Non-syndromic Autism Spectrum Disorder Research Articles

Clinical and Family Implications of Cannabidiol (CBD)-Dominant Full-Spectrum Phytocannabinoid Extract in Children and Adolescents with Moderate to Severe Non-Syndromic Autism Spectrum Disorder (ASD): An Observational Study on Neurobehavioral Management.

Autism Spectrum Disorder (ASD) encompasses a wide range of neurodevelopmental conditions characterized by deficits in social interaction, communication and behavior. Current pharmacological options are limited and feature significant side effects. In this study, we conducted a retrospective, observational, and cross-sectional cohort study to evaluate the effects of Cannabidiol (CBD)-dominant, full-spectrum cannabis extract, containing Tetrahydrocannabinol (THC) in a ratio of 33:1 (CBD:THC), on non-syndromic children and adolescents (5-18 years old) with moderate to severe ASD. Thirty volunteers were recruited, underwent neuropsychological evaluations and were treated with individualized doses of CBD-dominant extract. Clinical assessments were conducted by the designated clinician. Additionally, parents or caregivers were independently interviewed to assess perceived treatment effects. We found significant improvements in various symptomatic and non-symptomatic aspects of ASD, with minimal untoward effects, as reported by both clinical assessments and parental perceptions. The observed improvements included increased communicative skills, attention, learning, eye contact, diminished aggression and irritability, and an overall increase in both the patient's and family's quality of life. Despite its limitations, our findings suggest that treatment with full-spectrum CBD-dominant extract may be a safe and effective option for core and comorbid symptoms of ASD, and it may also increase overall quality of life for individuals with ASD and their families.

Relationship and New Prospectives in Joint Hypermobility in Children with Autism Spectrum Disorder: Preliminary Data.

Autism spectrum disorder (ASD) and joint hypermobility (JH) are considered two different etiological and clinical entities that most often appear in childhood. Despite growing increased research showing a co-occurrence for both conditions, a link between them is rarely established in clinical settings, and the relationship between ASD and JH has not so far been completely investigated in all age groups of ASD children. This preliminary study examined a cohort of 67 non-syndromic ASD children aged 2-18 years (sex ratio M:F = 12:1) showing different degrees of cognitive impairment and autism severity, using the Beighton scale and its revised version. A total of 63% of ASD patients aged 2-4 years and 73% of ASD patients aged ≥5 years presented significant scores of hypermobility. No significant correlation was found comparing total laxity score and cognitive assessments and severity of autistic symptomatology (p > 0.05). The results suggest that JH could be considered as a clinical characteristic of ASD patients and it needs to be assessed in order to schedule a better rehabilitation program.

Impact of the COVID-19 pandemic on the eating behaviors of children and adolescents with autism spectrum disorder.

Introduction. Children with autism spectrum disorder (ASD) have difficulties adapting to stressful situations, such as the COVID-19 pandemic. Objective. To assess the impact of the first year of the pandemic on feeding difficulties in children with ASD. Population and methods. The caregivers of children and adolescents with non-syndromic ASD (age: 2-18 years) from a neurodevelopment unit were invited to participate. Participants completed a questionnaire and the Behavioral Pediatrics Feeding Assessment Scale (BPFAS) online before and during the first year of the pandemic. A priority score (product between the average frequency and the problem) for each BPFAS item was estimated. Results. Among the caregivers, 56.6% (86/152) completed the survey (mother: 74.4%); children's median age was 6.3 years (p25-p75: 4.7-8.2); 80.2% of children were males; 58.1% continued with their therapy during the pandemic; and 61.6% had behavioral problems before the pandemic. During the first year of the pandemic, children had greater behavioral problems (34.9%) and feeding difficulties (61.6%); however, 31.4% of caregivers referred improvements in feeding. There were no significant differences in the BPFAS scores before and during the pandemic. The following items obtained the highest priority scores: gets up from table during meal, does not try new food, does not eat vegetables, does not eat fruits. Conclusions. A high frequency of feeding difficulties was noted during the first year of the pandemic. No differences were observed in feeding characteristics before and during the pandemic.

NGS Custom Panel Implementation in Patients with Non-Syndromic Autism Spectrum Disorders in the Clinical Routine of a Tertiary Hospital.

Autism spectrum disorder (ASD) is a set of neurodevelopmental disorders characterized by deficiencies in communication, social interaction, and repetitive and restrictive behaviors. The discovery of genetic involvement in the etiology of ASD has made this condition a strong candidate for genome-based diagnostic tests. Next-generation sequencing (NGS) is useful for the detection of variants in the sequence of different genes in ASD patients. Herein, we present the implementation of a personalized NGS panel for autism (AutismSeq) for patients with essential ASD over a prospective period of four years in the clinical routine of a tertiary hospital. The cohort is composed of 48 individuals, older than 3 years, who met the DSM-5 (The Diagnostic and Statistical Manual of Mental Disorders) diagnostic criteria for ASD. The NGS customized panel (AutismSeq) turned out to be a tool with good diagnostic efficacy in routine clinical care, where we detected 12 "pathogenic" (including pathogenic, likely pathogenic, and VUS (variant of uncertain significance) possibly pathogenic variations) in 11 individuals, and 11 VUS in 10 individuals, which had previously been negative for chromosomal microarray analysis and other previous genetic studies, such as karyotype, fragile-X, or MLPA/FISH (Multiplex Ligation dependent Probe Amplification/Fluorescence in situ hybridization) analysis. Our results demonstrate the high genetic and clinical heterogeneity of individuals with ASD and the current difficulty of molecular diagnosis. Our study also shows that an NGS-customized panel might be useful for diagnosing patients with essential/primary autism and that it is cost-effective for most genetic laboratories.

Differential Effects of a Behavioral Treatment Probe on Social Gaze Behavior in Fragile X Syndrome and Non-Syndromic Autism Spectrum Disorder.

The purpose of this study was to examine potential differences in social learning between individuals with fragile X syndrome (FXS), the leading known inherited cause of intellectual disability, and individuals with non-syndromic autism spectrum disorder(ASD). Thirty school-aged males with FXS and 26 age and symptom-matched males with non-syndromic ASD, were administered a behavioral treatment probe designed to improve levels of social gaze during interactions with others. The treatment probe was administered by a trained behavior therapist over two days in our laboratory and included reinforcement of social gaze in two alternating training conditions - looking while listening and looking while speaking. Prior to each session, children in each group were taught progressive muscle relaxation and breathing techniques to counteract potential increased hyperarousal. Measures included the rate of learning in each group during treatment, in addition to levels of social gaze and heart rate obtained during administration of a standardized social conversation task administered prior to and following the treatment probe. Results showed that learning rates obtained during administration of the treatment probe were significantly less steep and less variable for males with FXS compared to males with non-syndromic ASD. Significant improvements in social gaze were also observed for males with FXS during the social conversation task. There was no effect of the treatment probe on heart rate in either group. These data reveal important differences in social learning between the two groups and have implications for early interventions in the two conditions.

Chromosomal Microarray in Patients with Non-Syndromic Autism Spectrum Disorders in the Clinical Routine of a Tertiary Hospital

Autism spectrum disorders (ASD) comprise a group of neurodevelopmental disorders (NDD) characterized by deficits in communication and social interaction, as well as repetitive and restrictive behaviors, etc. The genetic implications of ASD have been widely documented, and numerous genes have been associated with it. The use of chromosomal microarray analysis (CMA) has proven to be a rapid and effective method for detecting both small and large deletions and duplications associated with ASD. In this article, we present the implementation of CMA as a first-tier test in our clinical laboratory for patients with primary ASD over a prospective period of four years. The cohort was composed of 212 individuals over 3 years of age, who met DSM-5 diagnostic criteria for ASD. The use of a customized array-CGH (comparative genomic hybridization) design (KaryoArray®) found 99 individuals (45.20%) with copy number variants (CNVs); 34 of them carried deletions (34.34%) and 65 duplications (65.65%). A total of 28 of 212 patients had pathogenic or likely pathogenic CNVs, representing approximately 13% of the cohort. In turn, 28 out of 212 (approximately 12%) had variants of uncertain clinical significance (VUS). Our findings involve clinically significant CNVs, known to cause ASD (syndromic and non-syndromic), and other CNVs previously related to other comorbidities such as epilepsy or intellectual disability (ID). Lastly, we observed new rearrangements that will enhance the information available and the collection of genes associated with this disorder. Our data also highlight that CMA could be very useful in diagnosing patients with essential/primary autism, and demonstrate the existence of substantial genetic and clinical heterogeneity in non-syndromic ASD individuals, underscoring the continued challenge for genetic laboratories in terms of its molecular diagnosis.

Autism spectrum disorder symptom expression in individuals with 3q29 deletion syndrome

BackgroundThe 1.6 Mb 3q29 deletion is associated with neurodevelopmental and neuropsychiatric phenotypes, including a 19-fold increased risk for autism spectrum disorder (ASD). Previous work by our team identified elevated social disability in this population via parent-report questionnaires. However, clinical features of ASD in this population have not been explored in detail.MethodsThirty-one individuals with 3q29 deletion syndrome (3q29del, 61.3% male) were evaluated using two gold-standard clinical ASD evaluations: the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2), and the Autism Diagnostic Interview, Revised (ADI-R). Four matched comparators for each subject were ascertained from the National Database for Autism Research. Item-level scores on the ADOS-2 and ADI-R were compared between subjects with 3q29del and matched comparators.ResultsSubjects with 3q29del and no ASD (3q29del-ASD) had greater evidence of social disability compared to typically developing (TD) comparison subjects across the ADOS-2. Subjects with 3q29del and ASD (3q29del + ASD) were largely indistinguishable from non-syndromic ASD (nsASD) subjects on the ADOS-2. 3q29del + ASD performed significantly better on social communication on the ADI-R than nsASD (3q29 + ASD mean = 11.36; nsASD mean = 15.70; p = 0.01), and this was driven by reduced deficits in nonverbal communication (3q29 + ASD mean = 1.73; nsASD mean = 3.63; p = 0.03). 3q29del + ASD reported significantly later age at the first two-word phrase compared to nsASD (3q29del + ASD mean = 43.89 months; nsASD mean = 37.86 months; p = 0.01). However, speech delay was not related to improved nonverbal communication in 3q29del + ASD.LimitationsThere were not enough TD comparators with ADI-R data in NDAR to include in the present analysis. Additionally, our relatively small sample size made it difficult to assess race and ethnicity effects.Conclusions3q29del is associated with significant social disability, irrespective of ASD diagnosis. 3q29del + ASD have similar levels of social disability to nsASD, while 3q29del-ASD have significantly increased social disability compared to TD individuals. However, social communication is reasonably well preserved in 3q29del + ASD relative to nsASD. It is critical that verbal ability and social disability be examined separately in this population to ensure equal access to ASD and social skills evaluations and services.

Distinct social attention profiles in preschoolers with autism contrasted to fragile X syndrome.

Social attention is a critical skill for learning and development. Social attention difficulties are present in both non-syndromic autism spectrum disorder (nsASD) and fragile X syndrome (FXS), and our understanding of these difficulties is complicated by heterogeneity in both disorders, including co-occurring diagnoses like intellectual disability and social anxiety. Existing research largely utilizes a single index of social attention and rarely includes children with intellectual impairment or uses a cross-syndrome approach. This study investigated whether multi-trait social attention profiles including naturalistic initial eye contact, facial attention, and social scene attention differ in preschool children with nsASD and FXS matched on developmental ability (DQ) and contrasted to neurotypical (NT) controls. The relationship between DQ, ASD severity, and social anxiety and social attention profiles was also examined. Initial eye contact related to social scene attention, implicating that naturalistic social attention is consistent with responses during experimental conditions. Reduced eye contact and lower social scene attention characterized nsASD and FXS. Children with nsASD displayed less facial attention than FXS and NT children, who did not differ. Lower DQ and elevated ASD severity associated with decreased eye contact in nsASD and FXS, and lower DQ was associated with lower social scene attention in FXS. Sex, social anxiety, and age were not associated with social attention. These findings suggest social attention profiles of children with nsASD are highly similar to, yet distinct from, children with FXS. Children with nsASD may present with a global social attention deficit whereas FXS profiles may reflect context-dependent social avoidance.

Pharmacological approaches in the treatment of autism: a narrative review

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in communication and social interaction and by the presence of repetitive and restricted behaviors. To review the literature on drug interventions in the treatment of ASD in children and adolescents. Narrative review conducted at a university in São Paulo, Brazil. Search of the literature of studies published from 2005 to 2022, in Portuguese, English and Spanish, in the SciELO, PubMed, SCOPUS, LILACS and TripDatabase databases. Risperidone alone improved stereotyped patterns of behavior. Associations with aripiprazole or galantamine reduced irritability and managing the behavioral symptoms, respectively. Ginkgo biloba, associated to risperidone, led to an improvement in the Aberrant Behavior Checklist-Community (ABC-C) subscales scores. The association with sulforaphane exhibited a greater improvement in irritability and hyperactivity/noncompliance scores. Omega-3s reduced gesture use and hyperactivity. Bumetanide reduced restricted interests and repetitive behavior compared to placebo. Intranasal oxytocin improved social skills. The AB-2004 showed improvement in behavioral endpoints, especially anxiety and irritability. Folinic acid improved verbal communication in non-syndromic ASD children. Prednisolone increased language scores. There is not a drug that treats all of them and the possibility of significant adverse effects must be adjusted according to the symptoms and clinical response.

Barriers to Genetic Testing Faced by Pediatric Subspecialists in Autism Spectrum Disorders

ObjectivesWhile national medical guidelines recommend genetic testing for all individuals with non-syndromic autism spectrum disorder (ASD), there is underutilization of genetic testing. This study aims to define the perspectives and approaches to initial genetic testing of ASD diagnosticians in order to improve utilization.MethodsA prospective cross-sectional study was conducted using an anonymous online survey distributed to 59 staff neurologists, developmental-behavioral pediatricians, psychologists, post-graduate physician fellows, and nurse practitioners from a single academic medical center. Questions explored knowledge, attitudes, and practices of initial genetic testing for ASD among diagnosticians.ResultsAmong the 30 respondents (51% response rate), a lack of comprehensive pre-test genetic counseling was identified and forgetfulness was the most prevalent reason for not recommending genetic testing (n = 7/23, 30%). Insurance prior authorization (PA) for genetic testing was a major barrier for clinicians. More than half of respondents (n = 13/25, 52%) reported being uncomfortable with the PA process.ConclusionsVariability in knowledge and practices among ASD diagnosticians regarding genetic testing was identified. Therefore, potential interventions like clinician and administrative staff education, as well as genetic counselor integration into ASD clinics, may be useful to improve genetic testing utilization.

Study of Serum Level of L-Carnitine in Children with Non-Syndromic Autism Spectrum Disorder: A Biological Metabolic Marker

Study of Serum Level of L-Carnitine in Children with Non-Syndromic Autism Spectrum Disorder: A Biological Metabolic Marker

Autism Symptoms in Children and Young Adults With Fragile X Syndrome, Angelman Syndrome, Tuberous Sclerosis Complex, and Neurofibromatosis Type 1: A Cross-Syndrome Comparison.

ObjectiveThe etiology of autism spectrum disorder (ASD) remains unclear, due to genetic heterogeneity and heterogeneity in symptoms across individuals. This study compares ASD symptomatology between monogenetic syndromes with a high ASD prevalence, in order to reveal syndrome specific vulnerabilities and to clarify how genetic variations affect ASD symptom presentation.MethodsWe assessed ASD symptom severity in children and young adults (aged 0-28 years) with Fragile X Syndrome (FXS, n = 60), Angelman Syndrome (AS, n = 91), Neurofibromatosis Type 1 (NF1, n = 279) and Tuberous Sclerosis Complex (TSC, n = 110), using the Autism Diagnostic Observation Schedule and Social Responsiveness Scale. Assessments were part of routine clinical care at the ENCORE expertise center in Rotterdam, the Netherlands. First, we compared the syndrome groups on the ASD classification prevalence and ASD severity scores. Then, we compared individuals in our syndrome groups with an ASD classification to a non-syndromic ASD group (nsASD, n = 335), on both ASD severity scores and ASD symptom profiles. Severity scores were compared using MANCOVAs with IQ and gender as covariates.ResultsOverall, ASD severity scores were highest for the FXS group and lowest for the NF1 group. Compared to nsASD, individuals with an ASD classification in our syndrome groups showed less problems on the instruments' social domains. We found a relative strength in the AS group on the social cognition, communication and motivation domains and a relative challenge in creativity; a relative strength of the NF1 group on the restricted interests and repetitive behavior scale; and a relative challenge in the FXS and TSC groups on the restricted interests and repetitive behavior domain.ConclusionThe syndrome-specific strengths and challenges we found provide a frame of reference to evaluate an individual's symptoms relative to the larger syndromic population and to guide treatment decisions. Our findings support the need for personalized care and a dimensional, symptom-based diagnostic approach, in contrast to a dichotomous ASD diagnosis used as a prerequisite for access to healthcare services. Similarities in ASD symptom profiles between AS and FXS, and between NF1 and TSC may reflect similarities in their neurobiology. Deep phenotyping studies are required to link neurobiological markers to ASD symptomatology.

Sensory Processing Phenotypes in Phelan-McDermid Syndrome and SYNGAP1-Related Intellectual Disability.

Sensory processing differences are an established feature of both syndromic and non-syndromic Autism Spectrum Disorders (ASDs). Significant work has been carried out to characterize and classify specific sensory profiles in non-syndromic autism. However, it is not known if syndromic autism disorders, such as Phelan-McDermid Syndrome (PMD) or SYNGAP1-related Intellectual Disability (SYNGAP1-ID), have unique sensory phenotypes. Understanding the sensory features of these disorders is important for providing appropriate care and for understanding their underlying mechanisms. Our objective in this work was to determine the sensory processing abnormalities present in two syndromic ASDs: Phelan-McDermid Syndrome and SYNGAP1-related Intellectual Disability. Using a standardized instrument, the Short Sensory Profile-2, we characterized sensory features in 41 patients with PMD and 24 patients with SYNGAP1-ID, and sub-scores were then calculated for seeking, avoiding, sensitivity and registration, as well as overall sensory and behavior scores. We found both patient groups exhibited atypical sensory features, including high scores in the areas of avoiding and seeking. Thus, we discovered significant sensory processing abnormalities are common in these syndromic ASDs. Measurements of sensory processing could serve as useful clinical endpoints for trials of novel therapeutics for these populations.

Cardiac Startle Response and Clinical Outcomes in Preschool Children With Fragile X Syndrome and Autism Spectrum Disorder.

Objective: Poor physiological regulation in response to threat is linked to multiple negative developmental outcomes including anxiety, which is highly prevalent and impairing in young children with neurodevelopmental disabilities like fragile X syndrome (FXS) and autism spectrum disorder (ASD). The present study contrasted cardiac startle response in pre-school-aged children with FXS, with and without ASD, to children with non-syndromic ASD (nsASD) and neurotypical controls (NT). The relationship of cardiac startle to non-verbal mental age (NVMA), ASD severity, and parent-reported anxiety was also examined.Method: Four age-matched groups of pre-school children participated including those with FXS without ASD (FXS-Only, n = 21), FXS with ASD (FXS+ASD, n = 17), nsASD (n = 42), and NT children (n = 27). Participants viewed a silent movie during which a single 200 ms 98-decibel white noise burst occurred. Cardiac activity was analyzed for pre-stimulus respiratory sinus arrhythmia (RSA) and the inter-beat intervals (IBI) at the auditory stimulus and 10 s post-stimulus. The Spence Pre-school Anxiety Scale, Autism Diagnostic Observation Schedule-2nd Edition, and Mullen Scales of Early Learning were examined in relation to startle response.Results: The nsASD group demonstrated heightened cardiac activity at the auditory stimulus and 10 s post-stimulus compared to the NT controls. Neither of the FXS groups showed differences from any other group. Higher pre-stimulus RSA was associated with reduced cardiac response across groups, while the relationship between cognitive ability and ASD severity to cardiac response varied between groups. Parent-reported anxiety was not associated with cardiac response for any group.Conclusion: These findings demonstrate group distinctions in cardiac responses to auditory startle. Although FXS and ASD share behavioral characteristics, the nsASD group showed a heightened cardiac startle response compared to the NT group that was not present in the FXS groups with or without ASD. Non-verbal mental age was associated with greater stimulus or post-stimulus reactivity for all groups except the FXS+ASD group, which showed no association between startle response and any clinical outcomes. Increased understanding of the relationship between physiological regulation and clinical outcomes will assist in identifying the timing and targets for effective interventions for individuals with neurodevelopmental disabilities.

Neuroligin-3: A Circuit-Specific Synapse Organizer That Shapes Normal Function and Autism Spectrum Disorder-Associated Dysfunction.

Chemical synapses provide a vital foundation for neuron-neuron communication and overall brain function. By tethering closely apposed molecular machinery for presynaptic neurotransmitter release and postsynaptic signal transduction, circuit- and context- specific synaptic properties can drive neuronal computations for animal behavior. Trans-synaptic signaling via synaptic cell adhesion molecules (CAMs) serves as a promising mechanism to generate the molecular diversity of chemical synapses. Neuroligins (Nlgns) were discovered as postsynaptic CAMs that can bind to presynaptic CAMs like Neurexins (Nrxns) at the synaptic cleft. Among the four (Nlgn1-4) or five (Nlgn1-3, Nlgn4X, and Nlgn4Y) isoforms in rodents or humans, respectively, Nlgn3 has a heterogeneous expression and function at particular subsets of chemical synapses and strong association with non-syndromic autism spectrum disorder (ASD). Several lines of evidence have suggested that the unique expression and function of Nlgn3 protein underlie circuit-specific dysfunction characteristic of non-syndromic ASD caused by the disruption of Nlgn3 gene. Furthermore, recent studies have uncovered the molecular mechanism underlying input cell-dependent expression of Nlgn3 protein at hippocampal inhibitory synapses, in which trans-synaptic signaling of specific alternatively spliced isoforms of Nlgn3 and Nrxn plays a critical role. In this review article, we overview the molecular, anatomical, and physiological knowledge about Nlgn3, focusing on the circuit-specific function of mammalian Nlgn3 and its underlying molecular mechanism. This will provide not only new insight into specific Nlgn3-mediated trans-synaptic interactions as molecular codes for synapse specification but also a better understanding of the pathophysiological basis for non-syndromic ASD associated with functional impairment in Nlgn3 gene.

Brain mapping across 16 autism mouse models reveals a spectrum of functional connectivity subtypes

Autism Spectrum Disorder (ASD) is characterized by substantial, yet highly heterogeneous abnormalities in functional brain connectivity. However, the origin and significance of this phenomenon remain unclear. To unravel ASD connectopathy and relate it to underlying etiological heterogeneity, we carried out a bi-center cross-etiological investigation of fMRI-based connectivity in the mouse, in which specific ASD-relevant mutations can be isolated and modeled minimizing environmental contributions. By performing brain-wide connectivity mapping across 16 mouse mutants, we show that different ASD-associated etiologies cause a broad spectrum of connectional abnormalities in which diverse, often diverging, connectivity signatures are recognizable. Despite this heterogeneity, the identified connectivity alterations could be classified into four subtypes characterized by discrete signatures of network dysfunction. Our findings show that etiological variability is a key determinant of connectivity heterogeneity in ASD, hence reconciling conflicting findings in clinical populations. The identification of etiologically-relevant connectivity subtypes could improve diagnostic label accuracy in the non-syndromic ASD population and paves the way for personalized treatment approaches.

CNV profiles of Chinese pediatric patients with developmental disorders

To examine the overall genomic copy-number variant (CNV) landscape of Chinese pediatric patients with developmental disorders. De-identified chromosomal microarray (CMA) data from 10,026 pediatric patients with developmental disorders were collected for re-evaluating the pathogenic CNV (pCNV) yields of different medical conditions and for comparing the frequency and phenotypic variability of genomic disorders between the Chinese and Western patient populations. The overall yield of pCNVs in the Chinese pediatric patient cohort was 21.37%, with variable yields for different disorders. Yields of pCNVs were positively associated with phenotypic complexity and intellectual disability/developmental delay (ID/DD) comorbidity for most disorders. The genomic burden and pCNV yield in neurodevelopmental disorders supported a female protective effect. However, the stratification analysis revealed that it was seen only in nonsyndromic ID/DD, not in nonsyndromic autism spectrum disorders or seizure. Furthermore, 15 known genomic disorders showed significantly different frequencies in Chinese and Western patient cohorts, and profiles of referred clinical features for 15 known genomic disorders were also significantly different in the two cohorts. We defined the pCNV yields and profiles of the Chinese pediatric patients with different medical conditions and uncovered differences in the frequency and phenotypic diversity of genomic disorders between Chinese and Western patients.

8p21.3 deletions are rare causes of non-syndromic autism spectrum disorder.

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.

Comprehensive Genetic Analysis of Non-syndromic Autism Spectrum Disorder in Clinical Settings.

Although genetic factors are involved in the etiology of autism spectrum disorder (ASD), the significance of genetic analysis in clinical settings is unclear. Forty-nine subjects diagnosed with non-syndromic ASD were analyzed by microarray comparative genomic hybridization (CGH) analysis, whole-exome sequencing (WES) analysis, and panel sequencing analysis for 52 common causative genes of ASD to detect inherited rare variants. Genetic analysis by microarray CGH and WES analyses showed conclusive results in about 10% of patients, however, many inherited variants detected by panel sequencing analysis were difficult to interpret and apply in clinical practice in the majority of patients. Further improvement of interpretation of many variants detected would be necessary for combined genetic tests to be used in clinical settings.

Autism Spectrum Disorder Symptom Profile Across the RASopathies

Dysregulation of the Ras MAPK signaling pathway is implicated in the pathogenesis of autism spectrum disorder (ASD). The RASopathies, a group of disorders caused by mutations of the Ras/MAPK pathway genes, share many overlapping clinical features. Studies suggest a high prevalence of ASD in the RASopathies, but detailed characterization of the ASD profile is lacking. The aim of this study was to compare the ASD symptom profile of three distinct RASopathies associated with both gain-of-function and loss-of-function mutations: neurofibromatosis type 1 (NF1), Noonan syndrome (NS), and cardiofaciocutaneous syndrome (CFC). Participants were drawn from existing databases if they had a diagnosis of a RASopathy, met the criteria for ASD, and were able to communicate verbally. We compared the phenotypic profile of NF1 + ASD (n = 48), NS + ASD (n = 11), and CFC + ASD (n = 7) on the Autism Diagnostic Inventory (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS). We found subtle but non-significant group differences with higher levels of social impairments and lower restricted repetitive behaviors in the NF1 group as compared with the NS and CFC groups. We observed group differences in developmental milestones with most severe delays in CFC, followed by NS and NF1. Our results suggest that despite developmental differences, the ASD profile remains relatively consistent across the three RASopathies. Though our results need confirmation in larger samples, they suggest the possibility that treatment and mechanistic insights developed in the context of one RASopathy may be generalizable to others and possibly to non-syndromic ASD associated with dysregulation of Ras/MAPK pathway genes.