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Autism spectrum disorder is typical of the majority of neuropsychiatric syndromes in that it is defined by signs and symptoms, rather than by aetiology. Not surprisingly, the causes of this complex human condition are manifold and include a substantial genetic component. Recent developments in gene-hunting technologies and methods, and the resulting plethora of genetic findings, promise to open new avenues to understanding of disease pathophysiology and to contribute to improved clinical management. Despite remarkable genetic heterogeneity, evidence is emerging for converging pathophysiology in autism spectrum disorder, but how this notion of convergent pathways will translate into therapeutics remains to be established. Leveraging genetic findings through advances in model systems and integrative genomic approaches could lead to the development of new classes of therapies and a personalised approach to treatment.

This review addresses the issues that attend gene discovery in autism spectrum disorders (ASDs). It summarizes recent findings in human genetics and their relevance to models of pathology, highlights the issues raised by the apparent convergence of ASD genetic risks with distinct psychiatric disorders, and considers the interaction of neurobiology and genetics in our understanding of social disability syndromes. Recent advances in the genetics of autism spectrum disorders (ASDs) are offering new valuable insights into molecular and cellular mechanisms of pathology. At the same time, the emerging data challenge long-standing diagnostic conventions and the notion of phenotypic specificity. This review addresses the particular issues that attend gene discovery in neuropsychiatric and neurodevelopmental disorders and ASDs in particular, summarizes recent findings in human genetics broadly that are driving the reevaluation of the conventional wisdom regarding the allelic architecture of common psychiatric conditions, reviews selected discoveries in ASDs and their relevance to models of pathology, highlights the conceptual and practical issues raised by the observation of a convergence of ASD genetic risks with distinct psychiatric disorders, and considers the important interplay of studies of neurobiology and genetics in clarifying and extending our understanding of social disability syndromes.

Expression patterns of the diverse genes disrupted in autism spectrum disorders in the developing brain give a fresh perspective on the underlying biology. Autism spectrum disorders (ASD) are a genetically and phenotypically heterogeneous group of syndromes defined by fundamental impairments in social reciprocity and language development accompanied by highly restrictive interests and/or repetitive behaviors. Recent advances in genetics, genomics, developmental neurobiology, systems biology, monogenic neurodevelopment syndromes, and induced pluripotent stem cells (iPSC) are now offering remarkable insights into their etiologies and converging to provide a clear and immediate path forward from the bench to the bedside.

Recent studies implicate chromatin modifiers in autism spectrum disorder (ASD) through the identification of recurrent de novo loss of function mutations in affected individuals. ASD risk genes are co-expressed in human midfetal cortex, suggesting that ASD risk genes converge in specific regulatory networks during neurodevelopment. To elucidate such networks, we identify genes targeted by CHD8, a chromodomain helicase strongly associated with ASD, in human midfetal brain, human neural stem cells (hNSCs) and embryonic mouse cortex. CHD8 targets are strongly enriched for other ASD risk genes in both human and mouse neurodevelopment, and converge in ASD-associated co-expression networks in human midfetal cortex. CHD8 knockdown in hNSCs results in dysregulation of ASD risk genes directly targeted by CHD8. Integration of CHD8-binding data into ASD risk models improves detection of risk genes. These results suggest loss of CHD8 contributes to ASD by perturbing an ancient gene regulatory network during human brain development. Autism genes converge in midfetal cortical co-expression networks, and chromatin regulators such as CHD8 are increasingly associated with autism spectrum disorder (ASD). Here the authors map CHD8 targets in developing brain, and find that CHD8 directly regulates other ASD risk genes during human neurodevelopment.

De novo mutations affect risk for many diseases and disorders, especially those with early-onset. An example is autism spectrum disorders (ASD). Four recent whole-exome sequencing (WES) studies of ASD families revealed a handful of novel risk genes, based on independent de novo loss-of-function (LoF) mutations falling in the same gene, and found that de novo LoF mutations occurred at a twofold higher rate than expected by chance. However successful these studies were, they used only a small fraction of the data, excluding other types of de novo mutations and inherited rare variants. Moreover, such analyses cannot readily incorporate data from case-control studies. An important research challenge in gene discovery, therefore, is to develop statistical methods that accommodate a broader class of rare variation. We develop methods that can incorporate WES data regarding de novo mutations, inherited variants present, and variants identified within cases and controls. TADA, for Transmission And De novo Association, integrates these data by a gene-based likelihood model involving parameters for allele frequencies and gene-specific penetrances. Inference is based on a Hierarchical Bayes strategy that borrows information across all genes to infer parameters that would be difficult to estimate for individual genes. In addition to theoretical development we validated TADA using realistic simulations mimicking rare, large-effect mutations affecting risk for ASD and show it has dramatically better power than other common methods of analysis. Thus TADA's integration of various kinds of WES data can be a highly effective means of identifying novel risk genes. Indeed, application of TADA to WES data from subjects with ASD and their families, as well as from a study of ASD subjects and controls, revealed several novel and promising ASD candidate genes with strong statistical support.

The co-occurrence of autism and gastrointestinal distress is well-established, yet the molecular underpinnings remain unknown. The identification of high-confidence, large-effect autism genes offers the opportunity to identify convergent, underlying biology by studying these genes in the context of the gastrointestinal system. Here we show that the expression of these genes is enriched in human prenatal gut neurons and their migratory progenitors, suggesting that the development and/or function of these neurons may be disrupted by autism-associated genetic variants, leading to gastrointestinal dysfunction. Here we document the prevalence of gastrointestinal issues in patients with large-effect variants in sixteen autism genes, highlighting dysmotility, consistent with potential enteric neuron dysfunction. Using Xenopus tropicalis , we individually target five of these genes ( SYNGAP1 , CHD8 , SCN2A , CHD2 , and DYRK1A ) and observe disrupted enteric neuronal progenitor migration for each. Further analysis of DYRK1A reveals that perturbation causes gut dysmotility in vivo, which can be ameliorated by treatment with either of two serotonin signaling modulators, identified by in vivo drug screening. This work suggests that atypical development of enteric neurons contributes to the gastrointestinal distress commonly seen in individuals with autism and that serotonin signaling may be a productive therapeutic pathway. Gastrointestinal distress is common among individuals with autism. Here, authors show that autism gene variants disrupt enteric neuron migration and cause gut dysmotility. They identify a common SSRI that can ameliorate this dysmotility in Xenopus .

Susceptibility to Tourette's syndrome is known to have a genetic influence. This study, of a nonconsanguineous family in which the father and his eight children are affected by the disorder, implicates a deficit in L-histidine decarboxylase activity as one potential cause of the disorder. This study of a nonconsanguineous family in which the father and his eight children are affected by Tourette's syndrome implicates a deficit in L-histidine decarboxylase activity as one potential cause of the disorder. Tourette's syndrome is characterized by childhood onset, waxing and waning symptomatology, and typically, improvement in adulthood. The molecular underpinnings of the disorder remain uncertain, although multiple lines of evidence suggest involvement of dopaminergic neurotransmission and abnormalities involving cortical–striatal–thalamic–cortical circuitry. 1 Current treatment focuses on tic reduction and management of prevalent coexisting conditions such as obsessive–compulsive disorder and attention deficit–hyperactivity disorder. However, therapeutic options have limited efficacy and may carry clinically significant side effects. Consequently, the development of new treatments based on an improved understanding of disease pathophysiology is a high priority. 2 The large genetic contribution to Tourette's syndrome is well established. . . .

More than a hundred genes have been identified that, when disrupted, impart large risk for autism spectrum disorder (ASD). Current knowledge about the encoded proteins — although incomplete — points to a very wide range of developmentally dynamic and diverse biological processes. Moreover, the core symptoms of ASD involve distinctly human characteristics, presenting challenges to interpreting evolutionarily distant model systems. Indeed, despite a decade of striking progress in gene discovery, an actionable understanding of pathobiology remains elusive. Increasingly, convergent neuroscience approaches have been recognized as an important complement to traditional uses of genetics to illuminate the biology of human disorders. These methods seek to identify intersection among molecular-level, cellular-level and circuit-level functions across multiple risk genes and have highlighted developing excitatory neurons in the human mid-gestational prefrontal cortex as an important pathobiological nexus in ASD. In addition, neurogenesis, chromatin modification and synaptic function have emerged as key potential mediators of genetic vulnerability. The continued expansion of foundational ‘omics’ data sets, the application of higher-throughput model systems and incorporating developmental trajectories and sex differences into future analyses will refine and extend these results. Ultimately, a systems-level understanding of ASD genetic risk holds promise for clarifying pathobiology and advancing therapeutics.A large number of genes have been associated with risk of developing autism spectrum disorder (ASD). In this Review, State and colleagues examine the genetics and genomics of ASD and discuss findings from convergent neuroscience approaches that aim to understand how such genes may contribute to ASD pathobiology.

Psychiatric disorders are highly prevalent, often devastating diseases that negatively impact the lives of millions of people worldwide. Although their etiological and diagnostic heterogeneity has long challenged drug discovery, an emerging circuit-based understanding of psychiatric illness is offering an important alternative to the current reliance on trial and error, both in the development and in the clinical application of treatments. Here we review new and emerging treatment approaches, with a particular emphasis on the revolutionary potential of brain-circuit-based interventions for precision psychiatry. Limitations of circuit models, challenges of bringing precision therapeutics to market and the crucial advances needed to overcome these obstacles are presented. This Review provides a timely overview of new technological advances and treatment approaches, with a particular emphasis on brain-circuit-based interventions for precision psychiatry.

The combination of family-based linkage analysis with high-throughput sequencing is a powerful approach to identifying rare genetic variants that contribute to genetically heterogeneous syndromes. Using parametric multipoint linkage analysis and whole exome sequencing, we have identified a gene responsible for microcephaly (MCP), severe visual impairment, intellectual disability, and short stature through the mapping of a homozygous nonsense alteration in a multiply-affected consanguineous family. This gene, DIAPH1, encodes the mammalian Diaphanous-related formin (mDia1), a member of the diaphanous-related formin family of Rho effector proteins. Upon the activation of GTP-bound Rho, mDia1 generates linear actin filaments in the maintenance of polarity during adhesion, migration, and division in immune cells and neuroepithelial cells, and in driving tangential migration of cortical interneurons in the rodent. Here, we show that patients with a homozygous nonsense DIAPH1 alteration (p.Gln778*) have MCP as well as reduced height and weight. diap1 (mDia1 knockout (KO))-deficient mice have grossly normal body and brain size. However, our histological analysis of diap1 KO mouse coronal brain sections at early and postnatal stages shows unilateral ventricular enlargement, indicating that this mutant mouse shows both important similarities as well as differences with human pathology. We also found that mDia1 protein is expressed in human neuronal precursor cells during mitotic cell division and has a major impact in the regulation of spindle formation and cell division.