Psychopathology and cognitive performance in individuals with membrane-associated guanylate kinase mutations: a functional network phenotyping study
Journal of Neurodevelopmental Disorders
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Baker, K., Scerif, G., Astle, D., Fletcher, P., & Raymond, L. (2015). Psychopathology and cognitive performance in individuals with membrane-associated guanylate kinase mutations: a functional network phenotyping study. Journal of Neurodevelopmental Disorders, 7 (8)https://doi.org/10.1186/s11689-015-9105-x
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.
MAGUK, Intellectual disability, Genetics, Cognition, Psychiatric disorders, DLG3
We thank all study participants and their families for extensive contributions to this project. This study was funded by the Academy of Medical Sciences/Wellcome Trust via a Starter Grant for Clinical Lecturers to KB. KB is funded by a National Institute for Health Research Academic Clinical Lectureship. GS is funded by a Wellcome Trust project grant and a James S. McDonnell Foundation Understanding Human Cognition Scholar Award. DEA is funded by an MRC UK intramural programme (MC-A0606-5PQ41). FLR is funded by the National Institute for Health Research (Cambridge Biomedical Research Centre).
MEDICAL RESEARCH COUNCIL (G0001354)
Wellcome Trust (100140/Z/12/Z)
Wellcome Trust (095692/Z/11/Z)
External DOI: https://doi.org/10.1186/s11689-015-9105-x
This record's URL: https://www.repository.cam.ac.uk/handle/1810/250435
Attribution 2.0 UK: England & Wales
Licence URL: http://creativecommons.org/licenses/by/2.0/uk/
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