Combined genomics and proteomics unveils elusive variants and vast aetiologic heterogeneity in dystonia

作者：M. Zech, Ivana Dzinovic, M. Škorvánek, P. Harrer, J. Necpál, R. Kopajtich, Volker Kittke, E. Tilch, Chen Zhao, E. Tsoma, Ugo Sorrentino, E. Indelicato, Antonia M Stehr, A. Saparov, L. Abela, Miriam Adamovičová, A. Afenjar, Birgit Assmann, J. Baloghová, Matthias Baumann, Riccardo Berutti, Zuzana Brežná, M. Brugger, T. Brunet, B. Cogné, Isabel Colangelo, E. Conboy, F. Distelmaier, M. Eckenweiler, B. Garavaglia, Arie Geerlof, E. Graf, A. Hackenberg, D. Harvanová, Bernhard Haslinger, P. Havránková, Georg F. Hoffmann, W. Janzarik, B. Keren, M. Kolníková, K. Kolokotronis, Zuzana Košutzká, A. Koy, M. Krenn, Magdalena Krygier, K. Kušíková, O. Maier, T. Meitinger, C. Mertes, Ivan Milenković, E. Monfrini, A. Mourão, T. Musacchio, M. Nizon, M. Ostrožovičová, Martin Pavlov, I. Příhodová, I. Rektorová, L. Romito, Barbora Rybanska, A. Sadr-Nabavi, Susanne Schwenger, A. Shoeibi, A. Sitzberger, Dmitrii Smirnov, J. Švantnerová, Raushan Tautanova, S. Toelle, O. Ulmanová, F. Vetrini, K. Vill, Matias Wagner, D. Weise, Giovanna Zorzi, A. di Fonzo, K. Oexle, Steffen Berweck, Volker Mall, S. Boesch, B. Schormair, H. Prokisch, R. Jech, Juliane Winkelmann · 发表于：Brain : a journal of neurology · 年份：2025 · DOI：10.1093/brain/awaf059 · 被引用次数：30 · 研究领域：Medicine

Abstract Dystonia is a rare disease trait for which large-scale genomic investigations are still underrepresented. Genetic heterogeneity among patients with unexplained dystonia warrants interrogation of entire genome sequences, but this has not yet been systematically evaluated. To significantly enhance our understanding of the genetic contribution to dystonia, we (re)analysed 2874 whole-exome sequencing (WES), 564 whole-genome sequencing (WGS), as well as 80 fibroblast-derived proteomics datasets, representing the output of high-throughput analyses in 1990 patients and 973 unaffected relatives from 1877 families. Recruitment and precision-phenotyping procedures were driven by long-term collaborations of international experts with access to overlooked populations. By exploring WES data, we found that continuous scaling of sample sizes resulted in steady gains in the number of associated disease genes without plateauing. On average, every second diagnosis involved a gene not previously implicated in our cohort. Second-line WGS focused on a subcohort of undiagnosed individuals with high likelihood of having monogenic forms of dystonia, comprising large proportions of patients with early onset (81.3%), generalized symptom distribution (50.8%) and/or coexisting features (68.9%). We undertook extensive searches for variants in nuclear and mitochondrial genomes to uncover 38 (ultra)rare diagnostic-grade findings in 37 of 305 index patients (12.1%), many of which had remained undet...