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.
Highlights
Intellectual disability (ID) is defined as significant impairments in intellectual and adaptive functioning with onset before the age of 18 years
We have demonstrated that copynumber variations (CNVs) screening using clinically available chromosomal microarray analysis (CMA) offers over one in ten new aetiological diagnoses for adults with idiopathic ID presenting to psychiatric services in the UK
It may be appropriate for ID psychiatrists to offer CMA more routinely in assessment of people with ID and comorbid mental health problems, in forensic settings
Summary
Intellectual disability (ID) is defined as significant impairments in intellectual and adaptive functioning with onset before the age of 18 years. ID is a clinically heterogeneous disorder with a range of genetic and environmental causes. Copynumber variations (CNVs) and single-nucleotide variants in specific genes. There are a wide range of environmental causes, notably perinatal infection and hypoxic injury. Investigation of the cause of ID/developmental delay (DD) predominately occurs at onset in childhood and there is no formalised system of diagnostic review. Genetic testing in adulthood can be carried out by ID psychiatrists and other treating clinicians, such as neurologists. Clinical genetics services are organised regionally in the UK and treating clinicians can make onward referrals for patients and families. Screening for genetic causes of ID has advanced from G-banded karyotyping to high-resolution genome-wide chromosomal microarray analysis (CMA), which is often the recommended first-tier cytogenetic test for DD/ID.[3]
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