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Saparov, A. ; Dzinovic, I. ; Brunet, T.* ; Yépez, V.A.* ; Hölzlwimmer, F.* ; Indelicato, E.* ; Assmann, B.* ; Badmann, S.* ; Ballhausen, D.* ; Berweck, S.* ; Brechtmann, F.* ; Brugger, M.* ; Derderian, K.* ; Distelmaier, F.* ; Harrer, P. ; Harvanova, D.* ; Havrankova, P.* ; Jaroszynski, A.K.* ; Kolnikova, M.* ; Kopajtich, R. ; Koy, A.* ; Krygier, M.* ; Kunc, L.* ; Kusikova, K.* ; Maier, O.* ; Mazurkiewicz-Bełdzińska, M.* ; Mertes, C.* ; Oberlack, A.* ; Roser, T.* ; Sitzberger, A.* ; Sorrentino, U. ; Stehr, A.M.* ; Vill, K.* ; Wagner, M. ; Prokisch, H. ; Boesch, S.* ; Necpal, J.* ; Jech, R.* ; Winkelmann, J. ; Graf, E.* ; Gagneur, J.* ; Skorvanek, M.* ; Zech, M.

Fibroblast transcriptomics in molecular diagnostics of a comprehensive dystonia cohort.

Ann. Neurol., DOI: 10.1002/ana.78171 (2026)
Verlagsversion Forschungsdaten DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
OBJECTIVE: Genomic sequencing leaves >50% of dystonia-affected individuals without a diagnosis. Where DNA-oriented approaches remain insufficient, integrating multiomics is essential to advance genome interpretation. Herein, we incorporated RNA sequencing (RNA-seq) data from 167 patients with dystonia across a range of ages and presentations. METHODS: We leveraged an RNA-seq analysis pipeline, focused on the identification of expression and splicing aberrations, on RNA-seq from skin biopsies. The recruited patients had early-onset dystonia in 85.0%, non-focal dystonia in 92.2%, and coexisting features in 76.0%. Thirty-six patient samples with pre-identified variants (36/167, 21.6%) and 131 samples with no previously prioritized diagnostic candidates from genomic sequencing (131/167, 78.4%) were evaluated. RESULTS: We found that >80% of dystonia-associated genes were detected by fibroblast RNA-seq. Expression and splicing aberration analyses produced a manageable number of significant RNA defects affecting dystonia-associated genes. The approach was especially successful in validating pathogenic effects of loss-of-function variants, with disease-relevant RNA-underexpression detected for 66.7% (10/15). Studying aberrant expression and splicing in the context of other pre-identified variant types yielded relevant results in 28.6% (6/21 samples). We obtained a 6.9% (9/131) diagnostic uplift for patients without prior candidates, all of whom exhibited combined dystonia with autosomal recessive inheritance. The new diagnoses from RNA-seq and genomic reanalysis were based on previously neglected splice-region (3/9) and deep(er) intronic (6/9) variants. For the observed events, integration of new machine-learning scores predicted corresponding aberrant gene expression in the brain. INTERPRETATION: Fibroblast-based RNA-seq in our selected cohort improved variant interpretation and offered a modest yield in patients without prior candidate variants. ANN NEUROL 2026.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Joint Consensus Recommendation; Mutation Database; Medical Genetics; American-college; Genomics; Standards; Variants
ISSN (print) / ISBN 0364-5134
e-ISSN 1531-8249
Zeitschrift Annals of Neurology
Verlag Wiley
Verlagsort 111 River St, Hoboken 07030-5774, Nj Usa
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Neurogenomics (ING)
Förderungen
GENOMIT
MitoNET
Lander and Technical University of Munich-Institute for Advanced Study
Excellence Strategy of the Federal Government
DFG Research Infrastructure NGS_CC as part of the Next Generation Sequencing Competence Network
German Federal Ministry of Education and Research (BMBF, Bonn, Germany)-PreDYT (PREdictive biomarkers in DYsTonia)
EJP RD
EU Renewal and Resilience Plan "Large projects for excellent researchers"
Projekt DEAL
European Union
EXIST programme of the German Federal Ministry for Economic Affairs and Climate Action (BMWK)
Project National Institute for Neurological Research (Programme EXCELES)
Deutsche Forschungsgemeinschaft
Czech Ministry of Health-grant
European Union-Next Generation EU
Else Kroner-Fresenius-Stiftung