1154563_Parolin Schnekenberg,R_2015.pdf (917.4 kB)
De novo point mutations in patients diagnosed with ataxic cerebral palsy
journal contributionposted on 2021-04-20, 01:11 authored by R Parolin Schnekenberg, EM Perkins, JW Miller, Wayne Davies, MC D'Adamo, M Pessia, KA Fawcett, D Sims, E Gillard, K Hudspith, P Skehel, J Williams, M O'Regan, S Jayawant, R Jefferson, S Hughes, A Lustenberger, J Ragoussis, M Jackson, SJ Tucker, AH Németh
© 2015 The Author. Cerebral palsy is a sporadic disorder with multiple likely aetiologies, but frequently considered to be caused by birth asphyxia. Genetic investigations are rarely performed in patients with cerebral palsy and there is little proven evidence of genetic causes. As part of a large project investigating children with ataxia, we identified four patients in our cohort with a diagnosis of ataxic cerebral palsy. They were investigated using either targeted next generation sequencing or trio-based exome sequencing and were found to have mutations in three different genes, KCNC3, ITPR1 and SPTBN2. All the mutations were de novo and associated with increased paternal age. The mutations were shown to be pathogenic using a combination of bioinformatics analysis and in vitro model systems. This work is the first to report that the ataxic subtype of cerebral palsy can be caused by de novo dominant point mutations, which explains the sporadic nature of these cases. We conclude that at least some subtypes of cerebral palsy may be caused by de novo genetic mutations and patients with a clinical diagnosis of cerebral palsy should be genetically investigated before causation is ascribed to perinatal asphyxia or other aetiologies.
This work was supported by CNPq (National Council for Scientific and Technological Development), Brazil, to R.P.S.; by the Wellcome Trust (093077) to M.J. and E.P., part of an Australian Research Council (ARC) grants awarded to W.I.L.D. (Future Fellowship, FT110100176; Discovery Project, DP140102117); grants awarded by Telethon Italy, MIUR-PRIN, Ministry of Health (GGP11188, 20108WT59Y_004 and GR-2009-1580433) to M.P.; KF and DS are funded by the Medical Research Council (UK) Computational Genomics Analysis and Training programme (G1000902). Wellcome Trust Grant 075491/Z/04 to J.R.; grants from the Wellcome Trust to S.J.T. (WT084655MA); and awards to A.H.N. from Ataxia UK, Action Medical Research, the Thomas Smith Charity, the Oxford Partnership Comprehensive Biomedical Research Centre funded by the Department of Health National Institute of Health Research (NIHR) Biomedical Research Centre Programme and the Thames Valley Dementias and Neurodegenerative Diseases Research Network (DeNDRoN), UK.
JournalBrain: a journal of neurology
Pagination16p. (p. 1817-1832)
PublisherOxford University Press
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Science & TechnologyLife Sciences & BiomedicineClinical NeurologyNeurosciencesNeurosciences & Neurologycerebral palsyataxiade novointellectual disabilityNONPROGRESSIVE CONGENITAL ATAXIASPINOCEREBELLAR ATAXIACEREBELLAR HYPOPLASIAMOLECULAR-MECHANISMSSPECTRIN MUTATIONSSEQUENCING REVEALSTYPE-1 MUTATIONSIP3 RECEPTORPROTEINBINDINGHumansCerebral PalsyAtaxiaGenetic Diseases, InbornSpectrinPatch-Clamp TechniquesSequence Analysis, DNADNA Mutational AnalysisBase SequencePoint MutationChildChild, PreschoolInfantInfant, NewbornMaleShaw Potassium ChannelsInositol 1,4,5-Trisphosphate ReceptorsHigh-Throughput Nucleotide SequencingNeurology & Neurosurgery