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Harrer, P. ; Kittke, V. ; Saparov, A. ; Knaus, A.* ; Zeidler, S.* ; Schot, R.* ; Kraft, F.* ; Begemann, M.* ; Koudijs, S.* ; Sorrentino, U. ; Zhao, C. ; Dzinovic, I. ; Pavlov, M. ; Graf, E. ; Stehr, A.M.* ; Krawitz, P.M.* ; Wilhelm, C.* ; Biskup, S.* ; Alsalloum, F.* ; Berweck, S.* ; Winkelmann, J. ; Oexle, K. ; Kurth, I.* ; Korenke, G.C.* ; Zech, M.

Neurodevelopmental disorder with dystonia and chorea linked to de novo variants in the splicing regulator SRRM4.

Mov. Disord., DOI: 10.1002/mds.70297 (2026)
Publ. Version/Full Text Research data DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Alternative Splicing ; Chorea ; Dystonia ; Genome Editing ; Genomics ; Neurodevelopmental Disorder ; Transcriptomics; Intellectual Disability; Genes
ISSN (print) / ISBN 0885-3185
e-ISSN 1531-8257
Journal Movement Disorders
Publisher Wiley
Publishing Place 111 River St, Hoboken 07030-5774, Nj Usa
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
Grants Technical University of Munich-Institute for Advanced Study
EJP RD (EJP RD Joint Transnational Call 2022)
German Federal Ministry of Education and Research (BMBF, Bonn, Germany)
DFG Research Infrastructure NGS_CC
Next Generation Sequencing (NGS) Competence Network
DFG
DFG Sequencing call Sequencing Costs in Projects
BMBF
Free State of Bavaria under the Excellence Strategy of the Federal Government
Lander
Schlusselprojekt" grant from the Else Kroner-Fresenius-Stiftung