Abstract
SF3B1 is an essential and ubiquitous splicing factor that plays a pivotal role in the early steps of pre-mRNA splicing. Recurrent somatic missense mutations in SF3B1 are frequent in cancers, but no constitutional variant has been reported so far. We describe here a cohort of 26 individuals with neurodevelopmental disorders, harbouring SF3B1 constitutional heterozygous variants that appeared mostly de novo. Patients present with a global developmental delay, associated with variable neurological and facial dysmorphic traits. A dichotomy may emerge between patients harbouring predicted loss of function (n = 9) and missense variants (n = 17), the latter being associated with a more severe and syndromic phenotype, including heart and gastrointestinal anomalies. We focused on de novo SF3B1 missense variants, which were largely distinct from those reported in cancer. Functional complementation assays show that de novo SF3B1 missense variants did not cause a loss of function of the protein. Targeted and genome-wide analysis of RNA splicing reveal that they affect canonical and alternative splicing more moderately than somatic variants, and subtly modify the splicing of many transcripts. These findings place SF3B1 among the rare U2 snRNP components implicated in both cancer and neurodevelopmental disorders, highlighting its critical and multifaceted role in human disease.
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The RNA sequencing data generated from patient-derived lymphocytes have been deposited in the European Genome–Phenome Archive (EGA, http://www.ebi.ac.uk/ega), under accession code EGAS50000001473, and are subjected to a data processing agreement due to their sensitive nature. Access will be provided only for health or medical or biomedical research, only for non commercial use, and a collaboration with the primary study investigator is required. Due to the sensitive nature of human genetic data, controlled access to human genome data is necessary to protect participant privacy and to ensure compliance with ethical and legal standards. Individual genome data provided within a clinical diagnostic setting, which are stored on secure hospital servers, cannot be made available due to ethical and regulatory considerations, including patient consent limitations and data protection regulations. However, whole exome sequencing data performed in the framework of the HUGODIMS consortium, as well as the exome sequencing data generated in a research setting, are available from the corresponding author under controlled access. Access will be restricted to qualified researchers for non-commercial research purposes and subject to a data processing agreement. Data access requests for RNA sequencing and exome sequencing data generated in a research setting should be submitted to the corresponding author and will be reviewed within 30 days by a data accessibility committee to ensure that data access complies with ethical and legal standards respective to the corresponding projects. The RNA sequencing data generated in this study on K562 cells have been deposited in the Gene Expression Omnibus database (https://www.ncbi.nlm.nih.gov/gds) under accession code GSE287369. All other data supporting the findings of this study are available within the paper and its supplementary information files. The source data underlying Figs. 3 and 5 and Supplementary Fig . 4-6 are provided as a Source Data file. Source data are provided with this paper.
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Acknowledgements
The authors wish to thank the patients and families included as part of this study. The authors acknowledge HUGODIMS (Western France exome-based trio approach project to identify genes involved in intellectual disability); funding for HUGODIMS is supported by a grant from the French Ministry of Health and from the Health Regional Agency from Poitou-Charentes (HUGODIMS, 2013, RC14_0107). This study was funded by INSERM, by the French League against cancer (la Ligue contre le Cancer, committees 29 and 35), by the French Biomedecine Agency and by the association Gaetan Saleun. T.B. was funded by the Brittany Region and the Ministère de l’Enseignement Supérieur, S.Ch. and C. D. were funded by the Ministère de l’Enseignement Supérieur de la Recherche et de l’Innovation. This study was supported by the « Priority Research Programme on Rare Diseases » of the French Investments for the Future Programme, project MultiOmixCare. JRL was supported in part by US National Institutes of Health NS105078 and HG011758. D.G.C. was supported by the Child Neurologist Career Development Programme K12 and Muscular Dystrophy Association Development Grant (873841). The authors thank the vectorology core facility Vect’UB in Bordeaux for the production of lentiviral particles, and thank the Centre of Biological Resources in Brest (CHU).
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K.U. and T.B. contributed equally. K.U., T.B., and S.K. contributed to the design of the study; T.B., S.Ch., C.D., S.C. performed the experiments; M.P.S.-B. performed the bioinformatic analysis (RNAseq); D.G.B. and K.U. contributed to the bioinformatic analysis; T.Be., L.D.S.F and B. Co. provided data on human samples; K.U., T.B., S.K., S.Ch. and D.G.B. contributed to data interpretation; M.P., S.H., P.W., H.W., B.X., V.S., M.C., C.Z., C.C., T.P., S.G., B.T., T.C., C.P., T.H., T.R., M.M., K.I., J.L., E.Z., I.G., S.W., M.B., L.F., J.M., J.D., C.J., L.LM., H.VE., D.C., L.DW., G.B., C.Pe. and L.D. contributed to the clinical data collection; K.U., S.K., C.G., M.C., S.B., P.S., Y.X., Y.W., M.D-F., D.L., P.C., F.T-M-T., A.D-P., A.V., J. Lu., P.P-B., R.M. and D.S. contributed to the exome/genome data analysis; C.F. supported the study; K.U., S.K., T.B. and D.B wrote the manuscript; E.L., L.C. reviewed the manuscript; D.G.B. designed and supervised the research. All authors read the manuscript.
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Uguen, K., Bergot, T., Scott-Boyer, MP. et al. De novo variants in the splicing factor gene SF3B1 are associated with neurodevelopmental disorders. Nat Commun (2026). https://doi.org/10.1038/s41467-026-68284-9
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DOI: https://doi.org/10.1038/s41467-026-68284-9
