The CHD8/CHD7/Kismet family links blood-brain barrier glia and serotonin to ASD-associated sleep defects.

Sleep disturbances in autism and neurodevelopmental disorders are common and adversely affect patient's quality of life, yet the underlying mechanisms are understudied. We found that individuals with mutations in CHD8, among the highest-confidence autism risk genes, or CHD7 suffer from disturbed sleep maintenance. These defects are recapitulated in Drosophila mutants affecting kismet, the sole CHD8/CHD7 ortholog. We show that Kismet is required in glia for early developmental and adult sleep architecture. This role localizes to subperineurial glia constituting the blood-brain barrier. We demonstrate that Kismet-related sleep disturbances are caused by high serotonin during development, paralleling a well-established but genetically unsolved autism endophenotype. Despite their developmental origin, Kismet's sleep architecture defects can be reversed in adulthood by a behavioral regime resembling human sleep restriction therapy. Our findings provide fundamental insights into glial regulation of sleep and propose a causal mechanistic link between the CHD8/CHD7/Kismet family, developmental hyperserotonemia, and autism-associated sleep disturbances.

Intellectual disability and autism spectrum disorders 'on the fly': insights from Drosophila.

Intellectual disability (ID) and autism spectrum disorders (ASD) are frequently co-occurring neurodevelopmental disorders and affect 2-3% of the population. Rapid advances in exome and genome sequencing have increased the number of known implicated genes by threefold, to more than a thousand. The main challenges in the field are now to understand the various pathomechanisms associated with this bewildering number of genetic disorders, to identify new genes and to establish causality of variants in still-undiagnosed cases, and to work towards causal treatment options that so far are available only for a few metabolic conditions. To meet these challenges, the research community needs highly efficient model systems. With an increasing number of relevant assays and rapidly developing novel methodologies, the fruit fly Drosophila melanogaster is ideally positioned to change gear in ID and ASD research. The aim of this Review is to summarize some of the exciting work that already has drawn attention to Drosophila as a model for these disorders. We highlight well-established ID- and ASD-relevant fly phenotypes at the (sub)cellular, brain and behavioral levels, and discuss strategies of how this extraordinarily efficient and versatile model can contribute to 'next generation' medical genomics and to a better understanding of these disorders.

Genome-wide copy number variation analysis in adult attention-deficit and hyperactivity disorder.

Attention-deficit and hyperactivity disorder (ADHD) is a common psychiatric disorder with a worldwide prevalence of 5-6% in children and 4.4% in adults. Recently, copy number variations (CNVs) have been implicated in different neurodevelopmental disorders such as ADHD. Based on these previous reports that focused on pediatric cohorts, we hypothesize that structural variants may also contribute to adult ADHD and that such genomic variation may be enriched for CNVs previously identified in children with ADHD. To address this issue, we performed for the first time a whole-genome CNV study on 400 adults with ADHD and 526 screened controls. In agreement with recent reports in children with ADHD or in other psychiatric disorders, we identified a significant excess of insertions in ADHD patients compared to controls. The overall rate of CNVs >100 kb was 1.33 times higher in ADHD subjects than in controls (p = 2.4e-03), an observation mainly driven by a higher proportion of small events (from 100 kb to 500 kb; 1.35-fold; p = 1.3e-03). These differences remained significant when we considered CNVs that overlap genes or when structural variants spanning candidate genes for psychiatric disorders were evaluated, with duplications showing the greatest difference (1.41-fold, p = 0.024 and 2.85-fold, p = 8.5e-03, respectively). However, no significant enrichment was detected in our ADHD cohort for childhood ADHD-associated CNVs, CNVs previously identified in at least one ADHD patient or CNVs previously implicated in autism or schizophrenia. In conclusion, our study provides tentative evidence for a higher rate of CNVs in adults with ADHD compared to controls and contributes to the growing list of structural variants potentially involved in the etiology of the disease.