Abstract
RNA-binding proteins play a key role in post-transcriptional events, such as mRNA splicing, transport, stability, translation and decay. Dysregulation of RNA life can have dramatic consequences. CELF RNA-binding proteins appear to be essential during embryo development. In this study, we identified 15 patients with heterozygous missense or loss-of-function variants in the CELF4 gene by exome or genome sequencing. All variants affecting the N-terminus of the protein are essential and sufficient for the RNA-binding and splicing activity or RRM domains. Most patients presented with neurodevelopmental disorders including global developmental delay/intellectual disability (11/14), seizures (9/15) and overweight/obesity (10/14) that began in childhood. Clinical features are similar to the reported celf4-mouse mutant phenotype. This study highlights the essential role of CELF4 in development and its involvement as a novel etiology of neurodevelopmental disorders with obesity.
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Additional data are available from the corresponding author upon reasonable request.
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Acknowledgements
We are grateful to the patients and their families for their participation in this study. We thank the Centre de Calcul de l’Univeristé de Bourgogne (CCuB) for the technical support and management of the informatics platform. This study makes use of data generated by the French SequoiA platform (https://laboratoire-seqoia.fr/); and DECIPHER, ClinVAR and denovo-db community. A full list of centers who contributed to the generation of the data are available at https://deciphergenomics.org/about/stats, https://www.ncbi.nlm.nih.gov/clinvar/ and https://denovo-db.gs.washington.edu/denovo-db/. We thank Mohnish Suri, Jennifer Howe and Stephanie Einsele-Scholz for the data sharing. Patients cited in this study were gathered using GeneMatcher platform (https://genematcher.org/statistics/).
Funding
This work was supported by grants from the Dijon University Hospital, the Burgundy-Franche Comté regional council (Plan d’Actions Régional pour l’Innovation PARI and the European Union through the FEDER programs 2014/2020). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. This study is funded by Physicians’ Services Incorporated (PSI) Foundation Health Research Grant to Dr. Saadet Mercimek-Andrews. We would like to thank the PSI Foundation for their funding support (Patient 15).
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A-LB, CT-R and AV contributed to the writing of the manuscript. A-LB, CP, YD, FL and FB analyzed and/or interpreted exome data. ATV, GLG, BG-D, XLG, SR, MR, KNL, AB, MS, FG, LF, CT-R, VR, AG, FL, NB, RA, MI, X-RY, ER-O, MP-B, JCH, JC, AJ, RDK, SM-A, AA, ENW, IMW, ET, CG contributed to the phenotyping of patients. All authors discussed the results and contributed to the final manuscript.
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The authors declare no competing interests. ENW and IMW are employees of GeneDx, LLC.
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Parents signed consent forms for genetic analyses, participation to this study and for images and clinical data publication. Patient 15: this study is approved by the Institutional Research Ethics Boards (REB#100032244) and (ARISE# Pro00106741).
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Bruel, AL., Vulto-vanSilfhout, A.T., Bilan, F. et al. Heterozygous CELF4 variants in the N-term region crucial for the RNA-binding activity lead to neurodevelopmental disorder and obesity. Eur J Hum Genet 33, 852–859 (2025). https://doi.org/10.1038/s41431-025-01809-w
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DOI: https://doi.org/10.1038/s41431-025-01809-w
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