Abstract
BackgroundRare 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.MethodsThis 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.ResultsGroups 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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s11689-015-9105-x) contains supplementary material, which is available to authorized users.
Highlights
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
The current study provides a first exploration of the practicality and utility of this functional networks phenotyping approach, focusing on X-linked intellectual disability genes previously implicated in psychopathology risks and specific aspects of cognition
Demographics MAGUK and X-linked intellectual disability (XLID) comparison groups did not differ in age, severity of global intellectual impairment as estimated by Vineland Adaptive Behaviour Composite score, gross motor ability or history of epilepsy (Table 1)
Summary
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 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. Many studies have described psychiatric and cognitive phenotypes in relatively frequent genetic causes of ID such as 22q11.2 deletion syndrome and Fragile X syndrome, there have been remarkably few comparative studies of psychopathology and cognitive function in rare single gene causes of ID Such studies provide important prognostic information for clinicians and families and are the starting point for experimental studies of potential therapeutic relevance. This study set out to establish whether classification of cases according to the molecular functional network of the causative gene mutation, coupled with theoretically guided post-genomic phenotyping, might identify network-associated psychiatric risks and cognitive mechanisms, a key step towards linking genetic diagnosis to mental health and, improving outcomes in ID
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