Chromosomal microarray testing in adults with intellectual disability presenting with comorbid psychiatric disorders

Abstract

Chromosomal copy-number variations (CNVs) are a class of genetic variants highly implicated in the aetiology of neurodevelopmental disorders, including intellectual disabilities (ID), schizophrenia and autism spectrum disorders (ASD). Yet the majority of adults with idiopathic ID presenting to psychiatric services have not been tested for CNVs. We undertook genome-wide chromosomal microarray analysis (CMA) of 202 adults with idiopathic ID recruited from community and in-patient ID psychiatry services across England. CNV pathogenicity was assessed using standard clinical diagnostic methods and participants underwent comprehensive medical and psychiatric phenotyping. We found an 11% yield of likely pathogenic CNVs (22/202). CNVs at recurrent loci, including the 15q11-q13 and 16p11.2-p13.11 regions were most frequently observed. We observed an increased frequency of 16p11.2 duplications compared with those reported in single-disorder cohorts. CNVs were also identified in genes known to effect neurodevelopment, namely NRXN1 and GRIN2B. Furthermore deletions at 2q13, 12q21.2-21.31 and 19q13.32, and duplications at 4p16.3, 13q32.3-33.3 and Xq24-25 were observed. Routine CMA in ID psychiatry could uncover ~11% new genetic diagnoses with potential implications for patient management. We advocate greater consideration of CMA in the assessment of adults with idiopathic ID presenting to psychiatry services.

Neurodevelopmental risk copy number variants in adults with intellectual disabilities and comorbid psychiatric disorders

“…Previous investigations in this patient group identified a diagnostic yield of 11% CNVs classed as clinically relevant. 19 In this study, utilising data from three European research sites, we replicate this finding with a higher diagnostic yield of 13.0% pathogenic CNVs in 599 participants (or 13.9% with the previously reported cases removed). Given that CMA is being advocated for use in cohorts with schizophrenia, in which the diagnostic yields are lower (between 2.5 and 5%), 34,35 adults with intellectual disabilities presenting to psychiatric services appear to be a group to prioritise for CMA.…”

“…We previously reported a rate of 11% pathogenic CNVs in a subset of 202 of the 247 participants from the England sample. 19 When these 202 individuals are removed from the combined sample the diagnostic yield is 13.9%, thus replicating the initial finding.…”

Delineating the psychiatric and behavioral phenotype of recurrent 2q13 deletions and duplications

“…Additionally, patients with 2q13 CNVs on the DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources (DECIPHER) database (https://decipher.sanger.ac.uk/) were identified and further phenotypic information was sought from responsible clinicians. One participant was also included from a previous investigation of CNVs in adults recruited from ID psychiatry services (Wolfe et al, ). Informants or clinicians were asked whether the participant had taken place in previous research projects, and to the best of our knowledge none of the other patients have been presented in previous studies.…”

Improving access to genetic testing for adults with intellectual disability: A literature review and lessons from a quality improvement project in East London

“…Recent research found that around 10% of adults with presumed idiopathic intellectual disability presenting to psychiatric services had likely neurosusceptibilty variants, with deletions and duplications at 15q11‐q13 and 16p11.2‐p13.11 being most frequently observed (Wolfe et al, ). Other recent research has shown that patients with schizophrenia and neurosusceptibilty variants were significantly more likely to have lower IQs (Lowther et al, ).…”