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While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.

The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable ( approximately 90%), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 x 10(-4)). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.

Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins. Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs. Here we present the results from a whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry who were genotyped with approximately 550,000 single nucleotide polymorphism markers, in an attempt to comprehensively identify CNVs conferring susceptibility to ASDs. Positive findings were evaluated in an independent cohort of 1,336 ASD cases and 1,110 controls of European ancestry. Besides previously reported ASD candidate genes, such as NRXN1 (ref. 10) and CNTN4 (refs 11, 12), several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGN1 and ASTN2, were enriched with CNVs in ASD cases compared to controls (P = 9.5 x 10(-3)). Furthermore, CNVs within or surrounding genes involved in the ubiquitin pathways, including UBE3A, PARK2, RFWD2 and FBXO40, were affected by CNVs not observed in controls (P = 3.3 x 10(-3)). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 x 10(-6)). Although these variants may be individually rare, they target genes involved in neuronal cell-adhesion or ubiquitin degradation, indicating that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD.

Imbalanced glutamate signaling has been implicated in the development of autism spectrum disorder (ASD). This case-control study was to examine single nucleotide polymorphisms (SNPs) in glutamate receptor and carrier genes and determine their association with childhood ASD in a Chinese Han population. A total of 12 SNPs in genes encoding glutamate receptors (GRM7 and GRM8) and carriers (SLC1A1 and SLC25A12) were examined in 249 autistic children and 353 healthy controls. The Childhood Autism Rating Scale (CARS) and its verbal communication domain were applied to evaluate the severity of the disease and language impairment, respectively. The T allele of rs2292813 in the SLC25A12 gene was significantly associated with an increased risk of ASD (odds ratio (OD) = 1.7, 95% confidence interval (CI): 1.1–2.6, P = 0.0107). Neither the genotypes nor allele distributions of other SNPs were associated with the risk of ASD. Notably, rs1800656 and rs2237731 in the GRM8 gene, but not other SNPs, were related to the severity of language impairment. All SNPs were not correlated with the overall severity of ASD. Our findings support associations between the SLC25A12 gene variant and the risk of childhood ASD, and between the GRM8 gene variant and the severity of language impairment in the Chinese Han population. [ABSTRACT FROM AUTHOR]

Given the differential risk of type 1 diabetes (T1D) in offspring of affected fathers versus affected mothers and our observation that T1D cases have differential DNA methylation near the imprinted DLGAP2 gene compared to controls, we examined whether methylation near DLGAP2 mediates the association between T1D family history and T1D risk. In a nested case–control study of 87 T1D cases and 87 controls from the Diabetes Autoimmunity Study in the Young, we conducted causal mediation analyses at 12 DLGAP2 region CpGs to decompose the effect of family history on T1D risk into indirect and direct effects. These effects were estimated from two regression models adjusted for the human leukocyte antigen DR3/4 genotype: a linear regression of family history on methylation (mediator model) and a logistic regression of family history and methylation on T1D (outcome model). For 8 of the 12 CpGs, we identified a significant interaction between T1D family history and methylation on T1D risk. Accounting for this interaction, we found that the increased risk of T1D for children with affected mothers compared to those with no family history was mediated through differences in methylation at two CpGs (cg27351978, cg00565786) in the DLGAP2 region, as demonstrated by a significant pure natural indirect effect (odds ratio (OR) = 1.98, 95% confidence interval (CI): 1.06–3.71) and nonsignificant total natural direct effect (OR = 1.65, 95% CI: 0.16–16.62) (for cg00565786). In contrast, the increased risk of T1D for children with an affected father or sibling was not explained by DNA methylation changes at these CpGs. Results were similar for cg27351978 and robust in sensitivity analyses. Lastly, we found that DNA methylation in the DLGAP2 region was associated (P < 0.05) with gene expression of nearby protein-coding genes DLGAP2, ARHGEF10, ZNF596, and ERICH1. Results indicate that the maternal protective effect conferred through exposure to T1D in utero may operate through changes to DNA methylation that have functional downstream consequences. [ABSTRACT FROM AUTHOR]

Patients with neurodevelopmental disorders, such as autism spectrum disorder, often display abnormal circadian rhythms. The role of the circadian system in these disorders has gained considerable attention over the last decades. Yet, it remains largely unknown how these disruptions occur and to what extent they contribute to the disorders' development. In this review, we examine circadian system dysregulation as observed in patients and animal models of neurodevelopmental disorders. Second, we explore whether circadian rhythm disruptions constitute a risk factor for neurodevelopmental disorders from studies in humans and model organisms. Lastly, we focus on the impact of psychiatric medications on circadian rhythms and the potential benefits of chronotherapy. The literature reveals that patients with neurodevelopmental disorders display altered sleep-wake cycles and melatonin rhythms/levels in a heterogeneous manner, and model organisms used to study these disorders appear to support that circadian dysfunction may be an inherent characteristic of neurodevelopmental disorders. Furthermore, the pre-clinical and clinical evidence indicates that circadian disruption at the environmental and genetic levels may contribute to the behavioural changes observed in these disorders. Finally, studies suggest that psychiatric medications, particularly those prescribed for attention-deficit/hyperactivity disorder and schizophrenia, can have direct effects on the circadian system and that chronotherapy may be leveraged to offset some of these side effects. This review highlights that circadian system dysfunction is likely a core pathological feature of neurodevelopmental disorders and that further research is required to elucidate this relationship., (© 2024 The Author(s). European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Autism spectrum disorder (ASD) is a heterogeneous group of early-onset neurodevelopmental disorders known to be highly heritable with a complex genetic architecture. Abnormal brain developmental trajectories that impact synaptic functioning, excitation-inhibition balance and brain connectivity are now understood to play a central role in ASD. Ongoing efforts to identify the genetic underpinnings still prove challenging, in part due to phenotypic and genetic heterogeneity. This review focuses on parent-of-origin effects (POEs), where the phenotypic effect of an allele depends on its parental origin. POEs include genomic imprinting, transgenerational effects, mitochondrial DNA, sex chromosomes and mutational transmission bias. The motivation for investigating these mechanisms in ASD has been driven by their known impacts on early brain development and brain functioning, in particular for the most well-documented POE, genomic imprinting. Moreover, imprinting is implicated in syndromes such as Angelman and Prader-Willi, which frequently share comorbid symptoms with ASD. In addition to other regions in the genome, this comprehensive review highlights the 15q11-q13 and 7q chromosomal regions as well as the mitochondrial DNA as harbouring the majority of currently identified POEs in ASD. [ABSTRACT FROM AUTHOR]

Copy number variation (CNV) is a very common type of gene variation with high frequency. In recent years, CNV has been paid more attention in various fields, especially in livestock and poultry breeding, which has promoted the progress of breeding. WW domain binding protein 1-like (WBP1L) is a protein coding gene, which plays an important role in cattle populations, and its function has been extensively studied, but it is not clear whether the copy number of the gene can affect the growth and development of cattle populations. In this study, CNV of WBP1L gene was detected in 732 cattle of seven breeds (Qinchuan cattle, QC; Pinan cattle, PN; Yuengling cattle, YL; Xianan cattle, XN; Jiaxian cattle, JX; natural Guyuan cattle, NGY; Jian cattle, JA). In addition, the relationship between CNV and growth phenotype of cattle was studied. The experimental data indicate that the copy number of WBP1L was obviously correlated with heart girth of PN cattle (** P < 0.01), rump length (RL) and body weight (BW) of PN cattle (* P < 0.05), withers height (WH), RL, body length, chest depth and BW of JX cattle (* P < 0.05), WH of NGY cattle (* P < 0.05) and WH of JA cattle (* P < 0.05). It was proved that CNV of WBP1L gene could be used as molecular marker locus for genetic breeding of the above four cattle breeds. [ABSTRACT FROM AUTHOR]

The study explores the experiences of secondary school teacher-directed violence. Violence directed at teachers can have a negative attitude towards their job, as well as not performing to expectations. Thus, it is important to increase knowledge regarding violence as educators experience it, so as to be able to work preventively and minimise the violence. The study is guided by the ınterpretative phenomenological analysis which seeks to understand the experiences of teacher-directed violence. Interviews were conducted with 10 teachers from various secondary schools at a neutral venue outside the respondents' schools and homes. Analysis revealed five main themes, namely absenteeism due to fear, fear for their safety, teacher turnover as result of violence, harassment, and intimidation. The findings revealed that more serious acts of violence on teachers affected their performance at school. If not addressed, this problem of violence has the capacity to render the education system dysfunctional. In conclusion, authorities must act against this threat on teachers in order to normalise the situation at schools throughout the country. [ABSTRACT FROM AUTHOR]

Whole-exome and whole-genome sequencing studies in autism spectrum disorder (ASD) have identified hundreds of thousands of exonic variants. Only a handful of them, primarily loss-of-function variants, have been shown to increase the risk for ASD, while the contributory roles of other variants, including most missense variants, remain unknown. New approaches that combine tissue-specific molecular profiles with patients' genetic data can thus play an important role in elucidating the functional impact of exonic variation and improve understanding of ASD pathogenesis. Here, we integrate spatio-temporal gene co-expression networks from the developing human brain and protein–protein interaction networks to first reach accurate prioritization of ASD risk genes based on their connectivity patterns with previously known high-confidence ASD risk genes. We subsequently integrate these gene scores with variant pathogenicity predictions to further prioritize individual exonic variants based on the positive-unlabeled learning framework with gene- and variant-score calibration. We demonstrate that this approach discriminates among variants between cases and controls at the high end of the prediction range. Finally, we experimentally validate our top-scoring de novo mutation NP_001243143.1:p.Phe309Ser in the sodium/potassium-transporting ATPase ATP1A3 to disrupt protein binding with different partners. [ABSTRACT FROM AUTHOR]

This chapter will focus on microglial involvement in neurodevelopmental and neuropsychiatric disorders, particularly autism spectrum disorder (ASD), schizophrenia and major depressive disorder (MDD). We will describe the neuroimmune risk factors that contribute to the etiopathology of these disorders across the lifespan, including both in early life and adulthood. Microglia, being the resident immune cells of the central nervous system, could play a key role in triggering and determining the outcome of these disorders. This chapter will review preclinical and clinical findings where microglial morphology and function were examined in the contexts of ASD, schizophrenia and MDD. Clinical evidence points out to altered microglial morphology and reactivity, as well as increased expression of pro-inflammatory cytokines, supporting the idea that microglial abnormalities are involved in these disorders. Indeed, animal models for these disorders found altered microglial morphology and homeostatic functions which resulted in behaviours related to these disorders. Additionally, as microglia have emerged as promising therapeutic targets, we will also address in this chapter therapies involving microglial mechanisms for the treatment of neurodevelopmental and neuropsychiatric disorders., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Autism spectrum disorder (ASD) includes a heterogeneous group of complex neurodevelopmental disorders characterized by atypical behaviors with two core pathological manifestations: deficits in social interaction/communication and repetitive behaviors, which are associated with disturbed redox homeostasis. Modulation of cellular resilience mechanisms induced by low levels of stressors represents a novel approach for the development of therapeutic strategies, and in this context, neuroprotective effects of a wide range of polyphenol compounds have been demonstrated in several in vitro and in vivo studies and thoroughly reviewed. Mushrooms have been used in traditional medicine for many years and have been associated with a long list of therapeutic properties, including antitumor, immunomodulatory, antioxidant, antiviral, antibacterial, and hepatoprotective effects. Our recent studies have strikingly indicated the presence of polyphenols in nutritional mushrooms and demonstrated their protective effects in different models of neurodegenerative disorders in humans and rats. Although their therapeutic effects are exerted through multiple mechanisms, increasing attention is focusing on their capacity to induce endogenous defense systems by modulating cellular signaling processes such as nuclear factor erythroid 2 related factor 2 (Nrf2) and nuclear factor-kappa B (NF-&#954;B) pathways. Here we discuss the protective role of hormesis and its modulation by hormetic nutrients in ASD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Autism spectrum disorder (ASD) is a neurodevelopmental condition, which is characterized by clinical heterogeneity and high heritability. Core symptoms of ASD include deficits in social communication and interaction, as well as restricted, repetitive patterns of behavior, interests, or activities. Many genes have been identified that are associated with an increased risk for ASD. Proteins encoded by these ASD risk genes are often involved in processes related to fetal brain development, chromatin modification and regulation of gene expression in general, as well as the structural and functional integrity of synapses. Genes of the SH3 and multiple ankyrin repeat domains (SHANK) family encode crucial scaffolding proteins (SHANK1-3) of excitatory synapses and other macromolecular complexes. SHANK gene mutations are highly associated with ASD and more specifically the Phelan-McDermid syndrome (PMDS), which is caused by heterozygous 22q13.3-deletion resulting in SHANK3-haploinsufficiency, or by SHANK3 missense variants. SHANK3 deficiency and potential treatment options have been extensively studied in animal models, especially in mice, but also in rats and non-human primates. However, few of the proposed therapeutic strategies have translated into clinical practice yet. Main text: This review summarizes the literature concerning SHANK3-deficient animal models. In particular, the structural, behavioral, and neurological abnormalities are described and compared, providing a broad and comprehensive overview. Additionally, the underlying pathophysiologies and possible treatments that have been investigated in these models are discussed and evaluated with respect to their effect on ASD- or PMDS-associated phenotypes. Conclusions: Animal models of SHANK3 deficiency generated by various genetic strategies, which determine the composition of the residual SHANK3-isoforms and affected cell types, show phenotypes resembling ASD and PMDS. The phenotypic heterogeneity across multiple models and studies resembles the variation of clinical severity in human ASD and PMDS patients. Multiple therapeutic strategies have been proposed and tested in animal models, which might lead to translational implications for human patients with ASD and/or PMDS. Future studies should explore the effects of new therapeutic approaches that target genetic haploinsufficiency, like CRISPR-mediated activation of promotors. [ABSTRACT FROM AUTHOR]

A de novo 0.95 Mb 8p21.3 deletion had been identified in an individual with non-syndromic autism spectrum disorder (ASD) through high-resolution copy number variant analysis. Subsequent screening of in-house and publicly available databases resulted in the identification of six additional individuals with 8p21.3 deletions. Through case-based reasoning, we conclude that 8p21.3 deletions are rare causes of non-syndromic neurodevelopmental and neuropsychiatric disorders. Based on literature data, we highlight six genes within the region of minimal overlap as potential ASD genes or genes for neuropsychiatric disorders: DMTN, EGR3, FGF17, LGI3, PHYHIP, and PPP3CC. [ABSTRACT FROM AUTHOR]

The major biological function of the sperm cell is to transmit the paternal genetic and epigenetic information to the embryo as well as the following offspring. Sperm has a unique epigenome. An increasing body of epidemiological study supports that paternal stress induced by environmental exposures and lifestyle can modulate the sperm epigenome (including histone modification, DNA methylation, and noncoding RNA expression), sperm-egg fusion, embryo development, and offspring health. Based on the existing literature, we have summarized the paternal exposure on sperm epigenome along with the representative phenotypes of offspring and the possible mechanism involved. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a complex neurological disease characterized by impaired social communication and interaction skills, rigid behavior, decreased interest, and repetitive activities. The disease has a high degree of genetic heterogeneity, and the genetic cause of ASD in many autistic individuals is currently unclear. In this study, we report a patient with ASD whose clinical features included social interaction disorder, communication disorder, and repetitive behavior. We examined the patient's genetic variation using whole-exome sequencing technology and found new de novo mutations. After analysis and evaluation, ARRB2 was identified as a candidate gene. To study the potential contribution of the ARRB2 gene to the human brain development and function, we first evaluated the expression profile of this gene in different brain regions and developmental stages. Then, we used weighted gene coexpression network analysis to analyze the associations between ARRB2 and ASD risk genes. Additionally, the spatial conformation and stability of the ARRB2 wild type and mutant proteins were examined by simulations. Then, we further established a mouse model of ASD. The results showed abnormal ARRB2 expression in the mouse ASD model. Our study showed that ARRB2 may be a risk gene for ASD, but the contribution of de novo ARRB2 mutations to ASD is unclear. This information will provide references for the etiology of ASD and aid in the mechanism-based drug development and treatment. [ABSTRACT FROM AUTHOR]

Exome sequencing is a prominent tool to identify novel and deleterious mutations which could be non-sense, frameshift, and canonical splice-site mutations in a specific gene. De novo mutations in SYNGAP1, which codes for synaptic RAS-GTPase activating the protein, causes Intellectual disability (ID) and Autism Spectrum Disorder (ASD). SYNGAP1 related ASD/ID is one of the rare diseases that are detrimental to the healthy neuronal developmental and disrupts the global development of a child. We report the first SYNGAP1 heterozygous patient from Indian cohort. We report a case of a child of 2-year old with global developmental delay, microcephaly subtle dysmorphism, absence seizures, disrupted sleep, delay in learning a language, and eating problems. Upon further validation, the child has a few traits of ASD. Here, based on focused exome sequencing, we report a de novo heterozygous mutation in SYNGAP1 exon 11 with c. 1861 C > T (p.arg621ter). Currently, the child is on Atorvastatin, a RAS inhibitor, already available in the market for the treatment of hypercholesterolemia and has shown considerable improvement in global behaviour and cognitive development. The long-term follow up of the child's development would contribute to the already existing knowledge of the developmental trajectory in individuals with SYNGAP1 heterozygous mutation. In this report, we discuss the finding of a novel mutation in one of the genes, SYNGAP1, implicated in ASD/ID. Besides, we discuss the current treatment prescribed to the patient and the progress of global developmental of the child. [ABSTRACT FROM AUTHOR]

A growing body of empirical research on teacher victimization indicates that it is widespread and yields negative consequences. However, limited research has investigated the relationship between teacher victimization and turnover. In this study, using longitudinal data from approximately 1,300 teachers in a metropolitan area in Texas, USA, we find that many different types of victimization – theft, physical assault, verbal abuse, nonphysical contact aggression, and in-person bullying – with varying levels of prevalence and frequency as well as multiple victimizations are significantly associated with teachers' attrition through transfer and/or career exit. Moreover, about half of leavers in our sample reported school administrators' indifference and ineffective intervention as an important reason for their career exit. [ABSTRACT FROM AUTHOR]

Copy-number variants (CNVs), in particular rare, small and large ones (< 1% frequency) and those encompassing brain-related genes, have been shown to be associated with neurodevelopmental disorders like autism spectrum disorders (ASDs), attention deficit hyperactivity disorder (ADHD), and intellectual disability (ID). However, the vast majority of CNV findings lack specificity with respect to autistic or developmental-delay phenotypes. Therefore, the aim of the study was to investigate the size and frequency of CNVs in high-functioning ASD (HFA) without ID compared with a random population sample and with published findings in ASD and ID. To investigate the role of CNVs for the "core symptoms" of high-functioning autism, we included in the present exploratory study only patients with HFA without ID. The aim was to test whether HFA have similar large rare (> 1 Mb) CNVs as reported in ASD and ID. We performed high-resolution chromosomal microarray analysis in 108 children and adolescents with HFA without ID. There was no significant difference in the overall number of rare CNVs compared to 124 random population samples. However, patients with HFA carried significantly more frequently CNVs containing brain-related genes. Surprisingly, six HFA patients carried very large CNVs known to be typically present in ID. Our findings provide new evidence that not only small, but also large CNVs affecting several key genes contribute to the genetic etiology/risk of HFA without affecting their intellectual ability. [ABSTRACT FROM AUTHOR]

Background the hallmark of the neurobehavioural phenotype of Williams-Beuren syndrome (WBS) is increased sociability and relatively preserved language skills, often described as opposite to autism spectrum disorders (ASD). However, the prevalence of ASD in WBS is 6-10 times higher than in the general population. We have investigated the genetic factors that could contribute to the ASD phenotype in individuals with WBS. Methods We studied four males and four females with WBS and a confirmed diagnosis of ASD by the autism Diagnostic interview-revised. We performed a detailed molecular characterisation of the deletion and searched for genomic variants using exome sequencing. Results a de novo deletion of 1.55 Mb (6 cases) or 1.83 Mb (2 cases) at 7q11.23 was detected, being in 7/8 patients of paternal origin. no common breakpoint, deletion mechanism or size was found. two cases were hemizygous for the rare t allele at rs12539160 in MLXIPL, previously associated with ASD. inherited rare variants in ASD-related or functionally constrained genes and a de novo nonsense mutation in the UBR5 gene were identified in six cases, with higher burden in females compared with males (p=0.016). Conclusions the increased susceptibility to ASD in patients with WBS might be due to additive effects of the common WBS deletion, inherited and de novo rare sequence variants in ASD-related genes elsewhere in the genome, with higher burden of deleterious mutations required for females, and possible hypomorphic variants in the hemizygous allele or cis-acting mechanisms on imprinting. [ABSTRACT FROM AUTHOR]

Genetic (G) and environmental (E) factors are involved in the etiology and course of the major psychoses (MP), i.e. major depressive disorder (MDD), bipolar disorder (BD), schizoaffective disorder (SZA) and schizophrenia (SZ). The neurobiological correlates by which these predispositions exert their influence on brain structure, function and course of illness are poorly understood. In the FOR2107 consortium, animal models and humans are investigated. A human cohort of MP patients, healthy subjects at genetic and/or environmental risk, and control subjects (N = 2500) has been established. Participants are followed up after 2 years and twice underwent extensive deep phenotyping (MR imaging, clinical course, neuropsychology, personality, risk/protective factors, biomaterials: blood, stool, urine, hair, saliva). Methods for data reduction, quality assurance for longitudinal MRI data, and (deep) machine learning techniques are employed. In the parallelised animal cluster, genetic risk was introduced by a rodent model (Cacna1c deficiency) and its interactions with environmental risk and protective factors are studied. The animals are deeply phenotyped regarding cognition, emotion, and social function, paralleling the variables assessed in humans. A set of innovative experimental projects connect and integrate data from the human and animal parts, investigating the role of microRNA, neuroplasticity, immune signatures, (epi-)genetics and gene expression. Biomaterial from humans and animals are analyzed in parallel. The FOR2107 consortium will delineate pathophysiological entities with common neurobiological underpinnings ("biotypes") and pave the way for an etiologic understanding of the MP, potentially leading to their prevention, the prediction of individual disease courses, and novel therapies in the future. [ABSTRACT FROM AUTHOR]

Various factors may contribute to the emergence of Autism Spectrum Disorder (ASD). Genetic factors are particularly prominent in the etiology of ASD, and genetic syndromes may frequently accompany the disorder. Coffin-Siris syndrome is a genetic condition characterized by mental retardation, coarse facial appearance, hirsutism/hypertrichosis or skin with sparse hair, distal phalanx aplasia or hypoplasia, and fifth-finger and nail abnormalities. This genetic syndrome is accompanied by numerous different cardiac, genitourinary, gastrointestinal, ophthalmological, and craniofacial systemic abnormalities. ARID1B gene mutation is thought to be involved both in Coffin-Siris syndrome and in the etiology of autism. Although common genetic factors are involved in the etiologies of both diseases, our review of the literature revealed only one case report demonstrating an association between Coffin-Siris syndrome and ASD. This report describes a male patient aged 2 years and 10 months with ARID1B mutation showing Coffin-Siris syndrome and ASD comorbidity. It may be beneficial for clinicians to remember the coexistence of genetic syndromes in patients diagnosed with ASD and to request consultations from relevant departments for early diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a neurodevelopmental disorder, with strong genetic influences as evidenced by its high heritability. Submicroscopic variations (ranging from one kilobase to several megabases) in DNA, called copy number variations (CNVs), have been associated with psychiatric diseases, including ASD. We aimed to identify CNVs in children diagnosed with idiopathic ASD. We used microarray-based comparative genomic hybridization analysis to detect the CNVs, and bioinformatic tools to evaluate their pathogenic potential, based on predicted functional aspects. Using combined cytogenetic and bioinformatic tools, we identified an autism network of genes/proteins related to the CNVs. Among the 40 children analyzed, we found 14 potentially pathogenic CNVs, including those previously associated with ASD (located at 16p11.2, 15q11.2, and 7p21 regions). We suggest that the most relevant biological process and functional attributes involve olfactory receptors. The CNV-related autism network comprised 90 proteins and 754 nodes and indicated the family of olfactory receptors as a significant pathway in ASD. Olfactory receptors were previously associated with neurologic diseases, and they are possibly related to cognition. This integrative analysis that combines cytogenetics and bioinformatics is a promising approach to understand complex conditions such as ASD. [ABSTRACT FROM AUTHOR]

Objective: The immune system has been suggested to be associated with neuropsychiatric disorders; for example, elevated levels of cytokines and the inflammation-related transcription factor nuclear factor kappa-B (NF-κB) have been reported in individuals with autism spectrum disorder (ASD). The aim of this study was to investigate possible associations between autistic-like traits (ALTs) and single nucleotide polymorphisms (SNPs) in NFKB1 (encoding a subunit of the NF-κB protein complex) and NF-κB inhibitor-like protein 1 (NFKBIL1). Methods: The study was conducted in a cohort from the general population: The Child and Adolescent Twin Study in Sweden (CATSS, n = 12 319, 9–12 years old). The subjects were assessed by the Autism-Tics, ADHD, and Other Comorbidities Inventory. Five SNPs within the two genes were genotyped (NFKBIL1 : rs2857605, rs2239707, rs2230365 and rs2071592; NFKB1 : rs4648022). Results: We found significant associations for two SNPs in NFKBIL1 : rs2239707 showed a significant distribution of genotype frequencies in the case-control analysis both for all individuals combined and in boys only, and rs2230365 was significantly associated with the ALTs-module language impairment in boys only. Furthermore, we found nominal association in the case-control study for rs2230365, replicating earlier association between this SNP and ASD in an independent genome-wide association study. Conclusion: The shown associations between polymorphisms in NFKBIL1 and ALTs are supporting an influence of the immune system on neuropsychiatric symptoms. [ABSTRACT FROM AUTHOR]

Autism is a wide spread neurodevelopmental disorder with growing morbidity rates, affecting more boys than girls worldwide. Activity-dependent neuroprotective protein (ADNP) was recently recognized as a leading gene accounted for 0.17% of autism spectrum disorder (ASD) cases globally. Respectively, mutations in the human ADNP gene (ADNP syndrome), cause multi-system body dysfunctions with apparent ASD-related traits, commencing as early as childhood. The Adnp haploinsufficient (Adnp+/−) mouse model was researched before in relations to Alzheimer's disease and autism. Adnp+/− mice suffer from deficient social memory, vocal and motor impediments, irregular tooth eruption and short stature, all of which corresponds with reported phenotypes in patients with the ADNP syndrome. Recently, a more elaborated description of the ADNP syndrome was published, presenting impediments such as hearing disabilities in > 10% of the studied children. Irregular auditory brainstem response (ABR) has been connected to ASD-related cases and has been suggested as a potential hallmark for autism, allowing diagnosis of ASD risk and early intervention. Herein, we present detriment hearing in the Adnp+/− mice with atypical ABR and significant protein expression irregularities that coincides with ASD and hearing loss studies in the brain. [ABSTRACT FROM AUTHOR]

Teacher victimization is a relatively understudied phenomenon that may contribute to teacher turnover. The purpose of this study is to explore the relationship between teacher reports of victimization and teachers leaving their school and the profession. Using nationally representative data (n = 104,840) from the Schools and Staffing Survey, we examine the extent to which being threatened or attacked by students predicts higher rates of teacher turnover and whether this relationship differs due to factors that may promote teacher resilience. We utilize conditional multinomial logistic regression, implicitly controlling for school-by-year fixed effects. Findings suggest that perceived victimization predicts an increased probability of leaving the school and profession. School-level promoters of resilience are found to lessen this relationship. We discuss ways schools can mitigate the impact of victimization. This work contributes to a nascent body of literature on teacher victimization and informs a policy lever by which turnover may be reduced. [ABSTRACT FROM AUTHOR]

MACRO Domain Containing 2 (MacroD2) is a neurodevelopmental disorder-related mono-ADP-ribosylhydrolase. Molecular features of this protein in neural tissues are largely unknown. In this study, we generated a specific antibody against MacroD2, and carried out expression and morphological analyses of the molecule during mouse brain development. In Western blotting, 2 MacroD2 isoforms with molecular masses of ∼70 and ∼75 kDa started to be expressed at embryonic day 16.5, reached the maximal level at postnatal day 8, and then gradually decreased through P30. In contrast, other isoforms with molecular masses of ∼110 and ∼140 kDa gradually increased during embryonic to postnatal development. In immunohistochemical analyses, MacroD2 was strongly detected in cortical neurons in layer II–V at P0 and P7, while the protein expression decreased significantly in the neurons at P30. Immunofluorescence analyses revealed that MacroD2 was mainly distributed in the soma and to a lesser extent in the axon and dendrite of immature primary cultured mouse hippocampal neurons. On the other hand, in the matured hippocampal neurons, while MacroD2 was detected in the soma, it displayed in dendrites a punctate distribution pattern with a partial colocalization with synaptic markers, synaptophysin, and PSD95. The obtained results indicate that MacroD2 is expressed and may have a physiological role in the central nervous system during brain development. [ABSTRACT FROM AUTHOR]

Aim: The development of whole-genome screening methodologies for the detection of copy number variations (CNVs), such as array-based comparative genomic hybridization (aCHG), provides a much higher resolution than karyotyping leading to the identification of novel microdeletion and microduplication syndromes often associated with an autism spectrum disease (ASD) phenotype. The aim of the study was to determine CNVs of patients with ASD by using array-based comparative genomic hybridization. Methods: Fifty-three patients diagnosed with ASD between 20.01.2014 and 14.01.2015 were included in the study. Chromosome analysis of the patients was performed from peripheral blood cultures and analysed as normal. All patients were evaluated with P064C1 and P096A2 MLPA probes in terms of 16 mental retardation related syndromes. For aCGH method, SurePrint G3 Human microarrays 8x60K were used with genomic DNA isolated from peripheral blood. Results: According to results of 53 patients who were included in and performed with arrayCGH, 8 (15%) patients had CNVs classified as pathogenic or variant of unknown significance (VOUS) in the study. We detected a pathogenic NRXN1 gene partial CNV deletion (2p16.3) in two patients. Also we identified a 900 kb duplication of 4p15.31 including SLIT2 gene, and a 245 kb duplication of 15q11.2 including PWRN1 gene in one patient. Our other findings are considered to be a variant of unknown significance (VOUS). Conclusion: The results of the study support the literature knowledge, where the copy number variations that cannot be detected with conventional cytogenetics methods in terms of size may happen in patients with ASD. [ABSTRACT FROM AUTHOR]

Mental disorders, such as schizophrenia, bipolar disorder, and autism spectrum disorder, are challenging to manage, worldwide. Understanding the molecular mechanisms underlying these disorders is essential and required. Studies investigating such molecular mechanisms are well performed and important findings are accumulating apace. Based on the fact that these disorders are due in part to the accumulation of genetic and environmental risk factors, consideration of multi-molecular and/or multi-system dependent phenomena might be important. Acidic glycans are an attractive family of molecules for understanding these disorders, because impairment of the fine-tuned glycan system affects a large number of molecules that are deeply involved in normal brain function. One of the candidates of this important family of glycan epitopes in the brain is polysialic acid (PSA/polySia). PSA is a well-known molecule because of its role as an oncodevelopmental antigen and is also widely used as a marker of adult neurogenesis. Recently, several reports have suggested that PSA and PSA-related genes are associated with multiple mental disorders. The relationships among PSA, PSA-related genes, and mental disorders are reviewed here. [ABSTRACT FROM AUTHOR]

A genetic analysis of unexplained mild-moderate intellectual disability and co-morbid psychiatric or behavioural disorders is not systematically conducted in adults. A cohort of 100 adult patients affected by both phenotypes were analysed in order to identify the presence of copy number variants (CNVs) responsible for their condition identifying a yield of 12.8% of pathogenic CNVs (19% when including clinically recognizable microdeletion syndromes). Moreover, there is a detailed clinical description of an additional 11% of the patients harbouring possible pathogenic CNVs—including a 7q31 deletion (IMMP2L) in two unrelated patients and duplications in 3q29, 9p24.2p24.1 and 15q14q15.1—providing new evidence of its contribution to the phenotype. This study adds further proof of including chromosomal microarray analysis (CMA) as a mandatory test to improve the diagnosis in the adult patients in psychiatric services. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is defined by the triad of deficits in social interactions, deficits in communication, and repetitive behaviors. Common co-morbidities in syndromic forms of ASD include intellectual disability, seizures, and obesity. We asked whether very obese children with ASD had different behavioral, physical and genetic characteristics compared to children with ASD who were not obese. We found that very obese children with ASD had significantly poorer scores on standardized behavioral tests. Very obese boys with ASD had lower full scale IQ and increased impairments with respect to stereotypies, communication and social skills. Very obese girls with ASD had increased impairments with respect to irritability and oppositional defiant behavior. We identified genetic lesions in a subset of the children with ASD and obesity and attempted to identify enriched biological pathways. Our study demonstrates the value of identifying co-morbidities in children with ASD as we move forward towards understanding the biological processes that contribute to this complex disorder and prepare to design customized treatments that target the diverse genetic lesions present in individuals with ASD. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is an early-onset neurodevelopmental disorder characterized by impairments in social behaviors and communication. Oxytocin and its signaling pathway are related to a range of human behaviors, from facial expression recognition to aggressive behaviors, and have been suggested as involved in the etiology of ASD. Our aim was to evaluate the influence of two polymorphisms (rs1042778, rs53576) at the oxytocin receptor gene (OXTR) on ASD diagnosis and on specific ASD-related clinical symptoms (seizures, panic, and aggressive behaviors). We also assessed if these SNPs could be related to changes in OXTR availability and functionality using a bioinformatic approach. The sample was composed by 209 probands with ASD and their biological parents. Family-based approach and logistic regression models were used to investigated the outcomes. We observed that panic and aggressive behaviors were nominally associated with presence of rs1042778 T allele (P = 0.019/Pcorr = 0.114; P = 0.046/Pcorr = 0.276 respectively). Also, in the family-based analysis, a trend towards association with ASD susceptibility was observed for rs1042778 (G allele) (P = 0.066). In a bioinformatic approach, we demonstrated that rs1042778 G allele is determinant for the binding of the transcription factor MAZ, suggesting that when the T allele is present, the absence of MAZ binding might be associated with lower transcription levels of the OXTR gene. The overall findings suggest that the OXTR gene may play a role in ASD diagnosis and some of its clinical phenotypes, supported by previous animal and clinical studies. Further investigations are necessary to replicate our findings and fully understand the effects of the oxytocin pathway on ASD. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) has a strong genetic basis, although the genetics of autism is complex and it is unclear. Genetic testing such as microarray or sequencing was widely used to identify autism markers, but they are unsuccessful in several cases. The objective of this study is to identify causative variants of autism in two Thai families by using whole-exome sequencing technique. Whole-exome sequencing was performed with autism-affected children from two unrelated families. Each sample was sequenced on SOLiD 5500xl Genetic Analyzer system followed by combined bioinformatics pipeline including annotation and filtering process to identify candidate variants. Candidate variants were validated, and the segregation study with other family members was performed using Sanger sequencing. This study identified a possible causative variant for ASD, c.2951G>A, in the FGD6 gene. We demonstrated the potential for ASD genetic variants associated with ASD using whole-exome sequencing and a bioinformatics filtering procedure. These techniques could be useful in identifying possible causative ASD variants, especially in cases in which variants cannot be identified by other techniques. [ABSTRACT FROM AUTHOR]

Background: Copy number variations (CNVs) are large segments of the genome that are duplicated or deleted. Structural variations in the genome have been linked to many complex diseases. Similar to how genome-wide association studies (GWAS) have helped discover single-nucleotide polymorphisms linked to disease phenotypes, the extension of GWAS to CNVs has aided the discovery of structural variants associated with human traits and diseases. Results: We present CoNVaQ, an easy-to-use web-based tool for CNV-based association studies. The web service allows users to upload two sets of CNV segments and search for genomic regions where the occurrence of CNVs is significantly associated with the phenotype. CoNVaQ provides two models: a simple statistical model using Fisher's exact test and a novel query-based model matching regions to user-defined queries. For each region, the method computes a global q-value statistic by repeated permutation of samples among the populations. We demonstrate our platform by using it to analyze a data set of HPV-positive and HPV-negative penile cancer patients. Conclusions: CoNVaQ provides a simple workflow for performing CNV-based association studies. It is made available as a web platform in order to provide a user-friendly workflow for biologists and clinicians to carry out CNV data analysis without installing any software. Through the web interface, users are also able to analyze their results to find overrepresented GO terms and pathways. In addition, our method is also available as a package for the R programming language. CoNVaQ is available at https://convaq.compbio.sdu.dk. [ABSTRACT FROM AUTHOR]

Copy number variation may be the most common form of structural genetic variation in the genome. Numerous studies have shown that gene copy number variation can correlate with phenotypic variation, where higher copy numbers correspond to increased expression of the protein and vice versa. Examples include some digestive enzyme genes, where variation in copy numbers and protein expression may be related to dietary differences. Increasing the expression of a digestive enzyme through higher gene copy numbers may thus be a potential mechanism for altering an organism’s digestive capabilities. I investigated copy number variation in genes coding for acidic mammalian chitinase, a chitinolytic digestive enzyme that may be used for the digestion of insect exoskeletons, in nonhuman primates with varying levels of insect consumption. I hypothesized that CHIA copy number correlates positively with level of insectivory, predicting higher copy numbers in more insectivorous primates. I assessed copy number variation with the QuantStudio 3D digital PCR platform, in a comparative sample of Old World and New World primate species (N = 10 species, one or two individuals each). Contrary to my prediction, no evidence of copy number variation was found and all species tested had two gene copies per diploid genome. These findings suggest that if acidic mammalian chitinase expression varies according to insect consumption in primates, it may be up- or downregulated through another mechanism. [ABSTRACT FROM AUTHOR]

Genetic studies in Tourette syndrome (TS) are characterized by scattered and poorly replicated findings. We aimed to replicate findings from candidate gene and genome-wide association studies (GWAS). Our cohort included 465 probands with chronic tic disorder (93% TS) and both parents from 412 families (some probands were siblings). We assessed 75 single nucleotide polymorphisms (SNPs) in 465 parent-child trios; 117 additional SNPs in 211 trios; and 4 additional SNPs in 254 trios. We performed SNP and gene-based transmission disequilibrium tests and compared nominally significant SNP results with those from a large independent case-control cohort. After quality control 71 SNPs were available in 371 trios; 112 SNPs in 179 trios; and 3 SNPs in 192 trios. 17 were candidate SNPs implicated in TS and 2 were implicated in obsessive-compulsive disorder (OCD) or autism spectrum disorder (ASD); 142 were tagging SNPs from eight monoamine neurotransmitter-related genes (including dopamine and serotonin); 10 were top SNPs from TS GWAS; and 13 top SNPs from attention-deficit/hyperactivity disorder, OCD, or ASD GWAS. None of the SNPs or genes reached significance after adjustment for multiple testing. We observed nominal significance for the candidate SNPs rs3744161 (TBCD) and rs4565946 (TPH2) and for five tagging SNPs; none of these showed significance in the independent cohort. Also, SLC1A1 in our gene-based analysis and two TS GWAS SNPs showed nominal significance, rs11603305 (intergenic) and rs621942 (PICALM). We found no convincing support for previously implicated genetic polymorphisms. Targeted re-sequencing should fully appreciate the relevance of candidate genes. [ABSTRACT FROM AUTHOR]

The process of development depends on a number of signaling systems that regulates the progressive sequence of developmental events. Infertility and neurodevelopmental diseases, such as attention deficit hyperactivity disorder, autism spectrum disorders, and schizophrenia, are caused by specific alterations in these signaling processes. Calcium signaling plays a prominent role throughout development beginning at fertilization and continuing through early development, implantation, and organ differentiation such as heart and brain development. Vitamin D plays a major role in regulating these signaling processes that control development. There is an increase in infertility and an onset of neurodevelopmental diseases when vitamin D is deficient. The way in which vitamin D deficiency acts to alter development is a major feature of this review. One of the primary functions of vitamin D is to maintain the phenotypic stability of both the Ca2+ and redox signaling pathways that play such a key role throughout development. [ABSTRACT FROM AUTHOR]

The genetic architecture underlying Autism spectrum disorder (ASD) has been suggested to differ between individuals with lower (IQ ≤ 70; LIQ) and higher intellectual abilities (IQ > 70; HIQ). Among the identified pathomechanisms, the glutamatergic signalling pathway is of specific interest in ASD. We investigated 187 common functional variants of this neurotransmitter system for association with ASD and with symptom severity in two independent samples, a German (German-ALL: N = 583 families) and the Autism Genome Project cohort (AGP-ALL: N = 2001 families), split into HIQ, and LIQ subgroups. We did not identify any association withstanding correction for multiple testing. However, we report a replicated nominal significant under-transmission (OR < 0.79, p < 0.04) of the AKAP13 rs745191-T allele in both LIQ cohorts, but not in the much larger HIQ cohorts. At the phenotypic level, we nominally replicated associations of CAMK2A-rs2241694 with non-verbal communication in both combined LIQ and HIQ ASD cohorts. Variants PLD1-rs2124147 and ADCY1-rs2461127 were nominally associated with impaired non-verbal abilities and AKAP2-rs3739456 with repetitive behaviour in both LIQ cohorts. All four LIQ-associated genes are involved in G-protein coupled signal transduction, a downstream pathway of metabotropic glutamate receptor activation. We conclude that functional common variants of glutamatergic genes do not have a strong impact on ASD, but seem to moderately affect ASD risk and phenotypic expression. Since most of our nominally replicated hits were identified in the LIQ cohort, further investigation of the glutamatergic system in this subpopulation might be warranted. [ABSTRACT FROM AUTHOR]

Alterations of the gamma-aminobutyric acid (GABA) signaling system has been strongly linked to the pathophysiology of autism spectrum disorder (ASD). Genetic associations of common variants in GABA receptor subunits, in particular GABRA4 on chromosome 4p12, with ASD have been replicated by several studies. Moreover, molecular investigations have identified altered transcriptional and translational levels of this gene and protein in brains of ASD individuals. Since the genotyped common variants are likely not the functional variants contributing to the molecular consequences or underlying ASD phenotype, this study aims to examine rare sequence variants in GABRA4, including those outside the protein coding regions of the gene. We comprehensively re-sequenced the entire protein coding and noncoding portions of the gene and putative regulatory sequences in 82 ASD individuals and 55 developmentally typical pediatric controls, all homozygous for the most significant previously associated ASD risk allele (G/G at rs1912960). We identified only a single common, coding variant, and no association of any single marker or set of variants with ASD. Functional annotation of noncoding variants identified several rare variants in putative regulatory sites. Finally, a rare variant unique to ASD cases, in an evolutionary conserved site of the 3′UTR, shows a trend toward decreasing gene expression. Hence, GABRA4 rare variants in noncoding DNA may be variants of modest physiological effects in ASD etiology. [ABSTRACT FROM AUTHOR]

Introduction: The mechanism of ubiquitination-related abnormalities causing neural development problems is still unclear. We examined the association between autism and serum transactive response DNA-binding protein-43 (TDP-43) and ubiquitin c-terminal hydrolase-L1 (UCH-L1) levels, both of which are members of the ubiquitin- proteosome system. Methods: We measured serum levels of TDP-43 and UCH-L1 in 24 children with autism and 24 healthy children. Childhood Autism Rating Scale (CARS) was used to assess symptom severity at admission. Results: The mean serum TDP-43 and UCH-L1 levels in children with autism spectrum disorder (ASD) were found to decrease compared to healthy controls (p<0.001, 506.21±780.97 ng/L and 1245.80±996.76 ng/L, respectively; 3.08±5.44 ng/mL and 8.64±6.67 ng/mL, respectively). A positive correlation between serum TDP-43 levels and UCH-L1 levels was found in the ASD group (r=0.947, n=24, p<0.001). The CARS score of children with ASD was 48.91 points (standard deviation [SD]: 5.82). Conclusion: Low serum levels of UCH-L1 and TDP-43 may reflect disturbed ubiquitination in autism. [ABSTRACT FROM AUTHOR]

Angelman syndrome (AS) is a neurodevelopmental disorder largely caused by the loss of function of maternally inherited UBE3A. UBE3A-maternal deficient mice (AS mice) exhibit many typical features of AS including cognitive and motor deficits but the underlying mechanism of these behavioral abnormalities is poorly understood. Here, we demonstrate that rearing of AS mice in the enriched environment for prolonged period significantly improved their cognitive and motor dysfunction. Enriched environment also restored elevated serum corticosterone level and reduced anxiety-like behaviors in these mice. Biochemical analysis further revealed restoration of altered levels of brain-derived neurotrophic factor, glucocorticoid receptor, and phoshphorylated calcium/calmodulin-dependent protein kinase IIα in the hippocampus of AS mice maintained in the enriched environment. Enriched environment also significantly increased the number of parvalbumin-positive GABAergic interneuron in the hippocampus and basolateral amygdala of AS mice. These results indicate potential beneficial effect of enriched environment in the reversal of AS phenotype. [ABSTRACT FROM AUTHOR]

Background Microdeletions are known to confer risk to epilepsy, particularly at genomic rearrangement 'hotspot' loci. However, microdeletion burden not overlapping these regions or within different epilepsy subtypes has not been ascertained. Objective To decipher the role of microdeletions outside hotspots loci and risk assessment by epilepsy subtype. Methods We assessed the burden, frequency and genomic content of rare, large microdeletions found in a previously published cohort of 1366 patients with genetic generalised epilepsy (GGE) in addition to two sets of additional unpublished genome-wide microdeletions found in 281 patients with rolandic epilepsy (RE) and 807 patients with adult focal epilepsy (AFE), totalling 2454 cases. Microdeletions were assessed in a combined and subtype-specific approaches against 6746 controls. Results When hotspots are considered, we detected an enrichment of microdeletions in the combined epilepsy analysis (adjusted p=1.06×10-6,OR 1.89, 95% CI 1.51 to 2.35). Epilepsy subtype-specific analyses showed that hotspot microdeletions in the GGE subgroup contribute most of the overall signal (adjusted p=9.79×10-12, OR 7.45, 95% CI 4.20-13.5). Outside hotspots, microdeletions were enriched in the GGE cohort for neurodevelopmental genes (adjusted p=9.13×10-3,OR 2.85, 95% CI 1.62-4.94). No additional signal was observed for RE and AFE. Still, gene-content analysis identified known (NRXN1, RBFOX1 and PCDH7) and novel (LOC102723362) candidate genes across epilepsy subtypes that were not deleted in controls. Conclusions Our results show a heterogeneous effect of recurrent and non-recurrent microdeletions as part of the genetic architecture of GGE and a minor contribution in the aetiology of RE and AFE. [ABSTRACT FROM AUTHOR]

ABSTRACT Ubiquitination regulates a broad array of cellular processes, and defective ubiquitination is implicated in several neurological disorders. Loss of the E3 ubiquitin-protein ligase UBE3A causes Angelman syndrome. Despite its clinical importance, the normal role of UBE3A in neurons is still unclear. As a step toward deciphering its possible functions, we performed high-resolution light and electron microscopic immunocytochemistry. We report a broad distribution of UBE3A in neurons, highlighted by concentrations in axon terminals and euchromatin-rich nuclear domains. Our findings suggest that UBE3A may act locally to regulate individual synapses while also mediating global, neuronwide influences through the regulation of gene transcription. J. Comp. Neurol. 525:233-251, 2017. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]