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Musante, L.* ; Janos, P.* ; Pianigiani, G.* ; Cappelli, S.* ; Longo, A.* ; Alves, C.* ; Schwaibold, E.M.* ; Wagner, M. ; Costain, G.* ; Fridriksdottir, R.* ; Stefansson, K.* ; Sulem, P.* ; Lichtenbelt, K.D.* ; van Binsbergen, E.* ; van Jaarsveld, R.H.* ; Brusco, A.* ; Pavinato, L.* ; Biamino, E.* ; Spano, A.* ; Hildebrandt, C.C.* ; Chan, Y.M.* ; Groopman, E.* ; Berkenstadt, M.* ; Koboldt, D.* ; Williamson, R.* ; Brunner, H.G.* ; Vissers, L.E.* ; Torring, P.M.* ; Hao, Q.* ; Gelb, B.D.* ; Goldmuntz, E.* ; Reed, K.* ; Bedoukian, E.C.* ; Vecchio, D.* ; Salzano, E.* ; Piccione, M.* ; Zanus, C.* ; Mio, C.* ; Eichler, E.E.* ; Wang, T.* ; Patterson, W.G.* ; Butler, K.M.* ; Piotrowski, M.* ; Mercier, S.* ; Cogné, B.* ; Wentzensen, I.M.* ; Buratti, E.* ; Magistrato, A.* ; Faletra, F.*

A novel spliceosomopathy caused by de novo SF3B3 variants.

Genome Med. 18:34 (2026)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Background: Spliceosomopathies are syndromes caused by pathogenic variants in genes involved in splicing and mRNA metabolism. Here, we report a novel spliceosomopathy caused by de novo variants in SF3B3, encoding a subunit of the spliceosomal SF3b complex. Methods: We performed genomic, clinical, computer-aided gestalt analysis, molecular dynamics simulations, and functional studies using patient-derived fibroblasts. Results: Through international data sharing, we collected clinical and molecular data from 24 unrelated individuals with heterozygous SF3B3 variants, mostly missense, consistent with autosomal dominant inheritance. Individuals exhibited a congruent phenotype including autism spectrum disorder (ASD), developmental delay (DD), intellectual disability (ID), language and motor delay, multiple congenital anomalies, and distinctive craniofacial features, confirmed by GestaltMatcher analysis. In patient fibroblasts, SF3B3 mRNA was within the normal range, whereas protein levels were reduced by approximately 15-30% depending on the variant. All-atom simulations revealed impaired interactions of mutant SF3B3 with SF3b components. Transcriptome profiling revealed widespread gene expression changes, including genes involved in cell-cycle regulation, urogenital development, heart morphogenesis, neural crest differentiation, and neurogenesis. Alternative splicing analyses demonstrated specific alterations, including increased retained intron events. Functional assays confirmed cell-cycle abnormalities in patient-derived fibroblasts. Conclusions: SF3B3 variants cause a novel spliceosomopathy with a continuous clinical spectrum, from extremely severe prenatal forms with perinatal lethality to a milder form with autism ASD and DD/ID. These variants alter both stability and function of the SF3b complex, resulting in dysregulated transcriptome, alternative splicing defects, and downstream cellular consequences such as cell-cycle perturbation.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter De Novo ; Sf3b3 ; All-atom Simulation ; Rna Sequencing ; Sf3b Complex ; Spliceosomopathy; Stability Changes; Intron Retention; Protein; Dynamics; Complex; Haploinsufficiency; Parameters; Mutation; Notch; Transcriptome
ISSN (print) / ISBN 1756-994X
e-ISSN 1756-994X
Zeitschrift Genome Medicine
Quellenangaben Band: 18, Heft: 1, Seiten: , Artikelnummer: 34 Supplement: ,
Verlag Springer
Verlagsort Campus, 4 Crinan St, London N1 9xw, England
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Neurogenomics (ING)
Förderungen PNRR
German Innovation Fund
US National Institutes of Health
National Heart, Lung, and Blood Institute and the Eunice Kennedy Shriver National Institute of Child Health and Human Development
National Human Genome Research Institute grant
National Natural Science Foundation of China
ERN-ITHACA
Fundamental Research Funds for the Central Universities
PRIN2020
Association for Cancer Research (AIRC)
Eunice K. Shriver National Institute of Child Health and Human Development
National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung and Blood Institute
Italian Ministry of Health