A novel spliceosomopathy caused by de novo SF3B3 variants

Abstract 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.