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Background <p>Spliceosomopathies are syndromes caused by pathogenic variants in genes involved in splicing and mRNA metabolism. Here, we report a novel spliceosomopathy caused by <i>de novo</i> variants in <i>SF3B3</i>, encoding a subunit of the spliceosomal SF3b complex.</p> Methods <p>We performed genomic, clinical, computer-aided gestalt analysis, molecular dynamics simulations, and functional studies using patient-derived fibroblasts.</p> Results <p>Through international data sharing, we collected clinical and molecular data from 24 unrelated individuals with heterozygous <i>SF3B3</i> 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, <i>SF3B3</i> 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.</p> Conclusions <p><i>SF3B3</i> 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.</p>

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A novel spliceosomopathy caused by de novo SF3B3 variants

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月19日

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  • Luciana Musante,
  • Pavel Janos,
  • Giulia Pianigiani,
  • Sara Cappelli,
  • Alessandra Longo,
  • Carolina Alves,
  • Eva MC Schwaibold,
  • Matias Wagner,
  • Gregory Costain,
  • Run Fridriksdottir,
  • Kari Stefansson,
  • Patrick Sulem,
  • Klaske D Lichtenbelt,
  • Ellen van Binsbergen,
  • Richard H van Jaarsveld,
  • Alfredo Brusco,
  • Lisa Pavinato,
  • Elisa Biamino,
  • Alessandra Spano,
  • Clara C Hildebrandt,
  • Yee-Ming Chan,
  • Emily Groopman,
  • Michal Berkenstadt,
  • Daniel Koboldt,
  • Rachel Williamson,
  • Han G Brunner,
  • Lisenka ELM Vissers,
  • Pernille M Torring,
  • Qin Hao,
  • Bruce D Gelb,
  • Elizabeth Goldmuntz,
  • Kristen Reed,
  • Emma C Bedoukian,
  • Davide Vecchio,
  • Emanuela Salzano,
  • Maria Piccione,
  • Caterina Zanus,
  • Catia Mio,
  • Evan E Eichler,
  • Tianyun Wang,
  • Wesley G Patterson,
  • Kameryn M Butler,
  • Mattie Piotrowski,
  • Sandra Mercier,
  • Benjamin Cogné,
  • Ingrid M. Wentzensen,
  • Emanuele Buratti,
  • Alessandra Magistrato,
  • Flavio Faletra

摘要

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.