{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"volume":["17(1)"],"submitter":["Menden B"],"pubmed_abstract":["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 var"],"journal":["Nature communications"],"pagination":["1698"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12910011"],"repository":["biostudies-literature"],"pubmed_title":["Loss-of-function variants in the CAPN1 activator CD99L2 cause X-linked spastic ataxia."],"pmcid":["PMC12910011"],"pubmed_authors":["Keßler C","Klinkhammer H","Butryn M","Boelmans K","Haack TB","Schutz L","Pereira Sena P","Henn W","Menden B","Buchert R","Radelfahr F","Rautenberg M","Hengel H","Kern J","Haaga M","Bender F","Peralta S","Kehrer M","Philipp M","Nguyen HP","Doebler-Neumann M","Diets IJ","Kehrer C","Wiethoff S","Thieme A","Herzog R","Manka E","Kupper H","Demidov G","Wilke C","Korenke GC","Vielhaber S","Schols L","Hayer S","Numann A","Kellner M","Wilke V","Harmuth F","Baumann S","Kuhlenbaumer G","Schule R","Baumann A","Magg J","Kurth I","Oehl-Jaschkowitz B","Tzschach A","Deschauer M","Raupach K","Herr B","Kaiser N","Pauly MG","Weissert N","Morlot S","Bader I","Incebacak Eltemur RD","Velic A","Cremer K","Winkler J","Kuster A","Traschutz A","Marquardt I","Kuechler A","Sturm M","Lichey N","Weber JJ","Schmidt A","Kohl Z","Ronnefarth M","Catarino CB","Kotzaeridou U","Hinojosa Amaya AB","Deppe J","Timmann D","Glaser D","Spranger S","Synofzik M","Graessner H","Khuller K","Auer-Grumbach M","Linden T","Zeuner KE","Macek B","Klockgether T","Steiner KM","Park J","Cordts I","Wunderlich G","Schlotter-Weigel B","Ehmke N","van Os N","Rattay TW","Kreiss M","Schwaibold EMC","Casadei N","Hellenbroich Y","Lesemann A","Zittel S","Stendel C","Ossowski S","Spahlinger V","Zuchner S","Mehnert K","Husain RA","Deininger N","Fleszar Z","Klopstock T","Falb RJ","Jacobi H","Hehr U","Klebe S","van de Warrenburg B","Dufke C","Riess O","Dufke A","Boschann F","Gerstner L","Regensburger M","Admard J","Hemmer B","Huridou C","Feindt T","Mangold E","Grundmann K","Bevot A","Riess A","Buchzik D","Krawitz P","Grosch S","Zeltner L","Mengel D","Kobeleva X","Distelmaier F","Bischoff A","Gross C","Fath F","Grasshoff U","Saft C","Solve-RD consortium","Elbracht M","Gutschalk A","Laugwitz L","Horber V"],"additional_accession":[]},"is_claimable":false,"name":"Loss-of-function variants in the CAPN1 activator CD99L2 cause X-linked spastic ataxia.","description":"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 var","dates":{"release":"2026-01-01T00:00:00Z","publication":"2026 Feb","modification":"2026-07-16T04:59:07.992Z","creation":"2026-07-09T13:10:05.089Z"},"accession":"S-EPMC12910011","cross_references":{"pubmed":["41690933"],"doi":["10.1038/s41467-026-69337-9"]}}