intellectual disability and seizures Eur J Hum Genet 2019 27 747 759 10.1038/s41431-018-0331-z 30664714 PMC6461771 · DOI · Paper page
  6. [6]Peng J Wang Y He F Novel West syndrome candidate genes in a Chinese cohort CNS Neurosci Ther 2018 24 1196 1206 10.1111/cns.12860 29667327 PMC6489871 · DOI · Paper page
  7. [7]Zhong M Liao S Li T Early diagnosis improving the outcome of an infant with epileptic encephalopathy with cytoplasmic FMRP interacting protein 2 mutation: case report and literature review Medicine (Baltimore) 2019 98 e17749 10.1097/MD.0000000000017749 31689829 PMC7017979 · DOI
  8. [8]Sobreira N Schiettecatte F Valle D Hamosh A GeneMatcher: a matching tool for connecting investigators with an interest in the same gene Hum Mutat 2015 36 928 930 10.1002/humu.22844 26220891 PMC4833888 · DOI · Paper page
  9. [9]Sayle RA Milner-White EJ RASMOL: biomolecular graphics for all Trends Biochem Sci 1995 20 374 10.1016/S0968-0004(00)89080-5 7482707 · DOI
  10. [11]Delgado J Radusky LG Cianferoni D Serrano L FoldX 5.0: working with RNA, small molecules and a new graphical interface Bioinformatics. 2019 35 4168 4169 10.1093/bioinformatics/btz184 30874800 PMC6792092 · DOI
  11. [12]Berg S Kutra D Kroeger T ilastik: interactive machine learning for (bio)image analysis Nat Methods 2019 16 1226 1232 10.1038/s41592-019-0582-9 31570887 · DOI
  12. [13]McQuin C Goodman A Chernyshev V CellProfiler 3.0: next-generation image processing for biology PLoS Biol 2018 16 e2005970 10.1371/journal.pbio.2005970 29969450 PMC6029841 · DOI
  13. [14]Chen B Chou HT Brautigam CA Rac1 GTPase activates the WAVE regulatory complex through two distinct binding sites eLife 2017 6 e29795. 10.7554/eLife.29795 28949297 PMC5614565 · DOI · Paper page
  14. [15]Suetsugu S Yamazaki D Kurisu S Takenawa T Differential roles of WAVE1 and WAVE2 in dorsal and peripheral ruffle formation for fibroblast cell migration Dev Cell 2003 5 595 609 10.1016/S1534-5807(03)00297-1 14536061 · DOI
  15. [16]Lee Y Zhang Y Ryu JR Reduced CYFIP2 stability by Arg87 variants Causing Human Neurological Disorders Ann Neurol 2019 86 803 805 10.1002/ana.25598 31509259 · DOI · Paper page
  16. [19]Schaks M Singh SP Kage F Distinct interaction sites of Rac GTPase with WAVE regulatory complex have non-redundant functions in vivo Curr Biol 2018 28 3674 3684 10.1016/j.cub.2018.10.002 30393033 PMC6264382 · DOI · Paper page
  17. [20]Hoon JL Wong WK Koh CG Functions and regulation of circular dorsal ruffles Mol Cell Biol 2012 32 4246 4257 10.1128/MCB.00551-12 22927640 PMC3486146 · DOI
  18. [21]Innocenti M New insights into the formation and the function of lamellipodia and ruffles in mesenchymal cell migration Cell Adh Migr 2018 12 401 416 29513145 PMC6363039
  19. [22]Hornbeck PV Zhang B Murray B PhosphoSitePlus, 2014: mutations, PTMs and recalibrations Nucleic Acids Res 2015 43 D512 D520 10.1093/nar/gku1267 25514926 PMC4383998 · DOI
  20. [23]Kim Y Sung JY Ceglia I Phosphorylation of WAVE1 regulates actin polymerization and dendritic spine morphology Nature. 2006 442 814 817 10.1038/nature04976 16862120 · DOI · Paper page
  21. [24]Mendoza MC Phosphoregulation of the WAVE regulatory complex and signal integration Semin Cell Dev Biol 2013 24 272 279 10.1016/j.semcdb.2013.01.007 23354023 PMC3637877 · DOI · Paper page
  22. [25]Lee Y Kim D Ryu JR Phosphorylation of CYFIP2, a component of the WAVE-regulatory complex, regulates dendritic spine density and neurite outgrowth in cultured hippocampal neurons potentially by affecting the complex assembly Neuroreport. 2017 28 749 754 10.1097/WNR.0000000000000838 28692454 · DOI
  23. [26]Sossey-Alaoui K Head K Nowak N Cowell JK Genomic organization and expression profile of the human and mouse WAVE gene family Mamm Genome 2003 14 314 322 10.1007/s00335-002-2247-7 12856283 · DOI · Paper page
  24. [27]Zhang Y Kang HR Han K Differential cell-type-expression of CYFIP1 and CYFIP2 in the adult mouse hippocampus Anim Cells Syst (Seoul) 2019 23 380 383 10.1080/19768354.2019.1696406 31853374 PMC6913624 · DOI
  25. [28]Zallen JA Cohen Y Hudson AM SCAR is a primary regulator of Arp2/3-dependent morphological events in Drosophila J Cell Biol 2002 156 689 701 10.1083/jcb.200109057 11854309 PMC2174092 · DOI
  26. [29]Han K Chen H Gennarino VA Fragile X-like behaviors and abnormal cortical dendritic spines in cytoplasmic FMR1-interacting protein 2-mutant mice Hum Mol Genet 2015 24 1813 1823 10.1093/hmg/ddu595 25432536 PMC4355018 · DOI · Paper page
  27. [30]Pittman AJ Gaynes JA Chien CB nev (cyfip2) is required for retinal lamination and axon guidance in the zebrafish retinotectal system Dev Biol 2010 344 784 794 10.1016/j.ydbio.2010.05.512 20537992 PMC2914190 · DOI
  28. [31]Cioni JM Wong HH Bressan D Axon-axon interactions regulate topographic optic tract sorting via CYFIP2-dependent WAVE complex function Neuron. 2018 97 1078 1093 10.1016/j.neuron.2018.01.027 29518358 PMC5855093 · DOI
  29. [32]Shakir MA Jiang K Struckhoff EC The Arp2/3 activators WAVE and WASP have distinct genetic interactions with Rac GTPases in Caenorhabditis elegans axon guidance Genetics. 2008 179 1957 1971 10.1534/genetics.108.088963 18689885 PMC2516072 · DOI
  30. [33]Ito Y Carss KJ Duarte ST De novo truncating mutations in WASF1 cause intellectual disability with seizures Am J Hum Genet 2018 103 144 153 10.1016/j.ajhg.2018.06.001 29961568 PMC6037130 · DOI · Paper page
  31. [34]Reijnders MRF Ansor NM Kousi M RAC1 missense mutations in developmental disorders with diverse phenotypes Am J Hum Genet 2017 101 466 477 10.1016/j.ajhg.2017.08.007 28886345 PMC5591022 · DOI · Paper page
  32. [35]Cuvertino S Stuart HM Chandler KE ACTB loss-of-function mutations result in a pleiotropic developmental disorder Am J Hum Genet. 2017 101 1021 1033 10.1016/j.ajhg.2017.11.006 29220674 PMC5812896 · DOI
  33. [36]Riviere JB van Bon BW Hoischen A De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome Nat Genet 2012 44 440 444 10.1038/ng.1091 22366783 PMC3677859 · DOI
  34. [37]Zhang Y Kang H Lee Y Smaller body size, early postnatal lethality, and cortical extracellular matrix-related gene expression changes of Cyfip2-null embryonic mice Front Mol Neurosci 2018 11 482 10.3389/fnmol.2018.00482 30687000 PMC6338024 · DOI
  35. [38]Kumar V Kim K Joseph C C57BL/6N mutation in cytoplasmic FMRP interacting protein 2 regulates cocaine response Science. 2013 342 1508 1512 10.1126/science.1245503 24357318 PMC4500108 · DOI · Paper page
  36. [39]Chung L Wang X Zhu L Parental origin impairment of synaptic functions and behaviors in cytoplasmic FMRP interacting protein 1 (Cyfip1) deficient mice Brain Res 2015 1629 340 350 10.1016/j.brainres.2015.10.015 26474913 PMC4744651 · DOI
  37. [40]Bozdagi O Sakurai T Dorr N Haploinsufficiency of Cyfip1 produces fragile X-like phenotypes in mice PLoS One 2012 7 e42422 10.1371/journal.pone.0042422 22900020 PMC3416859 · DOI · Paper page

Cited by

Sorted by citations

Authors
Begemann, A., Sticht, H., Begtrup, A., Vitobello, A., Faivre, L., Banka, S., Alhaddad, B., Asadollahi, R., Becker, J., Bierhals, T., Brown, K. E., Bruel, A.-L., Brunet, T., Carneiro, M., Cremer, K., Day, R., Denommé-Pichon, A.-S., Dyment, D. A., Engels, H., Fisher, R., Goh, E. S., Hajianpour, M. J., Haertel, L. R. M., Hauer, N., Hempel, M., Herget, T., Johannsen, J., Kraus, C., Le Guyader, G., Lesca, G., Mau-Them, F. T., McDermott, J. H., McWalter, K., Meyer, P., Õunap, K., Popp, B., Reimand, T., Riedhammer, K. M., Russo, M., Sadleir, L. G., Saenz, M., Schiff, M., Schuler, E., Syrbe, S., Van der Ven, A. T., Verloes, A., Willems, M., Zweier, C., Steindl, K., Zweier, M., & Rauch, A.
Affiliations
  • University of Zurich (CH)
  • Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
  • Inserm (FR)
  • University of Manchester (GB)
  • TUM Klinikum (DE)
  • University of Bonn (DE)
  • University Medical Center Hamburg-Eppendorf (DE)
  • Children's Hospital Colorado (US)
  • Hospices Civils de Lyon (FR)
  • University of Otago (NZ)
  • University of Ottawa (CA)
  • University of Michigan (US)
  • Trillium Health Centre (CA)
  • East Tennessee State University (US)
  • Centre National de la Recherche Scientifique (FR)
  • Tartu University Hospital (EE)
  • University Hospital Heidelberg (DE)
  • Centre Hospitalier Universitaire de Montpellier (FR)
Corresponding author
Rauch, Anita
ORCID
Venue
Genetics in Medicine
Publisher
Elsevier BV
Published
2021-03
Volume
23
Issue
3
Pages
543-554
ISSN
1098-3600 (ISSN-L)
DOI
10.1038/s41436-020-01011-x
PMC
PMC7935717
OpenAlex
W3095038456
Cited by
61
References
3
Citations by year
2026: 8 · 2025: 10 · 2024: 10 · 2023: 14 · 2022: 12 · 2021: 5 · 2020: 1
FWCI
4.77
Type
journal article
Language
en
Open access
Licence
Locations
  • Genetics in Medicine (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • Greenwich Academic Literature Archive (University of Greenwich) (acceptedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by)
  • Digital Commons - East Tennessee State University (East Tennessee State University) (submittedVersion)
  • Digital Commons - East Tennessee State University (East Tennessee State University) (submittedVersion, cc-by-nc-sa)
  • HAL (submittedVersion, other-oa)
  • HAL (submittedVersion)
  • mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion, other-oa)
  • mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
  • Research Explorer (The University of Manchester) (submittedVersion, other-oa)
  • Repository for Publications and Research Data (ETH Zurich) (submittedVersion, cc-by-nc-sa)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by)
  • ETH Zürich Research Collection
  • Zurich Open Repository and Archive (University of Zurich)
Funders
  • Swiss National Science Foundation (320030_179547)
  • Universität Zürich (Clinical Research Priority Program Praeclare)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Fetal and Pediatric Neurological Disorders
Keywords
CYFIP2, neurodevelopmental disorders, WAVE regulatory complex, actin polymerization, actin cytoskeleton, intellectual disability, seizures, hypotonia, de novo missense variant, genotype-phenotype correlation, loss-of-function mutations, protein stability, structural modeling
MeSH terms
Actins, Humans, Intellectual Disability, Seizures, Adaptor Proteins, Signal Transducing, Neurodevelopmental Disorders

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review