Most patients with a rare movement disorder (MD) do not receive a molecular diagnosis, and the underlying genetic variants and mediating genes remain elusive. Here, we evaluate the diagnostic accuracy of conventional and next-generation sequencing-based genetic testing strategies in a cohort of 2,811 individuals with ataxia, spastic paraplegia and dystonia. Exome sequencing establishes genetic diagnoses in 19.3% of cases, and specificity of phenotypic features and age at testing are positive predictors. Genome analysis ‘beyond the exome’ increases the diagnostic yield by 7.5%, mostly due to the improved detection of structural variants and repeat expansions. Unsolved cases are included in the Solve-RD cohort and subjected to gene-burden analysis, providing evidence for loss-of-function variants in X-chromosomal
CD99L2
causing spastic ataxia. Cellular studies show that the transmembrane protein CD99L2 occurs mainly in a ubiquitinated form and serves as an activating interactor of the calcium-dependent protease CAPN1. Ablation of cytoplasmic or extracellular domains of CD99L2 leads to its intracellular mislocalization and abrogation of its interplay with CAPN1. Transcriptome analysis in CD99L2 patient-derived fibroblasts reveals synaptic function-specific disturbances. Impaired CAPN1 activation and dysregulation of downstream neuronal pathways constitute the likely molecular cause for neurodegeneration.
Here the authors compare genetic testing strategies in rare movement disorders, improve diagnostic yield with genome analysis, and establish
CD99L2
as an X-linked spastic ataxia gene, showing that CD99L2–CAPN1 signaling disruption likely drives neurodegeneration.
- Loss-of-function variants in the CAPN1 activator CD99L2 cause X-linked spastic ataxia
- Benita Menden - University of TübingenRana D. Incebacak Eltemur - Ruhr University BochumGerman Demidov - University of TübingenMarc Sturm - University of TübingenJoohyun Park - University of TübingenChrisovalantou Huridou - University of TübingenFlorian Fath - St. Josef-HospitalAstrid Nümann - Humboldt-Universität zu BerlinAlexander Baumann - University Hospital Schleswig-HolsteinIllja J. Diets - Radboud University NijmegenClaudia Dufke - University of TübingenMartin Regensburger - Universitätsklinikum ErlangenMaria Rönnefarth - Humboldt-Universität zu BerlinVera Wilke - University Children's Hospital TübingenNienke van Os - Radboud University Medical CenterStefan Vielhaber - University Hospital MagdeburgTim W. Rattay - Christian-Albrechts-Universität zu KielZacharias Kohl - University Hospital RegensburgSusana Peralta - University of TübingenPriscila Pereira Sena - University of TübingenMelanie Kellner - University Children's Hospital TübingenNadine Weissert - University Children's Hospital TübingenAndreas Traschütz - Hertie Institute for Clinical Brain ResearchLena Zeltner - University Children's Hospital TübingenKai Boelmans - Universitätsklinikum WürzburgNatalie Deininger - University of TübingenLeon Schütz - University of TübingenCaspar Gross - University of TübingenAna Beatriz Hinojosa Amaya - University of TübingenKatrin Raupach - University of TübingenHolger Hengel - University Children's Hospital TübingenFlorian Harmuth - University of TübingenJakob Admard - University of TübingenIngrid Bader - University of TübingenSarah Baumann - University of TübingenFriedemann Bender - University Children's Hospital TübingenAndrea Bevot - University Children's Hospital TübingenAlmut Bischoff - Friedrich Baur StiftungFelix Boschann - Humboldt-Universität zu BerlinRebecca Buchert - University of TübingenDaniel Buchzik - Evangelisches DiakoniekrankenhausNicolas Casadei - University of TübingenClaudia B. Catarino - Friedrich Baur StiftungIsabell Cordts - Technical University of MunichKirsten Cremer - University Hospital BonnMarion Doebler-Neumann - University Children's Hospital TübingenNadja Ehmke - Humboldt-Universität zu BerlinMiriam Elbracht - Universitätsklinikum AachenRuth J. Falb - University of TübingenThomas Feindt - Klinikum MagdeburgZofia Fleszar - University Children's Hospital TübingenLea Gerstner - University of TübingenDieter Gläser - GenetikumUte Grasshoff - University of TübingenSarah Grosch - University of TübingenKathrin Grundmann - University of TübingenAlexander Gutschalk - Heidelberg UniversityManja Haaga - University Children's Hospital TübingenStefanie Hayer - Department of Neurology, University Hospital TübingenUte Hehr - University Hospital RegensburgYorck Hellenbroich - University Hospital Schleswig-HolsteinWolfram Henn - University of KaiserslauternBarbara Herr - University Medical Center FreiburgRebecca Herzog - University of LübeckVeronka Horber - University Children's Hospital TübingenJonas Deppe - Technical University of MunichNadja Kaiser - University Children's Hospital TübingenChristiane Kehrer - University Children's Hospital TübingenMartin Kehrer - University of TübingenJan Kern - University Children's Hospital TübingenChristoph Keßler - University Children's Hospital TübingenKatharina Khuller - Essen University HospitalHannah Klinkhammer - University of BonnUrania Kotzaeridou - Heidelberg UniversityPeter Krawitz - University of BonnMartina Kreiss - University Hospital BonnHanna Küpper - University Children's Hospital TübingenAlice Kuster - Nantes UniversitéLucia Laugwitz - University Children's Hospital TübingenAnne Lesemann - Humboldt-Universität zu BerlinNadine Lichey - Praxis für Humangenetik TübingenTobias Linden - Carl von Ossietzky Universität OldenburgBoris Macek - University of TübingenJanine Magg - University Children's Hospital TübingenElisabeth Mangold - University Hospital BonnEva Manka - Essen University HospitalIris Marquardt - Carl von Ossietzky Universität OldenburgKarl Mehnert - GenetikumDavid Mengel - University Children's Hospital TübingenSusanne Morlot - Leibniz University HannoverBarbara Oehl-Jaschkowitz - Praxis für Humangenetik TübingenMartje G. Pauly - University of LübeckMelanie Philipp - University of TübingenFlorentine Radelfahr - Friedrich Baur StiftungMaren Rautenberg - University of TübingenAngelika Riess - Institute of Medical Genetics and Applied Genomics, University Hospital TübingenCarsten Saft - Ruhr University BochumBeate Schlotter-Weigel - Ludwig-Maximilians-Universität MünchenAxel Schmidt - University of BonnEva M. C. Schwaibold - Heidelberg UniversityVeronika Spahlinger - University Children's Hospital TübingenStephanie Spranger - Praxis für Humangenetik TübingenKatharina Marie Steiner - Essen University HospitalClaudia Stendel - Friedrich Baur StiftungAndreas Thieme - University of Duisburg-EssenAndreas Tzschach - Institute of Human Genetics, University Hospital FreiburgAna Velic - University of TübingenSarah Wiethoff - Department of Neurology, University Hospital MünsterCarlo Wilke - Hertie Institute for Clinical Brain ResearchStephan Züchner - Dr. John T. Macdonald FoundationSimone Zittel - University Medical Center Hamburg-EppendorfRalf A. Husain - Jena University HospitalMarcus Deschauer - Technical University of MunichFelix Distelmaier - Düsseldorf University HospitalAndreas Dufke - University of TübingenHolm Graessner - University of TübingenBernhard Hemmer - Technical University of MunichHeike Jacobi - Heidelberg UniversityThomas Klockgether - University of BonnThomas Klopstock - German Center for Neurodegenerative DiseasesXenia Kobeleva - University of BonnGeorg-Christoph Korenke - Carl von Ossietzky Universität OldenburgAlma Kuechler - Essen University HospitalGregor Kuhlenbäumer - University Hospital Schleswig-HolsteinIngo Kurth - RWTH Aachen UniversityHuu Phuc Nguyen - Ruhr University BochumGilbert Wunderlich - University of CologneKirsten E. Zeuner - University Hospital Schleswig-HolsteinStephan Klebe - Essen University HospitalMichaela Auer-Grumbach - Vienna General HospitalMichaela Butryn - German Center for Neurodegenerative DiseasesJürgen Winkler - Universitätsklinikum ErlangenDagmar Timmann - University of Duisburg-EssenMatthis Synofzik - Division Translational Genomics of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research and Center of Neurology, University Hospital Tübingen, German Center for Neurodegenerative Diseases (DZNE) Site TübingenBart van de Warrenburg - Radboud University Medical CenterRebecca Schüle - Heidelberg UniversityLudger Schöls - German Center for Neurodegenerative DiseasesStephan Ossowski - University of TübingenOlaf Riess - Africa CenterJonasz J. Weber - University Hospitals of the Ruhr-University of BochumTobias B. Haack - University of TübingenSolve-RD consortium
- Nature communications, Vol.17(1), p.1698
- Nature Publishing Group UK; BERLIN
- 21
- Projekt DEAL
Open Access funding enabled and organized by Projekt DEAL.
- Leadership Department; Miller School of Medicine; John P. Hussman Institute for Human Genomics
- English
- Journal article
- 41690933
- 991033016833402976