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

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

The Role of Genetics in Bipolar Disorder

none1noBipolar disorder (BP) is a highly heritable disease, with heritability estimated between 60 and 85% by twin studies. The underlying genetic architecture was poorly understood for years since the available technology was limited to the candidate gene approach that did not allow to explore the contribution of multiple loci throughout the genome. BP is a complex disorder, which pathogenesis is influenced by a number of genetic variants, each with small effect size, and environmental exposures. Genome-wide association studies (GWAS) provided meaningful insights into the genetics of BP, including replicated genetic variants, and allowed the development of novel multi-marker methods for gene/pathway analysis and for estimating the genetic overlap between BP and other traits. However, the existing GWAS had also relevant limitations. Notably insufficient statistical power and lack of consideration of rare variants, which may be responsible for the relatively low heritability explained (~20% in the largest GWAS) compared to twin studies. The availability of data from large biobanks and automated phenotyping from electronic health records or digital phenotyping represent key steps for providing samples with adequate power for genetic analysis. Next-generation sequencing is becoming more and more feasible in terms of costs, leading to the rapid growth in the number of samples with whole-genome or whole-exome sequence data. These recent and unprecedented resources are of key importance for a more comprehensive understanding of the specific genetic factors involved in BP and their mechanistic action in determining disease onset and prognosis.mixedFabbri C.Fabbri C