No abstract

New technologies enabling genome-wide interrogation have led to a large and rapidly growing number of autism spectrum disorder (ASD) candidate genes. Although encouraging, the volume and complexity of these data make it challenging for scientists, particularly non-geneticists, to comprehensively evaluate available evidence for individual genes. Described here is the Gene Scoring module within SFARI Gene 2.0 (https://gene.sfari.org/autdb/GS_Home.do), a platform developed to enable systematic community driven assessment of genetic evidence for individual genes with regard to ASD.

Autism spectrum disorders (ASDs) are common and clinically heterogeneous neurodevelopmental disorders. Gastrointestinal disorders and associated symptoms are commonly reported in individuals with ASDs, but key issues such as the prevalence and best treatment of these conditions are incompletely understood. A central difficulty in recognizing and characterizing gastrointestinal dysfunction with ASDs is the communication difficulties experienced by many affected individuals. A multidisciplinary panel reviewed the medical literature with the aim of generating evidence-based recommendations for diagnostic evaluation and management of gastrointestinal problems in this patient population. The panel concluded that evidence-based recommendations are not yet available. The consensus expert opinion of the panel was that individuals with ASDs deserve the same thoroughness and standard of care in the diagnostic workup and treatment of gastrointestinal concerns as should occur for patients without ASDs. Care providers should be aware that problem behavior in patients with ASDs may be the primary or sole symptom of the underlying medical condition, including some gastrointestinal disorders. For these patients, integration of behavioral and medical care may be most beneficial. Priorities for future research are identified to advance our understanding and management of gastrointestinal disorders in persons with ASDs. Pediatrics 2010;125:S1-S18

There is strong evidence for a genetic predisposition to autism and an intense interest in discovering heritable risk factors that disrupt gene function. Based on neurobiological findings and location within a chromosome 7q31 autism candidate gene region, we analyzed the gene encoding the pleiotropic MET receptor tyrosine kinase in a family based study of autism including 1,231 cases. MET signaling participates in neocortical and cerebellar growth and maturation, immune function, and gastrointestinal repair, consistent with reported medical complications in some children with autism. Here, we show genetic association (P ‫؍‬ 0.0005) of a common C allele in the promoter region of the MET gene in 204 autism families. The allelic association at this MET variant was confirmed in a replication sample of 539 autism families (P ‫؍‬ 0.001) and in the combined sample (P ‫؍‬ 0.000005). Multiplex families, in which more than one child has autism, exhibited the strongest allelic association (P ‫؍‬ 0.000007). In case-control analyses, the autism diagnosis relative risk was 2.27 (95% confidence interval: 1.41-3.65; P ‫؍‬ 0.0006) for the CC genotype and 1.67 (95% confidence interval: 1.11-2.49; P ‫؍‬ 0.012) for the CG genotype compared with the GG genotype. Functional assays showed that the C allele results in a 2-fold decrease in MET promoter activity and altered binding of specific transcription factor complexes. These data implicate reduced MET gene expression in autism susceptibility, providing evidence of a previously undescribed pathophysiological basis for this behaviorally and medically complex disorder.autism spectrum disorder ͉ association ͉ candidate gene ͉ hepatocyte growth factor ͉ hepatocyte growth factor receptor

Autism spectrum disorder (ASD) is a common neurodevelopmental disorder with high heritability. Here, we discuss data supporting the view that there are at least two distinct genetic etiologies for ASD: rare, private (de novo) single gene mutations that may have a large effect in causing ASD; and inherited, common functional variants of a combination of genes, each having a small to moderate effect in increasing ASD risk. It also is possible that a combination of the two mechanisms may occur in some individuals with ASD. We further discuss evidence from individuals with a number of different neurodevelopmental syndromes, in which there is a high prevalence of ASD, that some private mutations and common variants converge on dysfunctional ERK and PI3K signaling, which negatively impacts neurodevelopmental events regulated by some receptor tyrosine kinases.Autism spectrum disorder (ASD) is a syndrome characterized by a triad of core deficits: disturbances in social behavior, atypical verbal and nonverbal communication, and restricted interests that can be accompanied by repetitive behavior. The clinical diagnosis, which includes individuals with any one of a spectrum of neurodevelopmental conditions (including autism, Rett syndrome, pervasive developmental disorder-not otherwise specified, and Asperger syndrome), is made in 1 of every 150 individuals and is four times more prevalent in boys than girls (1). While ASD is among the most heritable psychiatric disorders defined in the Diagnostic and statistical manual of mental disorders (4th edition) (2), it is not a static or simple disorder with fixed effects on a circumscribed age. Instead, equally fundamental facets of pathology emerge at different points of maturation of the child. Moreover, the disorder does not result in immutable social and cognitive deficits, but rather the core symptoms typically change over time and to different degrees. Co-occurring medical conditions (sleep problems, epilepsy, and gastrointestinal symptoms) and psychiatric disturbances (anxiety, obsessive-compulsive disorder, and aggression) are common and can appear at different ages in children on the spectrum.Contemporary hypotheses of the causes of ASD often include experience-dependent processes through which atypical gene-by-environment (G X E) interactions yield pathophysiology in later emerging systems that underlie social and communication competencies. The later emergence of symptoms is consistent with the concept that developmental differentiation, whether at the cellular, circuit, or systems level, occurs from the bottom up; behavior develops from basic sensory and perceptual systems that feed into higher integration centers (3-5). Impairments in initial basic processes become expressed in ever more complex systems, with the population heterogeneity of the clinical features of ASD expected to increase from infancy to childhood and through adolescence. However, it is not clear whether the factors that contribute to the developmental diversification and phenotypic heterogeneity of...