LAUSR

Background Rare Copy Number Variants (CNVs) are known to be important risk factors for Neurodevelopmental Disorders (NDDs). Pathogenic CNVs identified to date confer moderate to large effect sizes (OR 1.5 - 50 or higher) and have important clinical implications for affected individuals and at-risk family members. Several studies have investigated pathogenic CNVs in paediatric cohorts with Intellectual Disabilities (ID), or in schizophrenia/Autism Spectrum Disorders (ASD) only samples. However, adult populations – in particular those who exhibit ID and co-morbid psychiatric diagnoses – are less well characterised. Methods We undertook Chromosomal Microarray Analysis (CMA) and clinical phenotyping in 599 adults with ID and co-morbid psychiatric disorders recruited from three European research sites (Catalonia, Spain; Leuven, Belgium; and England, UK). We compared the carrier frequency of 63 established NDD CNV risk loci to reported frequencies in healthy controls, schizophrenia and ID/ASD populations. We determine the clinical diagnostic yield of CMA in our sample and describe likely pathogenic CNVs affecting NDD candidate genes. Results We identified 58 carriers of NDD risk CNVs at 23 of the 63 risk loci investigated. The five most frequent CNVs were: 22q11.2 deletion (N=7, 1.2%), 15q11.2 (Prader-Willi syndrome/Angelman syndrome region) duplication (N=6, 1%), 16p11.2 duplication (N=5, 0.8%), 15q13.3 deletion (N=5, 0.8%) and 16p12.1 deletion (N=4, 0.7%). The frequency of NDD risk CNVs was significantly higher in our cohort (10%), compared to healthy controls (1.2%, p Discussion There is a paucity of research on CNVs in adults with ID and co-morbid psychiatric diagnoses. This poses a challenge for genetic counselling of rare CNVs, as descriptions of later-life phenotypes are largely unavailable. In our sample, the largest multi-population sample of its kind to date, we find a significantly higher rate of NDD risk CNVs compared to schizophrenia and ID/ASD only cohorts. Our high diagnostic yield of 13% pathogenic CNVs demonstrates the diagnostic utility of CMA in this patient group. We also find a high yield of likely pathogenic CNVs (21.5%), which enables us to phenotypically characterise rare recurrent CNVs. Increased clinical testing and research in this population should be a priority for both clinicians and researchers in the field of psychiatric genetics.