Further evidence of a causal association between AGO1, a critical regulator of microRNA formation,and intellectual disability/autism spectrum disorder

Among the many regulators of microRNA formation, Argonaute 1 (AGO1) plays critical roles in RNA interference, which controls a wide range of biological activities. Recent large-scale genomic studies have identified at least five patients with intellectual disability/autism spectrum disorder who had de novo mutations in AGO1, but detailed clinical information was not available. The recognizable clinical features that are associated with AGO1 mutations remain to be determined. The proposita was a 15-year-old girl with diffuse hypotonia, infrequent seizures, and intellectual disability with an intelligence quotient of 41. She had characteristic facial features consisting of telecanthus, wide nasal bridge with bulbous nasal tip, and a round face with downslanted palpebral fissures. Serial computed tomography scans showed progressive calcification in the globus pallidus that became evident during childhood. A whole exome analysis in trio revealed a de novo heterozygous mutation in AGO1, i.e., c.595G > A p.(Gly199Ser). The distinctive facial features, i.e., telecanthus, wide nasal bridge with bulbous nasal tip, and a round face with downslanted palpebral fissures, closely resembled previously reported patients who had a chromosomal microdeletion encompassing AGO1 locus. The combinatory phenotype of such characteristic facial features and radiographic features, i.e. progressive calcification in the globus pallidus, in the presently reported patient suggest that AGO1 mutations lead to a syndromic form of intellectual disability/autism spectrum disorder. Distinctive facial features with early and progressive calcification in the globus pallidus may be suggestive of the presence of AGO1 mutations.     

ZDHHC15 as a candidate gene for autism spectrum disorder

The phenotypic repercussion of ZDHHC15 haploinsufficiency is not well-known. This gene was initially suggested as a candidate for X-linked mental retardation, but such an association was later questioned. We studied a multiplex family with three members with autism spectrum disorder (ASD) by array CGH, karyotype, exome sequencing and X-chromosome inactivation patterns. Medical history interviews, cognitive and physical examinations, and sensory profiling were also assessed. The three family members with ASD (with normal cognitive abilities and an abnormal sensory profile) were the only carriers of a 1.7 Mb deletion in the long arm of chromosome X, involving: ZDHHC15, MAGEE2, PBDC1, MAGEE1, MIR384 and MIR325. The normal chromosome X was preferentially inactivated in female carriers, and the whole exome sequencing of an affected family member did not reveal any additional genetic variant that could explain the phenotype. Thus, in the present family, ASD segregates with a deletion on chromosome X that includes ZDHHC15. Considering our results together with gene data (regarding function, expression, conservation and animal/cellular models), ZDHHC15 is a candidate gene for ASD. Emerging evidence also suggests that this gene could be associated with other neurodevelopmental disorders, with incomplete penetrance and variable expressivity.     

一例21号染色体三体嵌合型孤独症谱系障碍患儿的遗传学分析

目的对1例孤独症谱系障碍(autism spectrum disorder,ASD)伴有先天性心脏病的患儿进行细胞遗传学和分子遗传学分析,寻找其病因。方法取患儿及其父母的外周血进行常规染色体G显带核型分析,对患儿外周血提取的基因组DNA进行基于高通量测序的全外显子测序(whole exome sequencing,WES)和低覆盖度全基因组拷贝数变异测序(low-coverage massively parallel copy number variation sequencing,CNV-seq)检测分析,并利用染色体微阵列分析(chromosomal microarray analysis,CMA)进行验证。结果常规染色体G显带核型分析结果显示患儿及其父母染色体核型正常,患儿WES未检测到异常变异,而CNV-seq检测结果为47,XY,+21[10%]/46,XY[90%],提示存在低比例的21号染色体三体嵌合,CMA验证结果与CNV-seq结果一致。结论低比例的21号染色体三体嵌合除与唐氏综合征表型有关外,还可能与ASD的发生密切相关。基于高通量测序的WES及CNV-seq方法可为原因不明的ASD提供准确的遗传学诊断。     

Out of time: a possible link between mirror neurons, autism and electromagnetic radiation

Recent evidence suggests a link between autism and the human mirror neuron system. In this paper, I argue that temporal disruption from the environment may play an important role in the observed mirror neuron dysfunction, leading in turn to the pattern of deficits associated with autism. I suggest that the developing nervous system of an infant may be particularly prone to temporal noise that can interfere with the initial calibration of brain networks such as the mirror neuron system. The most likely source of temporal noise in the environment is artificially generated electromagnetic radiation. To date, there has been little evidence that electromagnetic radiation poses a direct biological hazard. It is clear, however, that time-varying electromagnetic waves have the potential to temporally modulate the nervous system, particularly when populations of neurons are required to act together. This modulation may be completely harmless for the fully developed nervous system of an adult. For an infant, this same temporal disruption might act to severely delay or disrupt vital calibration processes.     

A model-driven methodology for exploring complex disease comorbidities applied to autism spectrum disorder and inflammatory bowel disease

We propose a model-driven methodology aimed to shed light on complex disorders. Our approach enables exploring shared etiologies of comorbid diseases at the molecular pathway level. The method, Comparative Comorbidities Simulation (CCS), uses stochastic Petri net simulation for examining the phenotypic effects of perturbation of a network known to be involved in comorbidities to predict new roles for mutations in comorbid conditions. To demonstrate the utility of our novel methodology, we investigated the molecular convergence of autism spectrum disorder (ASD) and inflammatory bowel disease (IBD) on the autophagy pathway. In addition to validation by domain experts, we used formal analyses to demonstrate the model’s self-consistency. We then used CCS to compare the effects of loss of function (LoF) mutations previously implicated in either ASD or IBD on the autophagy pathway. CCS identified similar dynamic consequences of these mutations in the autophagy pathway. Our method suggests that two LoF mutations previously implicated in IBD may contribute to ASD, and one ASD-implicated LoF mutation may play a role in IBD. Future targeted genomic or functional studies could be designed to directly test these predictions.     

Electrophysiological signatures of visual statistical learning in 3-month-old infants at familial and low risk for autism spectrum disorder

Visual statistical learning (VSL) refers to the ability to extract associations and conditional probabilities within the visual environment. It may serve as a precursor to cognitive and social communication development. Quantifying VSL in infants at familial risk (FR) for Autism Spectrum Disorder (ASD) provides opportunities to understand how genetic predisposition can influence early learning processes which may, in turn, lay a foundation for cognitive and social communication delays. We examined electroencephalography (EEG) signatures of VSL in 3-month-old infants, examining whether EEG correlates of VSL differentiated FR from low-risk (LR) infants. In an exploratory analysis, we then examined whether EEG correlates of VSL at 3 months relate to cognitive function and ASD symptoms at 18 months. Infants were exposed to a continuous stream of looming shape pairs with varying probability that the shapes would occur in sequence (high probability-deterministic condition; low probability-probabilistic condition). EEG was time-locked to shapes based on their transitional probabilities. EEG analysis examined group-level characteristics underlying specific components, including the late frontal positivity (LFP) and N700 responses. FR infants demonstrated increased LFP and N700 response to the probabilistic condition, whereas LR infants demonstrated increased LFP and N700 response to the deterministic condition. LFP at 3 months predicted 18-month visual reception skills and not ASD symptoms. Our findings thus provide evidence for distinct VSL processes in FR and LR infants as early as 3 months. Atypical pattern learning in FR infants may lay a foundation for later delays in higher level, nonverbal cognitive skills, and predict ASD symptoms well before an ASD diagnosis is made.     

An event‐related source localization study of response monitoring and social impairments in autism spectrum disorder

A number of studies suggest anterior cingulate cortex (ACC) abnormalities in autism spectrum disorder (ASD), which might underlie response monitoring and social impairments exhibited by children and adolescents with ASD. The goal of the present study was to extend this work by examining error and correct response monitoring using event‐related potentials (ERN, Pe, CRN) and LORETA source localization in high functioning adults with ASD and controls. Adults with ASD showed reduced ERN and Pe amplitudes and reduced rostral ACC activation compared with controls. Adults with ASD also showed less differentiation between error and correct ERP components. Social impairments and higher overall autism symptoms were related to reduced rostral ACC activity at the time of the ERN, particularly in adults with ASD. These findings suggest that reduced ACC activity may reflect a putative brain mechanism involved in the origins and maintenance of social impairments and raise the possibility of the presence of stable brain‐behavior relation impairment across development in some individuals with ASD.     

Predictive models for subtypes of autism spectrum disorder based on single-nucleotide polymorphisms and magnetic resonance imaging

PurposeAutism spectrum disorder (ASD) is a neurodevelopmental disorder, of which Asperger syndrome and high-functioning autism are subtypes. Our goal is: 1) to determine whether a diagnostic model based on single-nucleotide polymorphisms (SNPs), brain regional thickness measurements, or brain regional volume measurements can distinguish Asperger syndrome from high-functioning autism; and 2) to compare the SNP, thickness, and volume-based diagnostic models.Material and MethodsOur study included 18 children with ASD: 13 subjects with high-functioning autism and 5 subjects with Asperger syndrome. For each child, we obtained 25 SNPs for 8 ASD-related genes; we also computed regional cortical thicknesses and volumes for 66 brain structures, based on structural magnetic resonance (MR) examination. To generate diagnostic models, we employed five machine-learning techniques: decision stump, alternating decision trees, multi-class alternating decision trees, logistic model trees, and support vector machines.ResultsFor SNP-based classification, three decision-tree-based models performed better than the other two machine-learning models. The performance metrics for three decision-tree-based models were similar: decision stump was modestly better than the other two methods, with accuracy = 90%, sensitivity = 0.95 and specificity = 0.75. All thickness and volume-based diagnostic models performed poorly. The SNP-based diagnostic models were superior to those based on thickness and volume. For SNP-based classification, rs878960 in GABRB3 (gamma-aminobutyric acid A receptor, beta 3) was selected by all tree-based models.ConclusionOur analysis demonstrated that SNP-based classification was more accurate than morphometry-based classification in ASD subtype classification. Also, we found that one SNP—rs878960 in GABRB3—distinguishes Asperger syndrome from high-functioning autism.     

De novo missense variants in the E3 ubiquitin ligase adaptor KLHL20 cause a developmental disorder with intellectual disability,epilepsy, and autism spectrum disorder

PurposeKLHL20 is part of a CUL3-RING E3 ubiquitin ligase involved in protein ubiquitination. KLHL20 functions as the substrate adaptor that recognizes substrates and mediates the transfer of ubiquitin to the substrates. Although KLHL20 regulates neurite outgrowth and synaptic development in animal models, a role in human neurodevelopment has not yet been described. We report on a neurodevelopmental disorder caused by de novo missense variants in KLHL20.MethodsPatients were ascertained by the investigators through Matchmaker Exchange. Phenotyping of patients with de novo missense variants in KLHL20 was performed.ResultsWe studied 14 patients with de novo missense variants in KLHL20, delineating a genetic syndrome with patients having mild to severe intellectual disability, febrile seizures or epilepsy, autism spectrum disorder, hyperactivity, and subtle dysmorphic facial features. We observed a recurrent de novo missense variant in 11 patients (NM_014458.4:c.1069G>A p.[Gly357Arg]). The recurrent missense and the 3 other missense variants all clustered in the Kelch-type β-propeller domain of the KLHL20 protein, which shapes the substrate binding surface.ConclusionOur findings implicate KLHL20 in a neurodevelopmental disorder characterized by intellectual disability, febrile seizures or epilepsy, autism spectrum disorder, and hyperactivity.     

Jumonji domain containing 1C (JMJD1C) sequence variants in seven patients with autism spectrum disorder,intellectual disability and seizures

The Jumonji domain containing 1C (JMJD1C) gene encodes the Jumonji domain-containing protein 1C (JMJD1C) and is a member of the jmJC domain-containing protein family involved in histone demethylation that is expressed in the brain. We report seven, unrelated patients with developmental delays or intellectual disability and heterozygous, de novo sequence variants in JMJD1C. All patients had developmental delays, but there were no consistent additional findings. Two patients were reported to have seizures for which there was no other identified cause. De novo, deleterious sequence variants in JMJD1C have previously been reported in patients with autism spectrum disorder and a phenotype resembling classical Rett syndrome, but only one JMJD1C variant has undergone functional evaluation. In all of the seven patients in this report, there was a plausible, alternative explanation for the neurocognitive phenotype or a modifying factor, such as an additional potentially pathogenic variant, presence of the variant in a population database, heteroplasmy for a mitochondrial variant or mosaicism for the JMJD1C variant. Although the de novo variants in JMJD1C are likely to be relevant to the developmental phenotypes observed in these patients, we conclude that further data supporting the association of JMJD1C variants with intellectual disability is still needed.     

Novel truncating and missense variants extending the spectrum of EMC1-related phenotypes,causing autism spectrum disorder,severe global development delay and visual impairment

The EMC1 gene, located on 1p36.13, encodes the subunit 1 of the endoplasmic reticulum-membrane protein complex, a highly conserved and ubiquitous multiprotein transmembrane complex. Pathogenic monoallelic and biallelic variants in EMC1 in humans have been reported only in six families, causing isolated visual impairment or in association with psychomotor retardation and cerebellar atrophy. We report a ten-year-old boy, born to unrelated parents, with early-onset severe global development delay due to novel EMC1 biallelic pathogenic variants. A truncating variant, p.(Tyr378*) and a missense variant, p.(Phe953Ser), located in exon 11 and 23 of EMC1 gene respectively, have been found by reanalysis of exome sequencing data. The proband's phenotype included several signs that overlap with the phenotype of previously reported patients, associating severe global developmental delay, abnormal ophthalmological examination, and postnatal slow-down of the head circumference growth. Some distinguishing clinical signs were observed in comparison to patients from literature, such as autism spectrum disorder, absence of seizures, scoliosis or facial dysmorphic features, thus extending the spectrum of EMC1-related phenotypes. Similarly, brain MRI, performed at 2 years, showed normal cerebellar volume and structure, whereas cerebellar atrophy was described in literature. Moreover, difficulties of clinical differential diagnosis between EMC1-associated disease and other etiologies of global development delay support the importance of large-scale genetic investigations. Our diagnostic approach, through reanalysis of exome sequencing data, highlights the importance of reconsidering initial negative results for patients with a strong suspicion of genetic disease, and to update analytic pipelines in order to improve the diagnostic yield of exome sequencing.     

BAZ2B haploinsufficiency as a cause of developmental delay,intellectual disability,and autism spectrum disorder

The bromodomain adjacent to zinc finger 2B gene (BAZ2B) encodes a protein involved in chromatin remodeling. Loss of BAZ2B function has been postulated to cause neurodevelopmental disorders. To determine whether BAZ2B deficiency is likely to contribute to the pathogenesis of these disorders, we performed bioinformatics analyses that demonstrated a high level of functional convergence during fetal cortical development between BAZ2B and genes known to cause autism spectrum disorder (ASD) and neurodevelopmental disorder. We also found an excess of de novo BAZ2B loss‐of‐function variants in exome sequencing data from previously published cohorts of individuals with neurodevelopmental disorders. We subsequently identified seven additional individuals with heterozygous deletions, stop‐gain, or de novo missense variants affecting BAZ2B. All of these individuals have developmental delay (DD), intellectual disability (ID), and/or ASD. Taken together, our findings suggest that haploinsufficiency of BAZ2B causes a neurodevelopmental disorder, whose cardinal features include DD, ID, and ASD.     

Inflammation as an intermediate pathway in the association between psychosocial stress and obesity

Psychosocial stress is associated with risk of obesity although little is known about stress-induced biological mechanisms of obesity. We examined the potential mediating role of inflammatory processes. Data were collected from a nationally representative sample of 7540 individuals (54% women, mean age 46.8+/-15.4 years), from the Scottish Health Surveys. We calculated risk estimates of obesity for increasing numbers of psychosocial stressors (based on social position, education, psychological distress and marital/partner discord) using logistic regression analyses. Obesity was assessed using body mass index and central obesity using waist circumference. Potential mediators included inflammatory markers (C-reactive protein and fibrinogen) and health behaviours (physical activity, smoking, alcohol, and dietary intake). The unadjusted odds ratio of obesity for three or more psychosocial stressors was 1.81 (95% CI, 1.39-2.36, p<0.001). In multivariate analyses that adjusted for age, gender, health behaviours and inflammatory markers the association between psychosocial stress and obesity was attenuated but remained significant (1.49, 1.11-2.00, p<0.001). Inflammatory markers independently accounted for approximately 25% of the association between stress and obesity. We found similar associations in separate analyses of psychosocial stress and central obesity, although results were confounded by overall obesity. In summary, inflammatory processes appear to be an important intermediate pathway in the association between psychosocial stress and obesity.     

Autism spectrum disorder in females with ARHGEF9 alterations and a random pattern of X chromosome inactivation

Proper function of GABAergic synapses depends upon the postsynaptic compartment anchoring of neurotransmitter receptors to the membrane by gephyrin and collybistin (Cb). In humans, Cb is encoded by ARHGEF9 on Xq11.1. ARHGEF9 alterations, some inherited from unaffected mothers, have been reported in males with autism, seizures and severe neurodevelopmental abnormalities. In females, a spectrum of mild to moderate phenotype has been detected. We report two unrelated females with autism and mild intellectual disability. High resolution X-chromosome microarray analysis revealed de novo intragenic deletions in ARHGEF9 of 24?kb and 56?kb involving exons 5–8 and exons 3–8 and leading to truncated forms of collybistin. Peripheral blood samples revealed random X-chromosome inactivation in both patients. To explain phenotypic variability in female patients, we propose a model for disruption of collybistin and various irregular interactions in post-synaptic neurons based on X inactivation patterns. Our findings highlight the importance of ARHGEF9 integrity and suggest further research on its correlation with autism and neurobehavioral problems.     

Goal setting as a health behavior change strategy in overweight and obese adults: a systematic literature review examining intervention components

Objective

This paper describes goal setting components used for behavior change specific to diet and physical activity in community-based interventions targeting overweight and obese adults.

Methods

A systematic literature review was conducted. Studies were evaluated using the S.T.A.R.T. (Specificity, Timing, Acquisition, Rewards and feedback, and Tools) criteria which were developed for the purposes of this paper in order to elucidate which intervention features elicit optimal health behavior outcomes.

Results

Eighteen studies were included. Based on the S.T.A.R.T. criteria, it was determined that developing specific goals that are in close proximity, involve the participant in acquisition, and incorporate regular feedback, are common features in this context.

Conclusion

Goal setting can be useful for effecting health behavior changes in this population. However, as different intervention components were often implemented concurrently (e.g., education sessions, self-monitoring records), it was not possible to ascertain which were responsible for positive changes independently.

Practice implications

Goal setting shows promise as a tool that can be incorporated into weight reduction programs by health care professionals and researchers. Studies are warranted to identify the specific mechanisms through which individuals with overweight or obesity can apply the S.T.A.R.T. criteria with respect to goal setting for the purposes of weight loss.     

No association between a common single nucleotide polymorphism,rs4141463, in the MACROD2 gene and autism spectrum disorder

The Autism Genome Project (AGP) Consortium recently reported genome‐wide significant association between autism and an intronic single nucleotide polymorphism marker, rs4141463, within the MACROD2 gene. In the present study we attempted to replicate this finding using an independent case–control design of 1,170 cases with autism spectrum disorder (ASD) (874 of which fulfilled narrow criteria for Autism (A)) from five centers within Europe (UK, Germany, the Netherlands, Italy, and Iceland), and 35,307 controls. The combined sample size gave us a non‐centrality parameter (NCP) of 11.9, with 93% power to detect allelic association of rs4141463 at an alpha of 0.05 with odds ratio of 0.84 (the best odds ratio estimate of the AGP Consortium data), and for the narrow diagnosis of autism, an NCP of 8.9 and power of 85%. Our case–control data were analyzed for association, stratified by each center, and the summary statistics were combined using the meta‐analysis program, GWAMA. This resulted in an odds ratio (OR) of 1.03 (95% CI 0.944–1.133), with a P‐value of 0.5 for ASD and OR of 0.99 (95% CI 0.88–1.11) with P‐value = 0.85 for the Autism (A) sub‐group. Therefore, this study does not provide support for the reported association between rs4141463 and autism. © 2011 Wiley‐Liss, Inc.