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David G. Amaral1 and Petrus J. de Vries2 1Department of Psychiatry and Behavioral Sciences, The MIND Institute, UC Davis, Sacramento, California, USA 2Centre for Autism Research in Africa, Division of Child and Adolescent Psychiatry, University of Cape Town, South Africa Last year around this time, in preparation for the INSAR2019 meeting in Montreal, we asked members of the Autism Research editorial board as well as the Associate Editors to write short comments on what they considered to be the major gaps in autism research. The resulting Commentary was well received with nearly 3000 downloads. The INSAR meeting scheduled for Seattle in 2020 was, of course, cancelled due to the coronavirus pandemic. The pandemic has forced the reorganization and rethinking of all science, including autism research. To get a sense of how autism researchers are dealing with this unprecedented situation around the world, we asked for short comments about the situation from editorial board members, Associate Editors and from the INSAR Global Senior Leaders in Autism Research Committee, a relatively new INSAR initiative chaired by Petrus de Vries (South Africa) and Declan Murphy (UK). We will present perspectives by World Health Organization (WHO) Region. Before going further, we must acknowledge that over and above the hardships for autism researchers across the globe, the pandemic has cost so much more to the more than 400,000 families worldwide that have suffered the death of a loved one. We offer our condolences to those families and to those who will befall a similar fate in the future. We also acknowledge the global economic burden of the pandemic, both as a result of COVID‐19 and as a consequence of lockdown. This too will have a major impact on everyone, and perhaps disproportionately so on families who live with disabilities and those in low‐ and middle‐income countries. The contributions that make up the remainder of this commentary are in equal parts frightening and inspiring. On the down side, they talk about the difficulties in conducting autism research when social distancing is in place and when participants must wear masks. How does one recruit young subjects if the ADOS cannot be done with masked individuals? There is also the concern that, given the overall frightening environment of the current situation, it may be difficult to interpret behavioural research results. For example, are measures of anxiety now reflecting a trait of an individual or the state of heightened angst resulting from dealing with the virus? Others worry that the enormous costs of dealing with controlling the spread of the virus will eliminate academic positions and autism research funding in the future. This is a real concern. The state of California has gone from a $14 billion surplus to a projected $54 billion deficit. Public higher education in the state is now slated for a 10% reduction in funding. There are also implications for prevalence of autism in the future. One of the prominent, proposed nongenetic causes of autism is maternal immune activation [Patterson et al., 2011]. Naturally occurring pathogen exposures offer the strongest evidence of environmental etiology. The best example is maternal rubella (German measles) infection during pregnancy. Before development and widespread dissemination of effective vaccines, major pandemics occurred every 10 to 30 years [Duszak, 2009]. The last of these was from 1963 to 1965 and infected an estimated 10 percent of pregnant women, resulting in more than 13,000 fetal or early infant deaths; 20,000 infants born with major birth defects and 10,000 to 30,000 infants born with moderate to severe neurodevelopmental disorders. Stella Chess, a child psychiatrist at New York University, studied 243 children exposed to rubella during pregnancy [Chess, 1971; Chess, 1977] and found that the largest category of neurodevelopmental disorder was intellectual disability, which affected 37 percent of the sample. Nine of these children were also diagnosed with autism; another, without intellectual disability, had a possible diagnosis; and eight a partial syndrome of autism. These numbers would translate to an autism prevalence of 741 per 10,000 rubella‐exposed children, just over seven percent which was strikingly different from the 2‐3 per 10,000 typically found at the time in the general population. It is concerning therefore, that a recent survey of two New York hospitals found that 15% of pregnant woman coming for the delivery of their child were positive for coronavirus [Breslin et al., 2020] and many of these were asymptomatic. Given the inadequate testing in many countries, the true number of pregnant woman infected with the virus may not be known for some time and the implication for the prevalence of autism will undoubtedly be the basis for much future research. But, the contributions below also reflect an up side of resilience and resolve by the autism research community. Many investigators describe how testing and even clinical trials were rapidly converted from in person to telehealth strategies. Development of more efficient and technology driven assessment tools has been fast‐tracked due to the pandemic. Could robots provide a mechanism for providing therapy without the risk of viral exposure? The use of teleconferencing platforms like Zoom have transformed how scientists are communicating their research results leading some to suggest that this may also be a strategy to reduce air travel and global warming in the future. Here too the disparity between access to digital technology in richer countries relative to under resourced countries is amplified. One hopefully positive take‐a‐way message relates to the importance of science in solving problems such as pandemics. The development of diagnostic tests, vaccines and medications related to COVID‐19 highlights the work of the millions of scientists who labor, generally in obscurity, to gather knowledge about the natural world. We hope that you enjoy the thoughtful comments of many of our colleagues who are engaged in research dedicated to decreasing disability in individuals with autism spectrum disorder.

Autism is a neurodevelopmental disorder of complex etiology and is amongst the most heritable of neuropsychiatric disorders while sharing genetic liability with other neurodevelopmental disorders such as intellectual disability (ID). Autism spectrum disorders (ASDs) are defined more broadly and include autism, Asperger syndrome, childhood disintegrative disorder and pervasive developmental disorder not otherwise specified. Under the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition Revised (DSM-IVTR), these disorders are grouped together with Rett syndrome (“Rett’s disorder”) as pervasive developmental disorders. However, Rett syndrome has a reportedly distinct pathophysiology, clinical course, and diagnostic strategy (Levy & Schultz, 2009) and will likely be removed in the impending publication of DSM-V (APA, 2010). The new diagnostic manual will formally adopt the single diagnostic category “ASDs”, which is used here. Reported prevalence rates for ASDs range from 20 (Newschaffer et al. 2007) to 116 (Baird et al., 2006) per 10,000 children, and vary in accordance with diagnostic, sampling, and screening criteria. The Centers for Disease Control and Prevention (CDC) suggest that in the United States, the prevalence of ASDs is 1 in 110 (1/70 in boys and 1/315 in girls) (ADDM, 2009). The three primary characteristics of ASDs are communication impairments, social impairments, and repetitive/stereotyped behaviors. The DSM-IVTR, ICD-10, and many other diagnostic instruments require impairment in each of these domains for a diagnosis of autistic disorder. Within the last decade, a number of major technological developments have transformed our understanding of the genetic causes of autism, and the field continues to evolve rapidly. In this chapter, we will review three approaches to identifying genetic factors that contribute to the pathogenesis of ASDs: 1) common variants and genome-wide association studies (GWAS); 2) rare variants and copy number variation (CNV) studies, and 3) familial forms of autism and the role of next-generation sequencing (NGS) methods. Data from all three approaches underscores the conclusion that autism is a highly complex and heterogeneous disorder, involving a multifactorial etiology. Moreover, it is becoming increasingly apparent that autism is not a unitary disorder, and that the spectrum may consist of any number of different autisms that share similar symptoms or phenotypes. This conclusion has important implications for evaluation and treatment, which are discussed in the conclusion.

Lead poisoning is a continuing crisis impacting learning, neurological and behavioral development in children. This study investigated an important outcome from the environmental lead contamination which cause retardation of infant’s brain development. A total of 30 Swiss albino mice of both sexes were used in this study and divide into three groups consisting 6 female and 4 male in each group. Two groups of mice were given lead treated drinking (30 ppm and 230 ppm respectively) and rat pellets ad libitum and the control mice were supplied normal drinking water and rat pellets ad libitum. At 20-21th days of pregnancy lead-induced female mouse gave birth to a litter of 5-6 pups; whereas, control mouse gave birth to 10-13 pups at a time. Both lead-induced and controlled offspring were found normal; however, some lead-induced offspring were found comparatively smaller than the control one. Autism spectrum disorder behavioral diagnostic tools were used to explore the level of autism, if any. The anxiety assessment marble burying investigation did not reveal any significant differences among the group’s mice. Three chambered social interaction analysis found no significant differences among the mice. Blood serum level of lead for controlled mice were found 0.333mg/dL, whereas, 30 ppm and 230 ppm lead-induced born mice were found 3.833mg/dL and 9.666mg/dL respectively. This study suggested that a genetic predisposition pair with exposure to environmental toxicants play important role in the causes of autism spectrum disorder. Lead is not the pivotal factor of autism development in new born offspring in mice&nbsp

Background: Activity dependent neuroprotective protein (ADNP) syndrome is one of the most common single-gene causes of autism spectrum disorder (ASD) and intellectual disability, however, the phenotypes remain poorly described. Here we examine the sensory reactivity phenotype in children and adolescents with ADNP syndrome. Methods: Twenty-two individuals with ADNP syndrome received comprehensive clinical evaluations including standardized observations, caregiver interviews, and questionnaires to assess sensory reactivity symptoms. Relationships between sensory symptoms and age, sex, ASD, IQ, and adaptive behavior were examined. Genotype-phenotype correlations with the recurrent p.Tyr719* variant were also explored. Results: Sensory reactivity symptoms were observed and reported in all participants. A syndrome-specific phenotype was identified, characterized by high levels of sensory seeking across tactile, auditory, and visual domains. Tactile hyporeactivity, characterized by pain insensitivity, was reported in the majority of participants. Sensory symptoms were identified across individuals regardless of age, sex, IQ, adaptive ability, genetic variant, and most importantly, ASD status. No significant differences were identified between participants with and without the recurrent p.Tyr719* variant on any sensory measure. Conclusions: Sensory reactivity symptoms are a common clinical feature of ADNP syndrome. Quantifying sensory reactivity using existing standardized measures will enhance understanding of sensory reactivity in individuals with ADNP syndrome and will aid in clinical care. The sensory domain may also represent a promising target for treatment in clinical trials.

Duplications of chromosome 16p11.2, even though rare in the general population, are one of the most frequent known genetic causes of autism spectrum disorder and of other neurodevelopmental disorders. However, data about the neuro-behavioral phenotype of these patients are few. We described a sample of children with duplication of chromosome 16p11.2 focusing on the neuro-behavioral phenotype. The five patients reported presented with very heterogeneous conditions as for characteristics and severity, ranging from a learning disorder in a child with normal intelligence quotient to an autism spectrum disorder associated with an intellectual disability. Our case report underlines the wide heterogeneity of the neuropsychiatric phenotypes associated with a duplication of chromosome 16p11.2. Similarly to other copy number variations that are considered pathogenic, the wide variability of phenotype of chromosome 16p11.2 duplication is probably related to additional risk factors, both genetic and not genetic, often difficult to identify and most likely different from case to case.

Although germline de novo copy number variants are a known cause of autism spectrum disorder (ASD), the contribution of mosaic (early-developmental) copy number variants (mCNVs) has not been explored. Here, we assessed the contribution of mCNVs to ASD by ascertaining mCNVs in genotype array intensity data from 12,077 ASD probands and 5,500 unaffected siblings in the Simons Simplex Collection (SSC) and Simons Powering Autism Research for Knowledge (SPARK) cohorts. We detected 46 mCNVs in probands and 19 mCNVs in siblings ranging from 49 kb to 249 Mb and affecting 2.8-73.8% of cells. In both cohorts, probands carried a significant burden of large (>4 Mb) mCNVs (P = 0.043 and P = 6.6 × 10−3 in SSC and SPARK, respectively), which were present in a total of 25 probands but only 1 sibling (OR=11.4, 95% CI=1.5-84.2). Surprisingly, we did not observe mosaic analogues of the short de novo CNVs recurrently observed in ASD. Event size positively correlated with severity of ASD symptoms (P = 0.016), and four probands exhibited clinical symptoms consistent with syndromes previously associated with genes or regions disrupted by their respective mosaic mutations. In analyses of post-mortem brain tissue from 60 additional probands, we further detected and experimentally validated two mCNVs including a complex 10.3 Mb duplication on chromosome 2. These results indicate that mosaic CNVs contribute a previously unexplained component of ASD risk.

Identification of the biological features of autism is essential for designing an efficient treatment and for prevention of the disorder. Though the subject of extensive research, the neurophysiological features of autism remain unclear. One of the proposed biological causes of autism is malfunction of the pineal gland and deficiency of its principal hormone, melatonin. The main function of melatonin is to link and synchronize the body's homeostasis processes to the circadian and seasonal rhythms, and to regulate the sleep-wake cycle. Therefore, pineal dysfunction has been implicated based on the common observation of low melatonin levels and sleep disorders associated with autism. In this perspective, we highlight several recent findings that support the hypothesis of pineal gland/melatonin involvement in autism. Another common symptom of autism is abnormal neuroplasticity, such as cortical overgrowth and dendritic spine dysgenesis. Here, we synthesize recent information and speculate on the possibility that this abnormal neuroplasticity is caused by hyperactivity of endogenous N,N-dimethyltryptamine (DMT). The pineal gland was proposed as the source of DMT in the brain and therefore, our assumption is that besides melatonin deficiency, pineal dysfunction might also play a part in the development of autism through abnormal metabolism of DMT. We hope that this manuscript will encourage future research of the DMT hypothesis and reexamination of several observations that were previously attributed to other factors, to see if they could be related to pineal gland/melatonin malfunction. Such research could contribute to the development of autism treatment by exogenous melatonin and monitored light exposure.

Fragile X syndrome (FXS) is the most common form of familial mental retardation and one of the leading known causes of autism. The mutation responsible for FXS is a large expansion of the CGG repeats in the promoter region of the FMR1 gene resulting in the transcriptional silencing of the gene in the pathophysiology of Fragile X syndrome was hypothesized. 23 male patients affected by Fragile X syndrome (full mutation in the FMR1 gene) and 24 controls were included in the study. The serum levels of HDL-C were lower in FXS patients (p

BACKGROUND: Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental condition, which is typically characterized by a triad of symptoms: impaired social communication, social reciprocity and repetitive stereotypic behavior. While the behavioral phenotype of ASD is well described, the search for reliable ‘autism biomarkers’ continues.CONTENT: Insulin growth factor (IGF) is essential for the myelination of developing fetal neurons; this is in addition to the well-known links between IGF, maternal inflammation, infection and autism supporting IGF as a potential marker. Combining IGF data with data regarding levels of the known markers, serotonin and anti-myelin basic protein, in order to calculate an autism index, could provide a new diagnostic method for at-risk neonates. Disruptions to multiple pathophysiological systems, including redox, folate, methylation, tryptophan metabolism, and mitochondrial metabolism, have been well documented in autistic patients. Maternal infection and inflammation have known links with autism. Autoimmunity has therefore been a well-studied area of autism research. The potential of using autoantibodies as novel biomarkers for autism, in addition to providing insights into the neurodevelopmental processes that lead to autism.SUMMARY: The six proposed causes of autism involve both metabolic and immunologic dysfunctions and include: increased oxidative stress; decreased methionine metabolism and trans-sulfuration: aberrant free and bound metal burden; gastrointestinal (GI) disturbances; immune/inflammation dysregulation; and autoimmune targeting. A newborn screening program for early-onset ASD should be capable of utilizing a combination of ASD-associated biomarkers representative of the six proposed causes of autism in order to identify newborns at risk. The biomarkers discussed in this article are useful to guide the selection, efficacy and sufficiency of biomedical interventions, which would likely include nutritional supplementation, dietary changes and specific medications for treating GI pathogens and reducing inflammation.KEYWORDS: ASD, autism, biomarkers, newborn screening, diagnosis

International audience; Several genetic causes of autism spectrum disorder (ASD) have been identified. However, more recent work has highlighted that certain environmental exposures early in life may also account for some cases of autism. Environmental insults during pregnancy, such as infection or malnutrition, seem to dramatically impact brain development. Maternal viral or bacterial infections have been characterized as disruptors of brain shaping, even if their underlying mechanisms are not yet fully understood. Poor nutritional diversity, as well as nutrient deficiency, is strongly associated with neurodevelopmental disorders in children. For instance, imbalanced levels of essential fatty acids, and especially polyunsaturated fatty acids (PUFAs), are observed in patients with ASD and other neurodevelopmental disorders (e.g., attention deficit hyperactivity disorder (ADHD) and schizophrenia). Interestingly, PUFAs, and specifically n-3 PUFAs, are powerful immunomodulators that exert anti-inflammatory properties. These prenatal dietary and immunologic factors not only impact the fetal brain, but also affect the microbiota. Recent work suggests that the microbiota could be the missing link between environmental insults in prenatal life and future neurodevelopmental disorders. As both nutrition and inflammation can massively affect the microbiota, we discuss here how understanding the crosstalk between these three actors could provide a promising framework to better elucidate ASD etiology.

Though extensively characterized clinically, the causes of autism spectrum disorder (ASD) remain a mystery. ASD is known to have a strong genetic basis, but it is genetically very heterogeneous. Recent studies have estimated that de novo disruptive mutations in hundreds of genes may contribute to ASD. However, it is unclear how it is possible for mutations in so many different genes to contribute to ASD. Recent findings suggest that many of the mutations disrupt genes involved in transcription regulation that are expressed prenatally in the developing brain. De novo disruptive mutations are also more frequent in girls with ASD, despite the fact that ASD is more prevalent in boys. In this paper, we hypothesize that loss of robustness may contribute to ASD. Loss of phenotypic robustness may be caused by mutations that disrupt capacitors that operate in the developing brain. This may lead to the release of cryptic genetic variation that contributes to ASD. Reduced robustness is consistent with the observed variability in expressivity and incomplete penetrance. It is also consistent with the hypothesis that the development of the female brain is more robust, and it may explain the higher rate and severity of disruptive de novo mutations in girls with ASD.

International audience; Autism is the short name of a complex and heterogeneous group of disorders (autism spectrum disorders, ASD) with several lead symptoms required for classification, including compromised social interaction, reduced verbal communication and stereotyped repetitive behaviors/restricted interests. The etiology of ASD is still unknown in most cases but monogenic heritable forms exist that have provided insights into ASD pathogenesis and have led to the notion of autism as a 'synapse disorder'. Among the most frequent monogenic causes of autism are loss-of-function mutations of the NLGN4X gene which encodes the synaptic cell adhesion protein neuroligin-4X (NLGN4X). We previously described autism-like behaviors in male Nlgn4 null mutant mice, including reduced social interaction and ultrasonic communication. Here, we extend the phenotypical characterization of Nlgn4 null mutant mice to both genders and add a series of additional autism-relevant behavioral readouts. We now report similar social interaction and ultrasonic communication deficits in females as in males. Furthermore, aggression, nest-building parameters, as well as self-grooming and circling as indicators of repetitive behaviors/stereotypies were explored in both genders. The construction of a gender-specific autism severity composite score for Nlgn4 mutant mice markedly diminishes population/sample heterogeneity typically obtained for single tests, resulting in p values of 83% for female mice. Taken together, these data underscore the similarity of phenotypical consequences of Nlgn4/NLGN4X loss-of-function in mouse and man, and emphasize the high relevance of Nlgn4 null mutant mice as an ASD model with both construct and face validity.

At the heart of debates over underlying causes of autism is the "Kanner hypothesis" that autistic deficits in social reciprocity, and a cognitive/perceptual 'style' favouring detail-oriented cognition, co-vary in autistic individuals. A separate line of work indicates these two domains are normally distributed throughout the population, with autism representing an extremity. This realisation brings the Kanner debate into the realm of normative co-variation, providing more ways to test the hypothesis, and insights into typical development; for instance, in the context of normative functioning, the Kanner hypothesis implies social costs to spatial/numerical prowess.

Research on autism has been gaining more and more attention. However, its aetiology is not entirely known and several factors are thought to contribute to the development of this neurodevelopmental disorder. These potential contributing factors range from genetic heritability to environmental effects. A significant number of reviews have already been published on different aspects of autism research as well as focusing on using animal models to help expand current knowledge around its aetiology. However, the diverse range of symptoms and possible causes of autism have resulted in as equally wide variety of animal models of autism.In this update article we focus only on the animal models with neurobehavioural characteristics of social deficit related to autism and present an overview of the animal models with alterations in brain regions, neurotransmitters, or hormones that are involved in a decrease in sociability. (C) 2012 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

Fragile X syndrome (FXS) is a common form of mental disability and one of the known causes of autism. The mutation responsible for FXS is a large expansion of the trinucleotide CGG repeats which leads to DNA methylation of the fragile X mental retardation gene 1 (FMR1) and transcriptional silencing, resulting in the absence of fragile X mental retardation protein (FMRP), an mRNA binding protein. Although it is widely known that FMRP is critical for metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD), which has provided a general theme for developing pharmacological drugs for FXS, specific downstream targets of FMRP may also be of therapeutic value. Since alterations in potassium channel expression level or activity could underlie neuronal network defects in FXS, here we describe recent findings on how these channels might be altered in mouse models of FXS and the possible therapeutic avenues for treating FXS.

Autism is a neurodevelopmental disorder that manifests in childhood as social behavioral abnormalities, such as abnormal social interaction, impaired communication, and restricted interest or behavior. Of the known causes of autism, duplication of human chromosome 15q11–q13 is the most frequently associated cytogenetic abnormality. Chromosome 15q11–q13 is also known to include imprinting genes. In terms of neuroscience, it contains interesting genes such as Necdin, Ube3a, and a cluster of GABAA subunits as well as huge clusters of non-coding RNAs (small nucleolar RNAs, snoRNAs). Phenotypic analyses of mice genetically or chromosomally engineered for each gene or their clusters on a region of mouse chromosome seven syntenic to human 15q11–q13 indicate that this region may be involved in social behavior, serotonin metabolism, and weight control. Further studies using these models will provide important clues to the pathophysiology of autism. This review overviews phenotypes of mouse models of genes in 15q11–q13 and their relationships to autism.

We are delighted to announce the launch of Molecular Autism - a new open-access journal published by BioMed Central. Autism and associated conditions are now recognized as major disabilities with major implications for the public purse. A recent economic analysis of the total annual cost of autism in the UK estimated this to be £28 billion, assuming a prevalence of 1% of the population [1]. The social and communication deficits in this spectrum of conditions, as well as the strongly repetitive behaviors and unusual narrow interests, have their basis in neurodevelopmental changes caused, at the most fundamental level, by molecular alterations, some of which have been identified. The scope of Molecular Autism reflects this broad perspective, from molecular to cellular to systems to neural, cognitive and behavioral level analyses, and back again [2]. Molecular Autism joins other journals targeting autism and associated conditions but differs in key ways. First, Molecular Autism is both online and open access. In a field where dissemination of accurate information has become so important, where internationally, scientists, educators, clinicians, and families are tracking the developments and are looking for up-to-date, definitive and accessible sources of scientific information, Molecular Autism will provide such a forum. Open access means that the articles are freely available to all, worldwide, and at no cost to the reader. Online publication also allows for no restriction on number or length of articles and for the inclusion of all available digital technologies: large data sets, unlimited use of color, slide shows, animation, video clips, and links to other web pages, all at no additional charge. Articles are published online on the day of acceptance and, very soon after, are listed in bibliographic databases and full-text article repositories [3]. BioMed Central is a leader in online, open access journals ensuring that this mission will be seamless. Publication costs in subscription journals are paid by the reader; in Molecular Autism these costs are defrayed by the author via article processing charges (APCs). However, APCs can typically be covered by grants. In addition, individual APCs are waived in institutions that have full membership to BioMed Central. A discounted APC is provided for institutions with supporting membership and authors from countries in low or low-middle income categories defined by the World Bank may also have APC charges waived. Beyond this, we will also consider individual waivers on a case-by-case basis, making every effort to ensure that lack of funds does not impede the overall objective of publishing the best science, irrespective of authorship or country of origin [4]. The second way in which Molecular Autism differs from other journals in the autism science field is by having a focus on the molecular level. Whereas other journals have a broad remit, from clinical and educational psychological studies through cognitive experiments to neuroimaging and genetics, Molecular Autism will publish articles that have a bearing on the molecular basis of autism and related conditions. This does not preclude a behavioural or cognitive or neural study, so long as there is also a molecular measure in the study or the implications for the molecular basis of autism are considered. Our reason for this requirement is that part of our mission statement is to accelerate research into the fundamental determinants of the condition [2]. The first 60 years of autism research have had a bias towards the psychological, and we intend - via this new journal - to correct this emphasis. The third way in which Molecular Autism differs from other autism journals is that it aims to achieve integration across the multiple levels that these syndromes affect. We now recognize that autism will not be understood by a single discipline, be it genetics or neurology or psychology. Rather, each level has to be mapped on to the next, to reveal how mechanisms give rise to the phenotype within each system. This makes autism and related syndromes complex but the response to such a challenge has to be scientific articles that attempt to tackle such multi-level complexity. We are committed to publishing the highest quality articles in the field. Since we made our first call for manuscripts, we have attracted manuscripts from leaders in the field and have sustained a constant rate of submissions. Articles in Molecular Autism are peer-reviewed by at least two, and most typically more, experts, drawn from the Editorial Board and the wider scientific community. Manuscript review and processing is rapid while, with the assistance of the Editorial Board, we shall ensure that the highest standards are maintained, including fair refereeing and editorial decision-making [5]. Molecular Autism is also a forum for timely reviews of topics of interest and will be a site for discussion of open questions in the field. After the launch of the journal, we will review the state-of-the-art in association studies in psychiatric genetics and define the criteria for the highest quality studies, and will commit to this level of rigor in all articles published in Molecular Autism. We are in a transformative period in autism research. Behavioral interventions have been shown to be effective, and earlier diagnosis, using molecular and behavioral methods, becomes critical to take advantage of these interventions. In parallel, identification of etiological causes of autism has led to novel drug targets, and several large-scale clinical trials are being carried out based on these findings. We underline the important ethical issue that research into efficacy of medications should evaluate not only improvements in areas of known disability, but the lack of unwanted side-effects (particularly ensuring that areas of strength in autism are not compromised). Molecular Autism will be at the forefront of these breakthroughs.

Autism is a severe neurodevelopmental disorder known to have many different etiologies. In the last few years, significant progresses have been made in comprehending the causes of autism and their multiple impacts on the developing brain. This article aims to review the current understanding of the etiologies and the multiple pathogenetic pathways that are likely to lead to the autistic phenotype. The PubMed database was searched with the keywords “autism” and “chromosomal abnormalities”, “metabolic diseases”, “susceptibility loci”. Genetic syndromes, defined mutations, and metabolic diseases account for less than 20% of autistic patients. Alterations of the neocortical excitatory/inhibitory balance and perturbations of interneurons’ development represent the most probable pathogenetic mechanisms underlying the autistic phenotype in fragile X syndrome and tuberous sclerosis complex. Chromosomal abnormalities and potential candidate genes are strongly implicated in the disruption of neural connections, brain growth and synaptic/dendritic morphology. Metabolic and mitochondrial defects may have toxic effects on the brain cells, causing neuronal loss and altered modulation of neurotransmission systems. A wide variety of cytogenetic abnormalities have been recently described, particularly in the low functioning individuals with dysmorphic features. Routine metabolic screening studies should be performed in the presence of autistic regression or suggestive clinical findings. As etiologies of autism are progressively discovered, the number of individuals with idiopathic autism will progressively shrink. Studies of genetic and environmentally modulated epigenetic factors are beginning to provide some clues to clarify the complexities of autism pathogenesis. The role of the neuropediatrician will be to understand the neurological basis of autism, and to identify more homogenous subgroups with specific biologic markers.

Mouse models for the study of autistic-like behaviors are increasingly needed to test hypotheses about the causes of autism, and to evaluate potential treatments. Both the automated three-chambered social approach test and social transmission of food preference have been proposed as mouse behavioral assays with face validity to diagnostic symptoms of autism, including aberrant reciprocal social interactions and impaired communication. Both assays measure aspects of normal social behavior in the mouse. However, little is known regarding the salient cues present in each assay that elicit normal social approach and communication. To deconstruct the critical components, we focused on delivering discrete social and non-social olfactory and visual cues within the context of each assay. Results indicate that social olfactory cues were sufficient to elicit normal sociability in the three-chambered social approach test. On social transmission of food preference, isolated social olfactory cues were sufficient to induce social investigation, but not sufficient to induce food preference. These findings indicate that olfactory cues are important in mouse social interaction, but that additional sensory cues are necessary in certain situations. The present evidence that both the three-chambered social approach assay and the social transmission of food preference assay require socially relevant cues to elicit normal behavior supports the use of these two assays to investigate autism-related behavioral phenotypes in mice.

Background: The recorded prevalence of autistic spectrum disorders has risen over recent decades. Measles, mumps and rubella (MMR) vaccine has been blamed, by causing a “new variant” form of “regressive autism” associated with “autistic enterocolitis”. Aims: To estimate the prevalence of autism and to assess any changes in parental perception regarding the onset or causes of autism. Methods and Results: A total of 567 children with autistic spectrum disorder in five districts in north east London were identified, born 1979–98. Reported autism, excluding the 94 cases of Asperger’s syndrome, increased by year of birth until 1992, since when prevalence has plateaued. This flattening off persisted after allowing for expected delay in diagnosis in more recent birth cohorts. The age at diagnosis of autistic spectrum disorder was estimated to have decreased per five year period since 1983, by 8.7% for childhood autism and by 11.0% for atypical autism. There was some evidence that MMR was more likely to be mentioned as a trigger after August 1997 than before. Conclusions: The prevalence of autism, which was apparently rising from 1979 to 1992, reached a plateau from 1992 to 1996 at a rate of some 2.6 per 1000 live births. This levelling off, together with the reducing age at diagnosis, suggests that the earlier recorded rise in prevalence was not a real increase but was likely due to factors such as increased recognition, a greater willingness on the part of educationalists and families to accept the diagnostic label, and better recording systems. The proportion of parents attributing their child’s autism to MMR appears to have increased since August 1997.

Two lines of evidence suggest that endocrine disruption may be a factor in autism spectrum disorders (ASDs). First, the observation that males may be four times as likely to be diagnosed with ASDs as females suggests hormonal involvement.1 Second, adrenal, gonadal, and thyroid hormones play an important role in fetal neurodevelopment,2,3,4 and any chemical that interferes with the actions of these hormones therefore has the potential to disrupt brain development. By analyzing samples and data from a prospective birth cohort study, a team of U.S. and Canadian researchers have identified a handful of endocrine-disrupting chemicals (EDCs) they believe merit further study as possible contributors to ASDs.5 ASDs encompass a complex set of disorders that have been associated with more than 800 potential genetic risk factors, says Isaac Pessah, associate dean of research and graduate education at the University of California, Davis, who was not involved with the study. In March 2014 the Centers for Disease Control and Prevention revised its estimates of the number of children with ASDs to 1 in 68, up from 1 in 88.6 Researchers are investigating endocrine disruption as a possible route by which prenatal chemical exposures may contribute to ASDs. “We suspect that environment and genetics interact on the fetus prenatally or very early in life to increase or decrease the risk of autism,” says study author Joseph Braun, an epidemiologist at Brown University School of Public Health. Given the importance of identifying environmental risk factors for the conditions, he says surprisingly little research has investigated the role that exposure to EDCs may play in ASDs. The new study analyzed data for 175 women participating in the Health Outcomes and Measures of the Environment (HOME) Study. The cohort includes women who lived in the Cincinnati, Ohio, metropolitan area when they were pregnant between 2003 and 2006. The women provided blood and urine samples during pregnancy, which were analyzed for 52 endocrine-disrupting chemicals. At ages 4 and 5 years old, the children were rated by their mothers using the Social Responsiveness Scale (SRS), a tool that assesses behaviors typically related to ASDs. The women’s chemical exposures were similar to levels reported in the 2003–2004 iteration of the National Health and Nutrition Examination Survey. After the researchers adjusted for potential confounding variables, they found that higher maternal exposures to trans-nonachlor and PBDE-28 were associated with higher average SRS scores. Trans-nonachlor is a component of the highly persistent banned pesticide chlordane, and PBDE-28 is one of the polybrominated diphenyl ether compounds used as flame retardants in commercial goods containing polyurethane foam (including furniture and mattresses) made before 2005. The study also found negative associations between four additional chemicals and average SRS scores. These included β-hexachlorocyclohexane, an organochlorine pesticide; perfluorooctanoic acid, a compound used to make many industrial polymers and products including Teflon; PCB-178, one of the polychlorinated biphenyls once used in hundreds of industrial and commercial applications; and PBDE-85, another PBDE congener. These results are consistent with some earlier studies but not others; the authors suggest the apparent contradictions may result from differences in the end points studied and the timing of exposure assessment. “[The new study’s] multi-chemical and multi-outcome approach is innovative and mirrors the real world, where we are all exposed to a mixture of chemicals, and where the neurotoxicants may have different effects that may even depend on the time of exposure,” says Philippe Grandjean, an adjunct professor of environmental health at the Harvard School of Public Health, who was not involved with the study. But Grandjean also cautions against comparing apples and oranges. “Those substances that have been measured with large imprecision, e.g., because of common short-term variability, are likely to be underestimated as possible contributors to autism-like behaviors,” he explains. On the other hand, “persistent substances will have less imprecision and could therefore erroneously appear as if they are more important.” Although the study measured only 52 of the many thousands of environmental chemicals to which participants may have been exposed, it is important “because it represents a systematic search for potentially preventable environmental causes of autism,” says Philip Landrigan, professor and chair of preventive medicine in the Icahn School of Medicine at Mount Sinai. He says the study’s approach “falls precisely in line” with the strategy for discovering environmental causes of autism and other neurodevelopmental disabilities that he and other experts outlined in a 2012 EHP editorial.7

Background The causes of autism spectrum disorders (ASD) remain largely unknown and widely debated; however, evidence increasingly points to the importance of environmental exposures. A growing number of studies use geographic variability in ASD prevalence or exposure patterns to investigate the association between environmental factors and ASD. However, differences in the geographic distribution of established risk and predictive factors for ASD, such as maternal education or age, can interfere with investigations of ASD etiology. We evaluated geographic variability in the prevalence of ASD in central North Carolina and the impact of spatial confounding by known risk and predictive factors. Methods Children meeting a standardized case definition for ASD at 8 years of age were identified through records-based surveillance for 8 counties biennially from 2002 to 2008 (n=532). Vital records were used to identify the underlying cohort (15% random sample of children born in the same years as children with an ASD, n=11,034), and to obtain birth addresses. We used generalized additive models (GAMs) to estimate the prevalence of ASD across the region by smoothing latitude and longitude. GAMs, unlike methods used in previous spatial analyses of ASD, allow for extensive adjustment of individual-level risk factors (e.g. maternal age and education) when evaluating spatial variability of disease prevalence. Results Unadjusted maps revealed geographic variation in surveillance-recognized ASD. Children born in certain regions of the study area were up to 1.27 times as likely to be recognized as having ASD compared to children born in the study area as a whole (prevalence ratio (PR) range across the study area 0.57-1.27; global P=0.003). However, geographic gradients of ASD prevalence were attenuated after adjusting for spatial confounders (adjusted PR range 0.72-1.12 across the study area; global P=0.052). Conclusions In these data, spatial variation of ASD in central NC can be explained largely by factors impacting diagnosis, such as maternal education, emphasizing the importance of adjusting for differences in the geographic distribution of known individual-level predictors in spatial analyses of ASD. These results underscore the critical importance of accounting for such factors in studies of environmental exposures that vary across regions.

Autism is a neurodevelopmental disorder presenting in the first 3 years of life. Deficits occur in the core areas of social communication and interaction and restricted, repetitive patterns of behavior, interests or activities. The causes of autism are unknown, but clinical genetic studies show strong evidence in favor of the involvement of genetic factors in etiology. Molecular genetic studies report some associations with candidate genes, and candidate regions have emerged from several genome-wide linkage studies. Here, we report a clinical case of autism in a 6-year-old boy with double duplication on 10q11.22q11.23 with ASD (Autism Spectrum Disorder), intellectual disability, developmental delay, hypotonia, gross-motor skills deficit, overgrowth and mild dysmorphic features. In the literature, only five cases of ASD with 10q11.21q11.23 duplication are reported. This is the first extensive clinical description of an ASD subject with 10q11.22q11.23 duplication. Our findings suggest that 10q11.21q11.23 microduplication could represent a copy number variant that predisposes to autism.