title: Epilepsy, cognitive deficits and neuroanatomy in males with ZDHHC9 mutations.
abstract: OBJECTIVE
  Systematic investigation of individuals with intellectual disability after genetic diagnosis can illuminate specific phenotypes and mechanisms relevant to common neurodevelopmental disorders. We report the neurological, cognitive and neuroanatomical characteristics of nine males from three families with loss-of-function mutations in ZDHHC9 (OMIM #300799).
  
  
  METHODS
  All known cases of X-linked intellectual disability (XLID) due to ZDHHC9 mutation in the United Kingdom were invited to participate in a study of neurocognitive and neuroimaging phenotypes.
  
  
  RESULTS
  Seven out of nine males with ZDHHC9 mutations had been diagnosed with epilepsy, exceeding epilepsy risk in XLID comparison subjects (P = 0.01). Seizure histories and EEG features amongst ZDHHC9 mutation cases shared characteristics with rolandic epilepsy (RE). Specific cognitive deficits differentiated males with ZDHHC9 mutations from XLID comparison subjects and converged with reported linguistic and nonlinguistic deficits in idiopathic RE: impaired oromotor control, reduced verbal fluency, and impaired inhibitory control on visual attention tasks. Consistent neuroanatomical abnormalities included thalamic and striatal volume reductions and hypoplasia of the corpus callosum.
  
  
  CONCLUSIONS
  Mutations in ZDHHC9 are associated with susceptibility to focal seizures and specific cognitive impairments intersecting with the RE spectrum. Neurocognitive deficits are accompanied by consistent abnormalities of subcortical structures and inter-hemispheric connectivity. The biochemical, cellular and network-level mechanisms responsible for the ZDHHC9-associated neurocognitive phenotype may be relevant to cognitive outcomes in RE.
authors.affiliation: Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge Cambridge, United Kingdom ; MRC Cognitive and Brain Sciences Unit Cambridge, United Kingdom.
authors.forename: Kate
authors.initials: K
authors.lastname: Baker
authors.affiliation: MRC Cognitive and Brain Sciences Unit Cambridge, United Kingdom.
authors.forename: Duncan E
authors.initials: DE
authors.lastname: Astle
authors.affiliation: Department of Experimental Psychology, University of Oxford Oxford, United Kingdom.
authors.forename: Gaia
authors.initials: G
authors.lastname: Scerif
authors.affiliation: MRC Cognitive and Brain Sciences Unit Cambridge, United Kingdom.
authors.forename: Jessica
authors.initials: J
authors.lastname: Barnes
authors.affiliation: Speech and Language Therapy Team, Cleft.Net.East, Addenbrookes Hospital Cambridge, United Kingdom.
authors.forename: Jennie
authors.initials: J
authors.lastname: Smith
authors.affiliation: Speech and Language Therapy Team, Cleft.Net.East, Addenbrookes Hospital Cambridge, United Kingdom.
authors.forename: Georgina
authors.initials: G
authors.lastname: Moffat
authors.affiliation: Department of Radiology, University of Cambridge Cambridge, United Kingdom.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Gillard
authors.affiliation: Developmental Neuroscience Programme, Institute of Child Health, University College London London, United Kingdom.
authors.forename: Torsten
authors.initials: T
authors.lastname: Baldeweg
authors.affiliation: Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge Cambridge, United Kingdom.
authors.forename: F Lucy
authors.initials: FL
authors.lastname: Raymond