title: Psychopathology and cognitive performance in individuals with membrane-associated guanylate kinase mutations: a functional network phenotyping study.
abstract: BACKGROUND
  Rare pathogenic variants in membrane-associated guanylate kinase (MAGUK) genes cause intellectual disability (ID) and have recently been associated with neuropsychiatric risk in the non-ID population. However, it is not known whether risk for psychiatric symptoms amongst individuals with ID due to MAGUK gene mutations is higher than expected for the degree of general intellectual impairment, nor whether specific cognitive differences are associated with disruption to this gene functional network.
  
  
  METHODS
  This study addresses these two questions via behavioural questionnaires and cognitive testing, applying quantitative methods previously validated in populations with ID. We compared males with X-linked ID caused by mutations in three MAGUK genes (PAK3, DLG3, OPHN1; n = 9) to males with ID caused by mutations in other X chromosome genes (n = 17). Non-parametric and parametric analyses were applied as appropriate to data.
  
  
  RESULTS
  Groups did not differ in age, global cognitive impairment, adaptive function or epilepsy prevalence. However, individuals with MAGUK gene mutations demonstrated significantly higher psychopathology risks, comprising elevated total problem behaviours, prominent hyperactivity and elevated scores on an autism screening checklist. Despite these overt difficulties, individuals in the MAGUK group performed more accurately than expected for age and intelligence quotient (IQ) on computerised tests of visual attention, convergent with mouse models of MAGUK loss-of-function.
  
  
  CONCLUSIONS
  Our findings support a role for MAGUK genes in influencing cognitive parameters relevant to psychiatric risk. In addition to establishing clear patterns of impairment for this group, our findings highlight the importance of careful phenotyping after genetic diagnosis, showing that gene functional network disruptions can be associated with specific psychopathological risks and cognitive differences within the context of ID.
authors: Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge, CB2 0XY UK.
authors: Kate
authors: K
authors: Baker
authors: Department of Experimental Psychology, University of Oxford, 9 South Parks Road, Oxford, OX1 3UD UK.
authors: Gaia
authors: G
authors: Scerif
authors: MRC Cognition and Brain Sciences Unit, 15 Chaucer Road, Cambridge, CB2 7EF UK.
authors: Duncan E
authors: DE
authors: Astle
authors: Department of Psychiatry, University of Cambridge, Herchel Smith Building for Brain & Mind Sciences, Forvie Site, Robinson Way, Cambridge, CB2 0SZ UK.
authors: Paul C
authors: PC
authors: Fletcher
authors: Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge, CB2 0XY UK.
authors: F Lucy
authors: FL
authors: Raymond
keywords: Cognition; DLG3; Genetics; Intellectual disability; MAGUK; Psychiatric disorders