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

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 undetected due to methodological inferiority of WES or pipeline limitations. WGS-identified elusive variations included alterations in exons poorly covered by WES, RNA-gene variants, mitochondrial-DNA mutations, small copy-number variants, complex rearranged genome structure and short tandem repeats. For improved variant interpretation in WGS-inconclusive cases, we employed systematic integration of quantitative proteomics. This aided in verifying diagnoses related to technically challenging variants and in upgrading a variant of uncertain significance (3 of 70 WGS-inconclusive index patients, 4.3%). Further, unsupervised proteomic outlier analysis supplemented with transcriptome sequencing revealed pathological gene underexpression induced by transcript disruptions in three more index patients with underlying (deep) intronic variants (3/70, 4.3%), highlighting the potential for targeted antisense-oligonucleotide therapy development. Finally, trio-WGS prioritized a de novo missense change in the candidate PRMT1, encoding a histone methyltransferase. Data-sharing strategies supported the discovery of three distinct PRMT1 de novo variants in four phenotypically similar patients, associated with loss-of-function effects in in vitro assays. This work underscores the importance of continually expanding sequencing cohorts to characterize the extensive spectrum of gene aberrations in dystonia. We show that a pool of unresolved cases is amenable to WGS and complementary multi-omic studies, directing advanced aetiopathological concepts and future diagnostic-practice workflows for dystonia.

Authors

Institutions

Publication Details

Journal
Brain
Published
2025-02-12
DOI
https://doi.org/10.1093/brain/awaf059
Citations
15
Primary Topic
Botulinum Toxin and Related Neurological Disorders
Type
article
Field-Weighted Citation Impact
20.84

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

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

Denisa Harvanová, Matthias Baumann, Jana Svantnerova, Melanie Brügger et al.
15 citations
Brain
Botulinum Toxin and Related Neurological Disorders
20.84
article

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

Denisa Harvanová, Matthias Baumann, Jana Svantnerova, Melanie Brügger, Riccardo Berutti, Isabel Colangelo, Thomas Meitinger, Iva Příhodová, Boris Keren, Ariane Sadr‐Nabavi, Eugenia Tsoma, Janette Baloghová, Theresa Brunet, Irena Rektorová, Petra Havránková, Miriam Adamovičová, Dmitrii Smirnov, Ivan Milenković, Barbara Garavaglia, Volker Mall, Chen Zhao, Matthias Eckenweiler, Oliver Maier, Magdalena Krygier, Olga Ulmanová, Konstantinos Kolokotronis, Anne Koy, André Mourão, Francesco Vetrini, Elisabetta Indelicato, Volker Kittke, Mathilde Nizon, Miriam Kolníková, David Weise, Philip Harrer, Elisabeth Graf, Robert Jech, Erin Conboy, Wibke G. Janzarik, Erik Tilch, Arie Geerlof, Holger Prokisch, Edoardo Monfrini, Annette Hackenberg, Sylvia Boesch, Matias Wagner, Miriam Ostrožovičová, Sandra P. Toelle, Christian Mertes, Alexandra Sitzberger, Lucia Abela, Katharina Vill, Thomas Musacchio, Alessio Di Fonzo, Susanne Schwenger, Katarína Kušíková, Luigi Romito, Bernhard Haslinger, Steffen Berweck, Ján Necpál, Ivana Dzinovic, Martin Krenn, Ugo Sorrentino, Zuzana Košutzká, Robert Kopajtich, Michael Zech, Konrad Oexle, Matěj Škorvánek, Giovanna Zorzi, Georg F. Hoffmann, Barbara Schormair, Ali Shoeibi, Benjamin Cogné, Alice Saparov, Alexandra Afenjar, A. Stehr, Martin Pavlov, Birgit Assmann, Zuzana Brežná, Barbora Rybanska, Raushana Tautanova
article en
15 citations

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 undetected due to methodological inferiority of WES or pipeline limitations. WGS-identified elusive variations included alterations in exons poorly covered by WES, RNA-gene variants, mitochondrial-DNA mutations, small copy-number variants, complex rearranged genome structure and short tandem repeats. For improved variant interpretation in WGS-inconclusive cases, we employed systematic integration of quantitative proteomics. This aided in verifying diagnoses related to technically challenging variants and in upgrading a variant of uncertain significance (3 of 70 WGS-inconclusive index patients, 4.3%). Further, unsupervised proteomic outlier analysis supplemented with transcriptome sequencing revealed pathological gene underexpression induced by transcript disruptions in three more index patients with underlying (deep) intronic variants (3/70, 4.3%), highlighting the potential for targeted antisense-oligonucleotide therapy development. Finally, trio-WGS prioritized a de novo missense change in the candidate PRMT1, encoding a histone methyltransferase. Data-sharing strategies supported the discovery of three distinct PRMT1 de novo variants in four phenotypically similar patients, associated with loss-of-function effects in in vitro assays. This work underscores the importance of continually expanding sequencing cohorts to characterize the extensive spectrum of gene aberrations in dystonia. We show that a pool of unresolved cases is amenable to WGS and complementary multi-omic studies, directing advanced aetiopathological concepts and future diagnostic-practice workflows for dystonia.

BrainVol. 148(8)
Centre National de la Recherche Scientifique (FR), Central European Institute of Technology (CZ), University of Padua (IT), Innsbruck Medical University (AT), Leipzig University of Applied Sciences (DE), Inserm (FR), University of Freiburg (DE), Mashhad University of Medical Sciences (IR), University of Cologne (DE), University of Milan (IT), Universität Innsbruck (AT), University of Zurich (CH), University of St.Gallen (CH), University of Pavol Jozef Šafárik (SK), Charles University (CZ), Masaryk University (CZ), Heidelberg University (DE), Center for Advanced Studies Research and Development in Sardinia (IT), University Medical Center Freiburg (DE), University Hospital Heidelberg (DE), TUM Klinikum (DE), Academic Center for Education, Culture and Research (IR), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), Helmholtz Zentrum München (DE), LMU Klinikum (DE), Centre Hospitalier Universitaire de Nantes (FR), Sorbonne Université (FR), German Center for Pediatric and Adolescent Rheumatology (DE), Hôpital Armand-Trousseau (FR), Ospedale Maggiore (IT), Asklepios Fachklinikum Brandenburg (DE), Düsseldorf University Hospital (DE), Central European Institute of Technology – Masaryk University (CZ), Railway Repair and Engineering Works (Slovakia) (SK), Comprehensive Cancer Center Vienna (AT), Schön Klinik Vogtareuth (DE), University Hospital Bratislava (SK), Assistance Publique – Hôpitaux de Paris (FR), Technická univerzita vo Zvolene (SK), Center for Children (US), Kliniken des Bezirks Oberbayern (DE), Deutsche Akademie für Kinder- und Jugendmedizin (DE), Univerzitná Nemocnica Louisa Pasteura (SK), Centre for Biomedical Network Research on Rare Diseases (ES), Munich Cluster for Systems Neurology (DE), Pitié-Salpêtrière Hospital (FR), University Hospital Leipzig (DE), Universitätsklinikum Würzburg (DE), University Children's Hospital Zurich (CH), Deutsches Jugendinstitut (DE), St. Anne's University Hospital Brno (CZ), Institute for Advanced Study (DE), Medizinische Zentrum für Gesundheit (DE), Astana Medical University (KZ), Institut du Thorax (FR), Thomayer University Hospital (CZ), Zentrum für Kinderheilkunde (DE), Global Health Research Center of Central Asia (KZ), Deutsches Diabetes-Zentrum e.V. (DE), University Hospital Cologne (DE), Génétique Médicale & Génomique Fonctionelle (FR), Ferrari (Italy) (IT), General University Hospital in Prague (CZ), Fondazione IRCCS Istituto Neurologico Carlo Besta (IT), Indiana University School of Medicine, Heinrich Heine University Düsseldorf (DE), Indiana University – Purdue University Indianapolis (US), Technical University of Munich (DE), Comenius University Bratislava (SK), Gdańsk Medical University (PL), Medical University of Vienna (AT), Uzhhorod National University (UA), Ludwig-Maximilians-Universität München (DE), Leipzig University (DE), Nantes Université (FR)
Deutsche Forschungsgemeinschaft, Deutsche Dystonie Gesellschaft
Partnerships for the goals
Openalex Percentile: Top 0%
Botulinum Toxin and Related Neurological Disorders
20.84
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.