SNAPC4-related neurodevelopmental disorder defines a stage-dependent spliceosomopathy with heterogeneous clinical trajectories

Background The small nuclear RNA-activating complex polypeptide 4 (SNAPC4) encodes the largest scaffolding subunit of the SNAPc complex, essential for transcription of spliceosomal small nuclear RNAs (snRNAs) by RNA polymerase II and III. Although pathogenic variants in SNAPC4 have been associated with a rare neurodevelopmental disorder, the full phenotypic spectrum and underlying molecular mechanisms remain poorly defined. Methods We assembled an international cohort of 14 individuals harboring 18 distinct pathogenic SNAPC4 variants and one multi-exon deletion, three of which had been previously reported, including frameshift, splice-site, multi-exon deletions, and missense alleles. Detailed clinical and neuroimaging data were integrated with in silico structural and protein–protein interaction analyses to assess the impact of these variants on SNAPc architecture and function. Results SNAPC4 -related disease emerges as a highly heterogeneous clinical continuum rather than a uniform progressive disorder. Core features included global developmental delay and microcephaly, with variable trajectories ranging from static cognitive impairment to adult-onset progressive motor dysfunction, alongside neurobehavioral phenotypes such as autism and ADHD. Neuroimaging revealed abnormalities suggestive of impaired neurogenesis and gliogenesis, including lissencephaly-pachygyria and hypomyelinating leukodystrophy. Structural modeling supports a unifying loss-of-function (LoF) mechanism, whereby variants destabilize the SNAPc complex or disrupt key interfaces required for DNA binding and RNA polymerase recruitment, consistent with impaired SNAPc function and transcriptional dysregulation. Conclusion These findings redefine SNAPC4 -related disease as a stage-dependent neurodevelopmental spliceosomopathy, linking disruption of SNAPC4 to impaired SNAPc function and transcriptional dysregulation, with direct implications for diagnosis and variant interpretation.