De novo point mutations in patients diagnosed with ataxic cerebral palsy

Ricardo Parolin Schnekenberg, Emma M Perkins, Jack W Miller, Wayne I L Davies, Maria Cristina D'Adamo, Mauro Pessia, Katherine A Fawcett, David Sims, Elodie Gillard, Karl Hudspith, Paul Skehel, Jonathan Williams, Mary O'Regan, Sandeep Jayawant, Rosalind Jefferson, Sarah Hughes, Andrea Lustenberger, Jiannis Ragoussis, Mandy Jackson, Stephen J TuckerAndrea H Németh

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.

Original languageEnglish
Pages (from-to)1817-1832
Number of pages16
Issue number7
Early online date16 May 2015
Publication statusPublished - 31 Jul 2015

Keywords / Materials (for Non-textual outputs)

  • Ataxia
  • Base Sequence
  • Cerebral Palsy
  • Child
  • Child, Preschool
  • DNA Mutational Analysis
  • Genetic Diseases, Inborn
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Infant
  • Infant, Newborn
  • Inositol 1,4,5-Trisphosphate Receptors
  • Male
  • Patch-Clamp Techniques
  • Point Mutation
  • Sequence Analysis, DNA
  • Shaw Potassium Channels
  • Spectrin


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