title: De novo point mutations in patients diagnosed with ataxic cerebral palsy.
abstract: 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.
authors.affiliation: 1 Wellcome Trust Centre for Human Genetics, University of Oxford, OX3 7BN, UK 2 Universidade Positivo, School of Medicine, Rua Parigot de Souza 5300, 81280-330, Curitiba, Brazil.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Parolin Schnekenberg
authors.affiliation: 3 Centre for Integrative Physiology, Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, UK.
authors.forename: Emma M
authors.initials: EM
authors.lastname: Perkins
authors.affiliation: 4 Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
authors.forename: Jack W
authors.initials: JW
authors.lastname: Miller
authors.affiliation: 4 Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK 5 School of Animal Biology, University of Western Australia, Perth, Australia 6 Section of Physiology & Biochemistry, Department of Experimental Medicine, School of Medicine & Surgery, University of Perugia, P.le Gambuli 1, Edificio D, Piano 106132 San Sisto, Perugia, Italy.
authors.forename: Wayne I L
authors.initials: WI
authors.lastname: Davies
authors.affiliation: 6 Section of Physiology & Biochemistry, Department of Experimental Medicine, School of Medicine & Surgery, University of Perugia, P.le Gambuli 1, Edificio D, Piano 106132 San Sisto, Perugia, Italy.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: D'Adamo
authors.affiliation: 6 Section of Physiology & Biochemistry, Department of Experimental Medicine, School of Medicine & Surgery, University of Perugia, P.le Gambuli 1, Edificio D, Piano 106132 San Sisto, Perugia, Italy 7 Department of Neural and Behavioral Sciences, Pennsylvania State University College of Medicine, Hershey, PA 17033-0850, USA.
authors.forename: Mauro
authors.initials: M
authors.lastname: Pessia
authors.affiliation: 8 CGAT Programme, MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, OX1 3PT, UK.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fawcett
authors.affiliation: 8 CGAT Programme, MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, OX1 3PT, UK.
authors.forename: David
authors.initials: D
authors.lastname: Sims
authors.affiliation: 4 Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
authors.forename: Elodie
authors.initials: E
authors.lastname: Gillard
authors.affiliation: 4 Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
authors.forename: Karl
authors.initials: K
authors.lastname: Hudspith
authors.affiliation: 3 Centre for Integrative Physiology, Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Skehel
authors.affiliation: 9 Oxford Medical Genetics Laboratories, Churchill Hospital, Oxford, OX3 7LJ, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Williams
authors.affiliation: 10 Fraser of Allander Neurosciences Unit, Royal Hospital for Sick Children, Glasgow G3 8SJ, UK.
authors.forename: Mary
authors.initials: M
authors.lastname: O'Regan
authors.affiliation: 11 Department of Paediatrics, Oxford University Hospitals NHS Trust, Oxford, OX3 9DU, UK.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Jayawant
authors.affiliation: 12 Department of Paediatrics, Royal Berkshire Foundation Trust Hospital, Reading, UK.
authors.forename: Rosalind
authors.initials: R
authors.lastname: Jefferson
authors.affiliation: 12 Department of Paediatrics, Royal Berkshire Foundation Trust Hospital, Reading, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hughes
authors.affiliation: 13 Department of Neuropaediatrics, Development and Rehabilitation, University Children's Hospital, Inselspital, Bern, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Lustenberger
authors.affiliation: 1 Wellcome Trust Centre for Human Genetics, University of Oxford, OX3 7BN, UK.
authors.forename: Jiannis
authors.initials: J
authors.lastname: Ragoussis
authors.affiliation: 3 Centre for Integrative Physiology, Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, UK andrea.nemeth@ndcn.ox.ac.uk Mandy.Jackson@ed.ac.uk stephen.tucker@physics.ox.ac.uk.
authors.forename: Mandy
authors.initials: M
authors.lastname: Jackson
authors.affiliation: 14 Clarendon Laboratory, Department of Physics, University of Oxford, OX1 3PU, UK 15 OXION Initiative in Ion Channels and Disease, University of Oxford, OX1 3PT, UK andrea.nemeth@ndcn.ox.ac.uk Mandy.Jackson@ed.ac.uk stephen.tucker@physics.ox.ac.uk.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Tucker
authors.affiliation: 4 Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK 16 Department of Clinical Genetics, Churchill Hospital, Oxford University Hospitals NHS Trust, Oxford, OX3 7LJ, UK andrea.nemeth@ndcn.ox.ac.uk Mandy.Jackson@ed.ac.uk stephen.tucker@physics.ox.ac.uk.
authors.forename: Andrea H
authors.initials: AH
authors.lastname: Németh
mesh_terms: D001259:Ataxia / Q000235:genetics*; D001483:Base Sequence; D002547:Cerebral Palsy / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics*; D008297:Male; D018408:Patch-Clamp Techniques; D017354:Point Mutation; D017422:Sequence Analysis, DNA; D051670:Shaw Potassium Channels / Q000235:genetics*; D013049:Spectrin / Q000235:genetics*
chemical_list: C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; C489594:KCNC3 protein, human; C495133:SPTBN2 protein, human; D051670:Shaw Potassium Channels; D013049:Spectrin
keywords: ataxia; cerebral palsy; de novo; intellectual disability