Movement disorders : official journal of the Movement Disorder Society · 2026
Neurodevelopmental Disorder with Dystonia and Chorea Linked to De Novo Variants in the Splicing Regulator SRRM4.
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Harrer Philip, Kittke Volker, Saparov Alice, Knaus Alexej, Zeidler Shimriet, Schot Rachel, Kraft Florian, Begemann Matthias, Koudijs Suzanna, Sorrentino Ugo, Zhao Chen, Dzinovic Ivana, Pavlov Martin, Graf Elisabeth, Stehr Antonia M, Krawitz Peter M, Wilhelm Christian, Biskup Saskia, Alsalloum Fahd, Berweck Steffen, Winkelmann Juliane, Oexle Konrad, Kurth Ingo, Korenke G Christoph, Zech Michael
Аннотация
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.
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.