biostudies-literatureUnknown17(1)Menden BMost 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 varNature communications1698https://www.ebi.ac.uk/biostudies/studies/S-EPMC12910011biostudies-literatureLoss-of-function variants in the CAPN1 activator CD99L2 cause X-linked spastic ataxia.PMC12910011Keßler CKlinkhammer HButryn MBoelmans KHaack TBSchutz LPereira Sena PHenn WMenden BBuchert RRadelfahr FRautenberg MHengel HKern JHaaga MBender FPeralta SKehrer MPhilipp MNguyen HPDoebler-Neumann MDiets IJKehrer CWiethoff SThieme AHerzog RManka EKupper HDemidov GWilke CKorenke GCVielhaber SSchols LHayer SNumann AKellner MWilke VHarmuth FBaumann SKuhlenbaumer GSchule RBaumann AMagg JKurth IOehl-Jaschkowitz BTzschach ADeschauer MRaupach KHerr BKaiser NPauly MGWeissert NMorlot SBader IIncebacak Eltemur RDVelic ACremer KWinkler JKuster ATraschutz AMarquardt IKuechler ASturm MLichey NWeber JJSchmidt AKohl ZRonnefarth MCatarino CBKotzaeridou UHinojosa Amaya ABDeppe JTimmann DGlaser DSpranger SSynofzik MGraessner HKhuller KAuer-Grumbach MLinden TZeuner KEMacek BKlockgether TSteiner KMPark JCordts IWunderlich GSchlotter-Weigel BEhmke Nvan Os NRattay TWKreiss MSchwaibold EMCCasadei NHellenbroich YLesemann AZittel SStendel COssowski SSpahlinger VZuchner SMehnert KHusain RADeininger NFleszar ZKlopstock TFalb RJJacobi HHehr UKlebe Svan de Warrenburg BDufke CRiess ODufke ABoschann FGerstner LRegensburger MAdmard JHemmer BHuridou CFeindt TMangold EGrundmann KBevot ARiess ABuchzik DKrawitz PGrosch SZeltner LMengel DKobeleva XDistelmaier FBischoff AGross CFath FGrasshoff USaft CSolve-RD consortiumElbracht MGutschalk ALaugwitz LHorber VfalseLoss-of-function variants in the CAPN1 activator CD99L2 cause X-linked spastic ataxia.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 var2026-01-01T00:00:00Z2026 Feb2026-07-16T04:59:07.992Z2026-07-09T13:10:05.089ZS-EPMC129100114169093310.1038/s41467-026-69337-9