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De Novo Variants in the Splicing Factor Gene SF3B1 Are Associated with Neurodevelopmental Disorders

De Novo Variants

Constitutional variants in the splicing factor SF3B1 have been linked to neurodevelopmental disorders for the first time, according to a new multinational study co-authored by Phoenix Children’s Pediatric Neurologist and Neurogeneticist Michael Kruer, MD, et al. 

SF3B1 is an essential splicing factor central to early pre-mRNA splicing. While recurrent somatic missense mutations in SF3B1 are well-described in cancer, no constitutional variant had previously been reported. The authors describe a cohort of 26 individuals with global developmental delay and variable neurologic and facial dysmorphic features, harboring SF3B1 constitutional heterozygous variants – most arising de novo.

The cohort showed two distinct patterns: loss-of-function variants (n=9) and missense variants (n=17), with missense changes associated with a more severe, syndromic phenotype that can include cardiac and gastrointestinal anomalies. Functional complementation assays demonstrated that the de novo missense variants did not cause complete loss of SF3B1 function. Instead, they subtly altered canonical and alternative splicing across many transcripts – distinct from the splicing changes seen with SF3B1 somatic mutations in cancer.

The findings place SF3B1 among a rare group of U2 snRNP components implicated in both oncologic and neurodevelopmental diseases and support considering SF3B1 in diagnostic algorithms for children with unexplained developmental or syndromic presentations. Read the Study

Phoenix Children's Pediatric Movement Disorders Program accepts referrals for children with neurodevelopmental disorders, movement abnormalities, and rare genetic conditions affecting motor function. To refer a patient or request a consultation, call 602-933-KIDS (5437) or submit a referral online. 

REFERENCE

Bernard DG, et al. De novo variants in the splicing factor gene SF3B1 are associated with neurodevelopmental disorders. Nat Commun. 2026;17:1569. doi:10.1038/s41467-026-68284-9. PubMed ID 41577671.

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