Bi-allelic SNAPC4 variants dysregulate global alternative splicing and lead to neuroregression and progressive spastic paraparesis

The vast majority of human genes encode multiple isoforms through alternative splicing, and the temporal and spatial regulation of those isoforms is critical for organismal development and function. The spliceosome, which regulates and executes splicing reactions, is primarily composed of small nuclear ribonucleoproteins (snRNPs) that consist of small nuclear RNAs (snRNAs) and protein subunits. snRNA gene transcription is initiated by the snRNA-activating protein complex (SNAPc). Here, we report ten individuals, from eight fam-ilies, with bi-allelic, deleterious SNAPC4 variants. SNAPC4 encoded one of the five SNAPc subunits that is critical for DNA binding. Most affected individuals presented with delayed motor development and developmental regression after the first year of life, followed by pro-gressive spasticity that led to gait alterations, paraparesis, and oromotor dysfunction. Most individuals had cerebral, cerebellar, or basal ganglia volume loss by brain MRI. In the available cells from affected individuals, SNAPC4 abundance was decreased compared to un-affected controls, suggesting that the bi-allelic variants affect SNAPC4 accumulation. The depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing. Analysis of available fibroblasts from affected individuals showed decreased snRNA expression and global dysregulation of alternative splicing compared to unaffected cells. Altogether, these data suggest that these bi-allelic SNAPC4 variants result in loss of function and underlie the neuroregression and progressive spasticity in these affected individuals.

Automated summary

The majority of human genes undergo alternative splicing to generate multiple isoforms, and the regulation of these isoforms is crucial for development and function. The spliceosome, composed of small nuclear ribonucleoproteins (snRNPs), is responsible for splicing reactions. The snRNA gene transcription is initiated by SNAPc. In this study, ten individuals with bi-allelic SNAPC4 variants were identified. These variants led to motor developmental delay, regression, spasticity, and brain volume loss. The decrease in SNAPC4 levels resulted in reduced snRNA expression and dysregulation of alternative splicing. These findings demonstrate that bi-allelic SNAPC4 variants cause loss of function and contribute to neuroregression and progressive spasticity in affected individuals.