Neurodevelopmental Disorder with Dystonia and Chorea Linked to De Novo Variants in the Splicing Regulator SRRM4.
This study links de novo splice-donor variants in the neural splicing regulator SRRM4 to infantile dystonia–chorea syndromes and demonstrates variant-specific SRRM4 mRNA isoforms and downstream microexon mis-splicing (e.g., AP1S2) in patient cells.
What the AI sees
This study links de novo splice-donor variants in the neural splicing regulator SRRM4 to infantile dystonia–chorea syndromes and demonstrates variant-specific SRRM4 mRNA isoforms and downstream microexon mis-splicing (e.g., AP1S2) in patient cells.
Research significance
It highlights misregulated neuronal microexon splicing as a disease mechanism that could be targeted by splice-modulating therapies and may reveal mechanistic convergence across genetic movement disorders, though it has limited direct relevance to canonical Parkinson's disease pathways like…
Source abstract
BACKGROUND: SRRM4 is an exclusively neural-expressed splicing-factor gene not yet associated with a monogenic condition. OBJECTIVE: We sought to delineate movement disorders caused by SRRM4 variants. De novo splice-donor-site variants at position +2 of intron 5 of SRRM4 (c.464+2T>C, c.464+2T>A) occurred in three unrelated patients with dystonia and chorea. We present detailed phenotypic information on these individuals and characterize the effect of the splice-site alteration. METHODS: Exome and genome sequencing were used to identify SRRM4 variants. To assess the consequence of a mutant +2 residue at the affected splice donor of SRRM4, we performed transcriptomic analyses using short-read and long-read RNA-sequencing in patient fibroblasts in which SRRM4 expression was induced by genome editing. RESULTS: Clinical presentations were characterized by infantile combined dystonic and choreatic syndromes or chorea-predominant disease. Studies in SRRM4 expression-activated cells revealed two variant-specific SRRM4-mRNA isoforms including one that was characterized by a 69-nucleotide in-frame insertion without creation of a premature termination codon, suggestive of a mechanism other than loss-of-function. Additionally, we uncovered altered splicing patterns of known SRRM4 downstream mRNA-substrates in patient cells compared to SRRM4 expression-activated control fibroblasts, such as a conserved AP1S2 microexon. AP1S2 is linked to a monogenic syndrome with abnormal movements and missplicing of its microexon is a well-established outcome in neural models of SRRM4 disruption. CONCLUSIONS: We conclude that the patients' phenotypes are caused by a previously undiagnosed SRRM4-related disorder, offering a basis for improved understanding of mechanistic convergence in genetic movement disorders and potential therapeutic targeting of the misregulated splicing events. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.