Neurodevelopmental Disorder with Dystonia and Chorea Linked to De Novo Variants in the Splicing Regulator SRRM4

Philip Harrer ^{1 2}, Volker Kittke ^{1 2 3}, Alice Saparov ^{1 2 4}, Alexej Knaus ⁵, Shimriet Zeidler ⁶, Rachel Schot ⁶, Florian Kraft ⁷, Matthias Begemann ⁷, Suzanna Koudijs ⁸, Ugo Sorrentino ^{1 2}, Chen Zhao ^{1 2}, Ivana Dzinovic ^{1 2}, Martin Pavlov ^{1 2}, Elisabeth Graf ^{1 2}, Antonia M Stehr ¹, Peter M Krawitz ⁵, Christian Wilhelm ⁹, Saskia Biskup ⁹, Fahd Alsalloum ¹⁰, Steffen Berweck ¹¹, Juliane Winkelmann ^{1 2 3 12}, Konrad Oexle ^{1 2 13}, Ingo Kurth ⁷, G Christoph Korenke ¹⁴, Michael Zech ^{1 2 15}

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.

Keywords: alternative splicing; chorea; dystonia; genome editing; genomics; neurodevelopmental disorder; transcriptomics.