Early-onset Neurodevelopmental Disorders Research Articles

Adult onset cerebellar ataxia due to novel mutations in BRAT1

BRAT 1 (BRCA1-associated ATM activator 1) variants were first reported in 2012 in newborns with lethal neonatal rigidity and multifocal seizure syndrome (RMFSL). They have also been associated with early onset neurodevelopmental disorder with cerebellar atrophy and with or without seizures (NEDCAS). More recently a milder phenotype characterized by nonprogressive cerebellar ataxia (NPCA) has been reported. We describe the case of a 66 year old woman with sporadic cerebellar ataxia, spasticity and mental retardation in whom we detected two novel mutations in BRAT1.

Patterns of Lifetime Criminality in Mentally Disordered Offenders - Findings From a Nationally Representative Cohort.

Background: Treatment of mentally disordered offenders (MDOs) is challenging as their behavior and clinical conditions can be traced to a complex constellation of major mental disorders, substance use and antisocial lifestyle. Finding subgroups of these offenders, which could guide treatment and risk assessment, is desirable. There are few long-term, prospective studies of risk factors for persistent criminal behavior among MDOs.Aims: The aims are (1) to provide a map of lifetime criminality in MDOs, (2) to identify subgroups of offenders, and (3), if such clusters exist, to test whether they differ in lifetime criminality and patterns of negative events during in-patient treatment.Methods: Background data on all offenders from the Malmö University Hospital catchment area sentenced to forensic psychiatric in-patient treatment 1999–2005 (n = 125) was collected. Data on negative events during treatment (violence, threats, absconding and substance use) from date of admittance until discharge or until June 30, 2008 was gathered. Court decisions for 118 of the cohort-individuals were collected from the 1st of January 1973 until December 31, 2013. We used hierarchical cluster analysis to identify subgroups and MANOVA-analysis to examine differences between these clusters on lifetime criminality variables and negative events. A MANCOVA was used to control for time in treatment.Results: The cohort was sentenced to a total of 3,380 crimes (944 violent) during the study period. Median age at first crime was 20 years (range 15–72), and at first violent crime 27 years (range 15–72). A subgroup (n = 26) was characterized by childhood adversities, neurodevelopmental disorders and later substance use disorders and was more often associated with substance-related crimes, financial crimes and lower age at first crime. During treatment, this cluster showed higher rates of substance use and threats. When controlling for treatment time, no differences in negative events were found.Conclusions: This study replicated findings from prison populations of the existence of a more criminally persistent phenotype characterized by early-onset neurodevelopmental and behavior disorders, childhood adversities and later substance use disorders. We did not find this cluster of variables to be related to negative events during inpatient treatment when controlling for length of stay.

Differential Metabolites in Chinese Autistic Children: A Multi-Center Study Based on Urinary 1H-NMR Metabolomics Analysis.

Background: Autism spectrum disorder (ASD) is a group of early-onset neurodevelopmental disorders. However, there is no valuable biomarker for the early diagnosis of ASD. Our large-scale and multi-center study aims to identify metabolic variations between ASD and healthy children and to investigate differential metabolites and associated pathogenic mechanisms.Methods: One hundred and seventeen autistic children and 119 healthy children were recruited from research centers of 7 cities. Urine samples were assayed by 1H-NMR metabolomics analysis to detect metabolic variations. Multivariate statistical analysis, including principal component analysis (PCA), and orthogonal projection to latent structure discriminant analysis (OPLS-DA), as well as univariate analysis were used to assess differential metabolites between the ASD and control groups. The differential metabolites were further analyzed by receiver operating characteristics (ROC) curve analysis and metabolic pathways analysis.Results: Compared with the control group, the ASD group showed higher levels of glycine, guanidinoacetic acid, creatine, hydroxyphenylacetylglycine, phenylacetylglycine, and formate and lower levels of 3-aminoisobutanoic acid, alanine, taurine, creatinine, hypoxanthine, and N-methylnicotinamide. ROC curve showed relatively significant diagnostic values for hypoxanthine [area under the curve (AUC) = 0.657, 95% CI 0.588 to 0.726], creatinine (AUC = 0.639, 95% CI 0.569 to 0.709), creatine (AUC = 0.623, 95% CI 0.552 to 0.694), N-methylnicotinamide (AUC = 0.595, 95% CI 0.523 to 0.668), and guanidinoacetic acid (AUC = 0.574, 95% CI 0.501 to 0.647) in the ASD group. Combining the metabolites creatine, creatinine and hypoxanthine, the AUC of the ROC curve reached 0.720 (95% CI 0.659 to 0.777). Significantly altered metabolite pathways associated with differential metabolites were glycine, serine and threonine metabolism, arginine and proline metabolism, and taurine and hypotaurine metabolism.Conclusions: Urinary amino acid metabolites were significantly altered in children with ASD. Amino acid metabolic pathways might play important roles in the pathogenic mechanisms of ASD.

Predictors of an earlier diagnosis of Autism Spectrum Disorder in children and adolescents: a systematic review (1987-2017).

Autism Spectrum Disorder (ASD) is an early onset neurodevelopmental disorder in which the first signs generally emerge at approximately 12months of age but its diagnosis is feasible only from the age of 18months. According to the literature, the average age of diagnosis ranges from 2.7 to 7.2years, which raises the question of factors associated with early diagnosis as a condition for early intervention. In this systematic review, we aim to identify clinical, social, and environmental factors associated with the age at which the diagnosis of ASD is confirmed in children. A literature search was performed in the Pubmed, Web of Sciences, PsycInfo, and Cochrane databases. Among the 530 publications identified, 50 were selected according to the inclusion criteria. This review focuses on studies conducted in 21 countries using data collected over a period from 1987 to 2017. These studies were published before December 31st, 2019. The results suggest that the diagnosis of ASD occurs earlier if there is a delay in social communication or the presence of intellectual disability. There is a low level of evidence concerning associations between the age at diagnosis and sex, race, parental education, or socioeconomic status and accessibility to health care. Further studies using large and well-characterized data sets are needed to simultaneously explore clinical and socio-environmental factors involved in early diagnosis.

A Review of the Efficacy of the Dietary Intervention in Autism Spectrum Disorder

BACKGROUND: Autism spectrum disorder (ASD) is an early-onset neurodevelopmental disorder with 1 in 68 children prevalence. The key symptoms of ASD include social deficits, verbal and non-verbal communication deficits, and restricted, repetitive patterns of behavior, interests, or activities. For unknown reasons, gastrointestinal symptoms are related to ASD. The aim of the current paper is to review the available literature on dietary interventions in children with ASD and provide up-to-date evidence. METHODS: Searches in online databases, using the search terms’ dietary intervention, “autism spectrum disorders,” and “autism” were conducted. The search targeted publications ranging from 2010 to 2020. RESULTS: Twenty-six studies with different study designs which evaluated the effectiveness of specific dietary interventions in children with ASD were included in our review. Several dietary interventions were of popular practice in the management of children with ASD, including elimination (gluten-/casein-free diet and oligoantigenic diet), modification (modified ketogenic diet), supplementation (minerals, vitamins, omega 3, and omega 6), and exclusion (food additives). Studies showed different results with varying degrees of evidence. Overall, data were inadequate to make accurate conclusions. CONCLUSION: There is little evidence to support the use of dietary interventions for children with ASD. Additional high-quality studies and further research are, therefore, needed.

31.1 INCORPORATING A FAMILY-BASED APPROACH IN SUPPORTING FAMILIES OF CHILDREN WITH NEURODEVELOPMENTAL DISORDERS

Early-onset neurodevelopmental disorders are more commonly diagnosed in boys than girls. It has been postulated that prenatal stress disproportionately affects male vs female fetuses. Epigenetic factors likely are at play throughout life as well, and ongoing stress can have an impact. As such, family functioning and existing comorbidities can have a significant effect on a child with neurodevelopmental disorders. This presentation aims to address the importance of assessing the family by recognizing the central role family plays in promoting health and wellness.

Exposure to a high dose of amoxicillin causes behavioral changes and oxidative stress in young zebrafish.

Autistic spectrum disorder (ASD) is a group of early-onset neurodevelopmental disorders characterized by impaired social and communication skills. Autism is widely described as a behavioral syndrome with multiple etiologies where may exhibit neurobiological, genetic, and psychological deficits. Studies have indicated that long term use of antibiotics can alter the intestinal flora followed by neuroendocrine changes, leading to behavioral changes. Indeed, previous studies demonstrate that a high dose of amoxicillin can change behavioral parameters in murine animal models. The objective was to evaluate behavioral and oxidative stress parameters in zebrafish exposed to a high dose of amoxicillin for 7days. Young zebrafish were exposed to a daily concentration of amoxicillin (100mg/L) for 7days. Subsequently, the behavioral analysis was performed, and the brain content was dissected for the evaluation of oxidative stress parameters. Zebrafish exposed to a high dose of amoxicillin showed locomotor alteration and decreased social interaction behavior. In addition, besides the significant decrease of sulfhydryl content, there was a marked decrease in catalase activity, as well as an increased superoxide dismutase activity in brain tissue. Thus, through the zebrafish model was possible to note a central effect related to the exposition of amoxicillin, the same as observed in murine models. Further, the present data reinforce the relation of the gut-brain-axis and the use of zebrafish as a useful tool to investigate new therapies for autistic traits.

A novel homozygous variant in an Iranian pedigree with cerebellar ataxia, mental retardation, and dysequilibrium syndrome type 4.

BackgroundCerebellar ataxia, mental retardation, and dysequilibrium (CAMRQ) syndrome is a rare and early‐onset neurodevelopmental disorder. Four subtypes of this syndrome have been identified, which are clinically and genetically different. To date, altogether 32 patients have been described with ATP8A2 mutations and phenotypic features assigned to CAMRQ type 4. Herein, three additional patients in an Iranian consanguineous family with non‐progressive cerebellar ataxia, severe hypotonia, intellectual disability, dysarthria, and cerebellar atrophy have been identified.MethodsFollowing the thorough clinical examination, consecutive detections including chromosome karyotyping, chromosomal microarray analysis, and whole exome sequencing (WES) were performed on the proband. The sequence variants derived from WES interpreted by a standard bioinformatics pipeline. Pathogenicity assessment of candidate variant was done by in silico analysis. The familial cosegregation of the WES finding was carried out by PCR‐based Sanger sequencing.ResultsA novel homozygous missense variant (c.1339G > A, p.Gly447Arg) in the ATP8A2 gene was identified and completely segregated with the phenotype in the family. In silico analysis and structural modeling revealed that the p.G477R substitution is deleterious and induced undesired effects on the protein stability and residue distribution in the ligand‐binding pocket. The novel sequence variant occurred within an extremely conserved subregion of the ATP‐binding domain.ConclusionOur findings expand the spectrum of ATP8A2 mutations and confirm the reported genotype‐phenotype correlation. These results could improve genetic counseling and prenatal diagnosis in families with clinical presentations related to CAMRQ4 syndrome.

Neurodevelopmental disorders among young adults and the risk of sickness absence and disability pension: a nationwide register linkage study.

ObjectivesAttention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD) and learning disabilities (LD) have an early onset and often persist into adulthood, although their relative contribution to incapacity for work is unclear. We examined this issue among young adults with ADHD, ASD or LD taking into account socioeconomic factors and comorbid mental disorders.MethodsRecorded diagnoses between the ages of 10–35 years between 2001 and 2010 were derived from nationwide inpatient and specialized outpatient hospital registers in Sweden. We identified 15 632 individuals with a main diagnosis of ADHD, 8238 with ASD, and 1038 with LD, and the matched control group without recorded mental disorders (N=124 536). The outcome was the number of register-based sickness absence and work disability pension (SA-DP) days during a maximum of three years follow-up.ResultsAmong men, the rate ratio (RR) of SA-DP was 11.17 [95% confidence interval (CI) 9.89–12.60] for ADHD, 35.59 (95% CI 30.30–41.81) for ASD, and 9.20 (95% CI 5.76–14.70) for LD, in comparison to those in the reference group. The corresponding risks among women were RR 12.05 (95% CI 10.30–14.09) for ADHD, RR 28.36 (95% CI 22.96–35.02) for ASD, and RR 9.60 (95% CI 5.83–15.81) for LD. The findings were, to a large extent, similar when individuals on DP at baseline were excluded. Comorbid mental disorders further increased the risk of SA-DP. Educational differences were smaller among the patients than in the reference group.ConclusionsEarly-onset neurodevelopmental disorders, particularly with comorbidity, have a far-reaching impact on adult life in terms of SA and DP.

Attention Deficit Hyperactivity Disorder And Borderline Personality Disorder In Adults: A Review Of Their Links And Risks.

Attention deficit hyperactivity disorder (ADHD) and borderline personality disorder (BPD) are particularly common disorders, that are highly comorbid in adult populations. The symptomatic overlap between adult ADHD and BPD includes impulsivity, emotional dysregulation and interpersonal impairment, which makes the differential diagnosis difficult. Our review aims at focusing on recent data on the comorbid ADHD+BPD form, as well as the risk factors involved in the emergence of the two disorders. While adult ADHD and BPD share some genetic and temperamental risk factors, adult ADHD is characterized by more severe trait-impulsivity compared to non-comorbid BPD; BPD patients display more severe trait-emotion regulation symptoms compared to non-comorbid ADHD. Patients with the comorbid ADHD+BPD form have severe symptoms in both dimensions. Early-life exposure to adverse events is a shared risk factor for the development of ADHD and BPD, but type and timing of adversity seem to play a differential role in the development of BPD and ADHD symptoms. Age of onset used to be a discriminative diagnostic criterion between ADHD, an early-onset neurodevelopmental disorder, and BPD, a late-onset psychological disorder. However, this distinction has been recently called into question, increasing the need for more research aiming at delineating the disorders from a developmental and clinical standpoint. Clinicians should carefully consider the comorbidity, and consider ADHD and BPD dimensionally, in order to provide more effective patient management. This might improve early preventive interventions, and treatment for comorbid conditions in adulthood.

Dynamic postnatal development of the cellular and circuit properties of striatal D1 and D2 spiny projection neurons.

Key points Imbalances in the activity of the D1‐expressing direct pathway and D2‐expressing indirect pathway striatal projection neurons (SPNs) are thought to contribute to many basal ganglia disorders, including early‐onset neurodevelopmental disorders such as obsessive–compulsive disorder, attention deficit hyperactivity disorder and Tourette's syndrome.This study provides the first detailed quantitative investigation of development of D1 and D2 SPNs, including their cellular properties and connectivity within neural circuits, during the first postnatal weeks.This period is highly dynamic with many properties changing, but it is possible to make three main observations: many aspects of D1 and D2 SPNs progressively mature in parallel; there are notable exceptions when they diverge; and many of the defining properties of mature striatal SPNs and circuits are already established by the first and second postnatal weeks, suggesting guidance through intrinsic developmental programmes.These findings provide an experimental framework for future studies of striatal development in both health and disease. Many basal ganglia neurodevelopmental disorders are thought to result from imbalances in the activity of the D1‐expressing direct pathway and D2‐expressing indirect pathway striatal projection neurons (SPNs). Insight into these disorders is reliant on our understanding of normal D1 and D2 SPN development. Here we provide the first detailed study and quantification of the striatal cellular and circuit changes occurring for both D1 and D2 SPNs in the first postnatal weeks using in vitro whole‐cell patch‐clamp electrophysiology. Characterization of their intrinsic electrophysiological and morphological properties, the excitatory long‐range inputs coming from cortex and thalamus, as well their local gap junction and inhibitory synaptic connections reveals this period to be highly dynamic with numerous properties changing. However it is possible to make three main observations. Firstly, many aspects of SPNs mature in parallel, including intrinsic membrane properties, increases in dendritic arbours and spine densities, general synaptic inputs and expression of specific glutamate receptors. Secondly, there are notable exceptions, including a transient stronger thalamic innervation of D2 SPNs and stronger cortical NMDA receptor‐mediated inputs to D1 SPNs, both in the second postnatal week. Thirdly, many of the defining properties of mature D1 and D2 SPNs and striatal circuits are already established by the first and second postnatal weeks, including different electrophysiological properties as well as biased local inhibitory connections between SPNs, suggesting this is guided through intrinsic developmental programmes. Together these findings provide an experimental framework for future studies of D1 and D2 SPN development in health and disease.

Genetic Landscape of Rett Syndrome Spectrum: Improvements and Challenges.

Rett syndrome (RTT) is an early-onset neurodevelopmental disorder that primarily affects females, resulting in severe cognitive and physical disabilities, and is one of the most prevalent causes of intellectual disability in females. More than fifty years after the first publication on Rett syndrome, and almost two decades since the first report linking RTT to the MECP2 gene, the research community’s effort is focused on obtaining a better understanding of the genetics and the complex biology of RTT and Rett-like phenotypes without MECP2 mutations. Herein, we review the current molecular genetic studies, which investigate the genetic causes of RTT or Rett-like phenotypes which overlap with other genetic disorders and document the swift evolution of the techniques and methodologies employed. This review also underlines the clinical and genetic heterogeneity of the Rett syndrome spectrum and provides an overview of the RTT-related genes described to date, many of which are involved in epigenetic gene regulation, neurotransmitter action or RNA transcription/translation. Finally, it discusses the importance of including both phenotypic and genetic diagnosis to provide proper genetic counselling from a patient’s perspective and the appropriate treatment.

The most recurrent monogenic disorders that overlap with the phenotype of Rett syndrome.

Rett syndrome (RTT) is an early-onset neurodevelopmental disorder that is caused by mutations in the MECP2 gene; however, defects in other genes (CDKL5 and FOXG1) can lead to presentations that resemble classic RTT, although they are not completely identical. Here, we attempted to identify other monogenic disorders that share features of RTT. A total of 437 patients with a clinical diagnosis of RTT-like were studied; in 242 patients, a custom panel with 17 genes related to an RTT-like phenotype was run via a HaloPlex-Target-Enrichment-System. In the remaining 195 patients, a commercial TruSight-One-Sequencing-Panel was analysed. A total of 40 patients with clinical features of RTT had variants which affect gene function in six genes associated with other monogenic disorders. Twelve patients had variants in STXBP1, nine in TCF4, six in SCN2A, five in KCNQ2, four in MEF2C and four in SYNGAP1. Genetic studies using next generation sequencing (NGS) allowed us to study a larger number of genes associated with RTT-like simultaneously, providing a genetic diagnosis for a wider group of patients. These new findings provide the clinician with more information and clues that could help in the prevention of future symptoms or in pharmacologic therapy.

Impaired development of neocortical circuits contributes to the neurological alterations in DYRK1A haploinsufficiency syndrome

Autism spectrum disorders are early onset neurodevelopmental disorders characterized by deficits in social communication and restricted repetitive behaviors, yet they are quite heterogeneous in terms of their genetic basis and phenotypic manifestations. Recently, de novo pathogenic mutations in DYRK1A, a chromosome 21 gene associated to neuropathological traits of Down syndrome, have been identified in patients presenting a recognizable syndrome included in the autism spectrum. These mutations produce DYRK1A kinases with partial or complete absence of the catalytic domain, or they represent missense mutations located within this domain. Here, we undertook an extensive biochemical characterization of the DYRK1A missense mutations reported to date and show that most of them, but not all, result in enzymatically dead DYRK1A proteins. We also show that haploinsufficient Dyrk1a+/− mutant mice mirror the neurological traits associated with the human pathology, such as defective social interactions, stereotypic behaviors and epileptic activity. These mutant mice present altered proportions of excitatory and inhibitory neocortical neurons and synapses. Moreover, we provide evidence that alterations in the production of cortical excitatory neurons are contributing to these defects. Indeed, by the end of the neurogenic period, the expression of developmental regulated genes involved in neuron differentiation and/or activity is altered. Therefore, our data indicate that altered neocortical neurogenesis could critically affect the formation of cortical circuits, thereby contributing to the neuropathological changes in DYRK1A haploinsufficiency syndrome.

Aberrant functional connectivity of neural circuits associated with social and sensorimotor deficits in young children with autism spectrum disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by atypical functional integration of brain regions. The vast majority of neuroimaging studies of ASD have focused on older children, adolescents, and adults with the disorder. Very little work has explored whole-brain functional connectivity of young children with ASD. Here, we collected resting-state functional magnetic resonance imaging data from 58 young children (mean age 4.98 years; 29 with ASD; 29 matched healthy controls [HC]). All children were under sedation during scanning. A functional "connectedness" method was first used to seek for brain regions showing atypical functional connectivity (FC) in children with ASD. Then, a recurrent-seek strategy was applied to reveal atypical FC circuits in ASD children. FC matrices between regions-of-interest (ROIs) were compared between ASD and HC. Finally, a support vector regression (SVR) method was used to assess the relationship between the FC circuits and ASD symptom severity. Two atypical FC circuits comprising 23 ROIs in ASD were revealed: one predominantly comprised brain regions involved with social cognition showing under-connectivity in ASD; the other predominantly comprised sensory-motor and visual brain regions showing over-connectivity in ASD. The SVR analysis showed that the two FC circuits were separately related to social deficits and restricted behavior scores. These findings indicate disrupted FC of neural circuits involved in the social and sensorimotor processes in young children with ASD. The finding of the atypical FC patterns in young children with ASD underscores the utility of studying younger children with the disorder, and highlights nuanced patterns of brain connectivity underlying behavior closer to disorder onset. Autism Research 2018, 11: 1643-1652. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Autism spectrum disorder (ASD) is an early-onset neurodevelopmental disorder. Understanding brain functional alterations at early ages is important for understanding biological mechanisms of ASD. Here, we found two atypical brain functional circuits in young children with ASD that were related to social and sensorimotor function. These results show how atypical patterns of brain functional connectivity in young children with of ASD may underlie core symptoms of the disorder.

Sex- and region-specific differences in microglia phenotype and characterization of the peripheral immune response following early-life infection in neonatal male and female rats

Early-life infection has been shown to have profound effects on the brain and behavior across the lifespan, a phenomenon termed “early-life programming”. Indeed, many neuropsychiatric disorders begin or have their origins early in life and have been linked to early-life immune activation (e.g. autism, ADHD, and schizophrenia). Furthermore, many of these disorders show a robust sex bias, with males having a higher risk of developing early-onset neurodevelopmental disorders. The concept of early-life programming is now well established, however, it is still unclear how such effects are initiated and then maintained across time to produce such a phenomenon. To begin to address this question, we examined changes in microglia, the immune cells of the brain, and peripheral immune cells in the hours immediately following early-life infection in male and female rats. We found that males showed a significant decrease in BDNF expression and females showed a significant increase in IL-6 expression in the cerebellum following E.coli infection on postnatal day 4; however, for most cytokines examined in the brain and in the periphery we were unable to identify any sex differences in the immune response, at least at the time points examined. Instead, neonatal infection with E.coli increased the expression of a number of cytokines in the brain of both males and females similarly including TNF-α, IL-1β, and CD11b (a marker of microglia activation) in the hippocampus and, in the spleen, TNF-α and IL-1β. We also found that protein levels of GRO-KC, MIP-1a, MCP1, IP-10, TNF-α, and IL-10 were elevated 8-hours postinfection, but this response was resolved by 24-hours. Lastly, we found that males have more thin microglia than females on P5, however, neonatal infection had no effect on any of the microglia morphologies we examined. These data show that sex differences in the acute immune response to neonatal infection are likely gene, region, and even time dependent. Future research should consider these factors in order to develop a comprehensive understanding of the immune response in males and females as these changes are likely the initiating agents that lead to the long-term, and often sex-specific, effects of early-life infection.

Medical consequences of pathogenic CNVs in adults: analysis of the UK Biobank

BackgroundGenomic CNVs increase the risk for early-onset neurodevelopmental disorders, but their impact on medical outcomes in later life is still poorly understood. The UK Biobank allows us to study the...

Genetic association between SHANK2 polymorphisms and susceptibility to autism spectrum disorder.

Autism spectrum disorder (ASD), as one of early-onset neurodevelopmental disorders, is characterized by the following symptoms, including repetitive and stereotyped behaviors, impairments in social interaction, and dysfunctions in communication. ASD afflicts ∼1.5% of children aged 8 years in America and ∼4.5‰ of children aged 0-6 years in China. Existing studies suggest that SH3 and multiple ankyrin repeat domains protein 2 (SHANK2) is implicated in ASD. However, associations between SNPs in SHANK2 introns and ASD risk have been less investigated. In this study, on the basis of case-control study (226 cases and 239 controls), we selected nine SNPs (rs76717360, rs11236697, rs74336682, rs77950809, rs17428526, rs35459123, rs75357229, rs61887413, and rs77716438) in SHANK2 introns to investigate genetic associations between SHANK2 polymorphisms and susceptibility to ASD using improved multiple ligase detection reaction (iMLDR). We identified that the polymorphism of rs76717360 was associated with risk of ASD in Chinese population; the haplotype of rs11236697 C (T) or rs74336682 G (A) increased ASD risk; and haplotypes with ≥ five SNPs containing rs11236697 and rs74336682 were associated with risk of ASD. Our results indicate SHANK2 is a susceptibility gene for ASD in Chinese children. © 2018 IUBMB Life, 70(8):763-776, 2018.

Evidence for Association Between OXTR Gene and ASD Clinical Phenotypes.

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.

The utility of Next Generation Sequencing for molecular diagnostics in Rett syndrome

Rett syndrome (RTT) is an early-onset neurodevelopmental disorder that almost exclusively affects girls and is totally disabling. Three genes have been identified that cause RTT: MECP2, CDKL5 and FOXG1. However, the etiology of some of RTT patients still remains unknown. Recently, next generation sequencing (NGS) has promoted genetic diagnoses because of the quickness and affordability of the method. To evaluate the usefulness of NGS in genetic diagnosis, we present the genetic study of RTT-like patients using different techniques based on this technology. We studied 1577 patients with RTT-like clinical diagnoses and reviewed patients who were previously studied and thought to have RTT genes by Sanger sequencing. Genetically, 477 of 1577 patients with a RTT-like suspicion have been diagnosed. Positive results were found in 30% by Sanger sequencing, 23% with a custom panel, 24% with a commercial panel and 32% with whole exome sequencing. A genetic study using NGS allows the study of a larger number of genes associated with RTT-like symptoms simultaneously, providing genetic study of a wider group of patients as well as significantly reducing the response time and cost of the study.