Autism Spectrum Disorder Families Research Articles

Prevalence and characteristics of autistic children attending autism centres in 2 major cities in Saudi Arabia: A cross-sectional study.

ABSTRACTObjectives:To assess the prevalence and characteristics of Autism Spectrum Disorder (ASD)-affected children attending autistic centers in 2 major cities in Saudi Arabia.Methods:A cross-sectional study, including ASD centers and schools (37 centers) in Makkah and Jeddah, Saudi Arabia was conducted between January and March 2020. Data were collected from records and parents of children with ASD using a questionnaire on sociodemographic, family history, consanguinity, severity, and maternal risk factors.Results:All centers in Makkah and Jeddah participated, with a total of 1,023 ASD children. The prevalence of ASD was 2.618 per 1,000 children for Jeddah, 3.68 per 1,000 children for Makkah and 2.81 per 1,000 children for both Jeddah and Makkah. There was no statistically significant relationship between the severity of ASD and sociodemographic, family and maternal risk factors. However, there was statistically significant relationship between severe ASD and ASD family history (p=0.029, OR: 3.46 and 95% CI 1.14 to 10.5).Conclusions:The prevalence of ASD in Makkah and Jeddah was lower than the global prevalence of ASD. Individuals with a family history of ASD were more likely to have more severe ASD.

Whole Exome Sequencing Identifies Novel De Novo Variants Interacting with Six Gene Networks in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a highly heritable condition caused by a combination of environmental and genetic factors such as de novo and inherited variants, as well as rare or common variants among hundreds of related genes. Previous genome-wide association studies have identified susceptibility genes; however, most ASD-associated genes remain undiscovered. This study aimed to examine rare de novo variants to identify genetic risk factors of ASD using whole exome sequencing (WES), functional characterization, and genetic network analyses of identified variants using Korean familial dataset. We recruited children with ASD and their biological parents. The clinical best estimate diagnosis of ASD was made according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5TM), using comprehensive diagnostic instruments. The final analyses included a total of 151 individuals from 51 families. Variants were identified and filtered using the GATK Best Practices for bioinformatics analysis, followed by genome alignments and annotation to the reference genome assembly GRCh37 (liftover to GRCh38), and further annotated using dbSNP 154 build databases. To evaluate allele frequencies of de novo variants, we used the dbSNP, gnomAD exome v2.1.1, and genome v3.0. We used Ingenuity Pathway Analysis (IPA, Qiagen) software to construct networks using all identified de novo variants with known autism-related genes to find probable relationships. We identified 36 de novo variants with potential relations to ASD; 27 missense, two silent, one nonsense, one splice region, one splice site, one 5′ UTR, and one intronic SNV and two frameshift deletions. We identified six networks with functional relationships. Among the interactions between de novo variants, the IPA assay found that the NF-κB signaling pathway and its interacting genes were commonly observed at two networks. The relatively small cohort size may affect the results of novel ASD genes with de novo variants described in our findings. We did not conduct functional experiments in this study. Because of the diversity and heterogeneity of ASD, the primary purpose of this study was to investigate probable causative relationships between novel de novo variants and known autism genes. Additionally, we based functional relationships with known genes on network analysis rather than on statistical analysis. We identified new variants that may underlie genetic factors contributing to ASD in Korean families using WES and genetic network analyses. We observed novel de novo variants that might be functionally linked to ASD, of which the variants interact with six genetic networks.

Investigation of the Relationship Between the Burnout Level of Parents of Children with Autism Spectrum Disorder (ASD) and ASD Symptom Level and Family Needs by Regression Analysis

Autism spectrum disorder (ASD) is a neuro-developmental disorder, which manifests itself with severe social interaction and communication disorder, social behavior, language, perceptual functions, repetitive behaviors and interests in the first years of life, which continues throughout life and displays differences in the appearance and level of symptoms due to various reasons from individual to individual. It is known in the literature that the participation of an individual, diagnosed with ASD with these characteristics, in the family, has significant effects on the family and the functioning of the family. In families that have a member diagnosed with ASD, it is known that the needs of the family increase, stress sources are varied, and family functioning is affected by this situation. There are also research results indicating that this situation causes depression and traumatic stress. This study aimed to investigate the relationship between the burnout levels of parents of children diagnosed with ASD, and ASD symptom level, and family needs. For this purpose, data were collected from 273 parents using the Gilliam Autism Rating Scale-2-TV (GARS-2-TV), Family Needs Survey (FNS), and Parental Burnout Inventory (PBI). Based on the collected data, the relationship between the GARS-2-TV and FNS subscale scores and the PBI total score was examined and reported by hierarchical regression analysis. As a result of the analyses, it was observed that the two subscales of the GARS-2-TV and the four subscales of the FNS were related to the PBI total score and explained 40% of the observed variance in the PBI total score.

Stress and emotional wellbeing of parents due to change in routine for children with Autism Spectrum Disorder (ASD) at home during COVID-19 pandemic in Saudi Arabia

BackgroundParents of children with Autism Spectrum Disorder (ASD) experience considerable amounts of stress and impaired emotional well-being. Consequently, it is likely that these have been adversely impacted by COVID-19 outbreak due to disruptions to the schedules of children with ASD. AimThis study investigated the stress and emotional well-being of parents of children with ASD in Saudi Arabia during the COVID-19 pandemic. MethodThe study obtained quantitative data from 150 parents of children with ASD from different regions in Saudi Arabia using an online survey. The data collected included demographic data of the parents, ASD status of the family, ASD support during COVID-19 pandemic, severity of ASD behaviours in comparison to the pre- COVID-19 status eating behaviour of the child with ASD, Parental Stress, and emotional well-being. The PSI-short form (PSI-SF) (Abidin, 1995) scale was utilised to obtain data related to parental stress and the General Health Questionnaire (GHQ-12) (Goldberg, 1992) scale was utilised to obtain data related to parents’ emotional well-being. ResultsThe study found that family ASD status (in particular, age and gender of child with ASD, and severity of his/her symptoms) had a significant impact on parental stress and emotional well-being. Moreover, parental stress and emotional well-being were negatively impacted by the frequency and usefulness of ASD support received during COVID-19 pandemic. These were also adversely impacted by the change in severity of ASD behaviours of the children with ASD. Finally, parental stress was found to have a negative impact on the emotional well-being of parents. Overall, the study found that the parental stress and emotional well-being of parents of children with ASD in Saudi Arabia had been unfavourably impacted by COVID-19 pandemic. ConclusionsOverall, the study found that the parental stress and emotional well-being of parents with ASD in Saudi Arabia had been unfavourably impacted by COVID-19 pandemic. This study recommends the involvement of the Saudi Ministry of Health to establish and extend support services to support parents of children with ASD. Moreover, the provision of training programs to help parents deal with the characteristic behaviour of their children with ASD such as, the ability to maintain routines, aggressive or repetitive behaviour, is also recommended.

Tracing Autism Traits in Large Multiplex Families to Identify Endophenotypes of the Broader Autism Phenotype.

Families comprising many individuals with Autism Spectrum Disorders (ASD) may carry a dominant predisposing mutation. We implemented rigorous phenotyping of the “Broader Autism Phenotype” (BAP) in large multiplex ASD families using a novel endophenotype approach for the identification and characterisation of distinct BAP endophenotypes. We evaluated ASD/BAP features using standardised tests and a semi-structured interview to assess social, intellectual, executive and adaptive functioning in 110 individuals, including two large multiplex families (Family A: 30; Family B: 35) and an independent sample of small families (n = 45). Our protocol identified four distinct psychological endophenotypes of the BAP that were evident across these independent samples, and showed high sensitivity (97%) and specificity (82%) for individuals classified with the BAP. Patterns of inheritance of identified endophenotypes varied between the two large multiplex families, supporting their utility for identifying genes in ASD.

Homozygous deletions implicate non-coding epigenetic marks in Autism spectrum disorder

More than 98% of the human genome is made up of non-coding DNA, but techniques to ascertain its contribution to human disease have lagged far behind our understanding of protein coding variations. Autism spectrum disorder (ASD) has been mostly associated with coding variations via de novo single nucleotide variants (SNVs), recessive/homozygous SNVs, or de novo copy number variants (CNVs); however, most ASD cases continue to lack a genetic diagnosis. We analyzed 187 consanguineous ASD families for biallelic CNVs. Recessive deletions were significantly enriched in affected individuals relative to their unaffected siblings (17% versus 4%, p < 0.001). Only a small subset of biallelic deletions were predicted to result in coding exon disruption. In contrast, biallelic deletions in individuals with ASD were enriched for overlap with regulatory regions, with 23/28 CNVs disrupting histone peaks in ENCODE (p < 0.009). Overlap with regulatory regions was further demonstrated by comparisons to the 127-epigenome dataset released by the Roadmap Epigenomics project, with enrichment for enhancers found in primary brain tissue and neuronal progenitor cells. Our results suggest a novel noncoding mechanism of ASD, describe a powerful method to identify important noncoding regions in the human genome, and emphasize the potential significance of gene activation and regulation in cognitive and social function.

Huntingtin gene CAG repeat size affects autism risk: Family-based and case-control association study.

The Huntingtin (HTT) gene contains a CAG repeat in exon 1, whose expansion beyond 39 repeats consistently leads to Huntington's disease (HD), whereas normal-to-intermediate alleles seemingly modulate brain structure, function and behavior. The role of the CAG repeat in Autism Spectrum Disorder (ASD) was investigated applying both family-based and case-control association designs, with the SCA3 repeat as a negative control. Significant overtransmission of "long" CAG alleles (≥17 repeats) to autistic children and of "short" alleles (≤16 repeats) to their unaffected siblings (all p < 10-5 ) was observed in 612 ASD families (548 simplex and 64 multiplex). Surprisingly, both 193 population controls and 1,188 neurological non-HD controls have significantly lower frequencies of "short" CAG alleles compared to 185 unaffected siblings and higher rates of "long" alleles compared to 548 ASD patients from the same families (p < .05-.001). The SCA3 CAG repeat displays no association. "Short" HTT alleles seemingly exert a protective effect from clinically overt autism in families carrying a genetic predisposition for ASD, while "long" alleles may enhance autism risk. Differential penetrance of autism-inducing genetic/epigenetic variants may imply atypical developmental trajectories linked to HTT functions, including excitation/inhibition imbalance, cortical neurogenesis and apoptosis, neuronal migration, synapse formation, connectivity and homeostasis.

Telomere Length and Glutathione Level as Potential Biomarkers for Autism

Oxidative stress is a common feature in nearly all neurodegenerative disorders including autism spectrum disorder (ASD). ASD is behaviorally defined disorder associated with abnormalities in social communication, behavior, language and perception. Chronic exposure to different common stress factors like immune inflammation, malnutrition, alcohol, abuse and drugs induce congenital and behavioral impairment. To the best of our knowledge this study is the first exploring the rate of oxidative stress and its effect on telomere length simultaneously in Egyptian autistic children. In this study we investigated the effect of oxidative stress associated with ASD. Patients were selected based on full clinical and neurological examination and the severity of autism evaluated using childhood autism rating scale (CARS) and Autism Diagnostic Interview–Revised (ADI™-R). Expectedly we found the majority of autism affected children were males, and consanguinity rate between the ASD families was ~ 27% while it was completely absent in the control subjects. We found a highly significant correlation between ASD and low levels of total glutathione (P&lt;0.001) compared to controls. We reported a remarkable highly significant correlation between ASD children and shorter relative telomere length (P&lt;0.001). Moreover we identified a correlation between telomere length and behavioral characteristics in autistic children represented by social interaction impairment (ADI-R 1st domain) (r= - 0.354, P = 0.025). Here we conclude that oxidative stress represented by low glutathione level is an early sign of autism, and is affecting the telomere length that protecting the genetic material. Behavioral abnormalities associated with autism are dependent on telomere length

Problems Experienced by Adolescents with Autism Spectrum Disorder: Exploring Social, Educational and Economic Variables

The study investigates the problems of adolescents with Autism Spectrum Disorder (ASD) from the perspective of ASD specialists and adolescent’s families. It comprises of 228 ASD specialists and 294 families of ASD adolescents. The sample represents all areas of the Kingdom of Saudi Arabia (henceforth – KSA): north, south, east, west and centre. Variables of the study are adolescents’ gender, age, residential area, as well as the qualification of ASD specialists and family members. To accomplish the study, the researchers designed a questionnaire that includes variables regarding six significant problems: Educational, Recreational, Economic, Health, Psychological, and Social. The results reveal that families rate the economic problems higher than average, while the recreational ones – lower; specialists rate economic problems higher than average and educational ones – the lowest. As for gender variable, specialists and families note the differences in favour of females; for age variable, specialists and families note that 15-18 years old ASD adolescents have more problems. The results show that qualification of specialists as well as family members is of significant relevance in relation to ASD adolescents. Both specialists and family members are mostly from the central regions.

Copy Number Variants and Polygenic Risk Scores Predict Need of Care in Autism and/or ADHD Families.

Autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are highly heritable neurodevelopmental disorders that frequently co-occur. Both rare and common genetic variants are important for ASD and ADHD risk but their combined contribution to clinical heterogeneity is unclear.In a sample of 39 ASD and/or ADHD families we estimated the overall variance explained by known rare copy number variants (CNVs) and polygenic risk score (PRS) from common variants to be10% in comorbid ASD/ADHD, 4% in ASD and 2% in ADHD. We show that burden of large, rare CNVs and PRS is significantly higher in adult ASD and/or ADHD patients with sustained need for specialist care compared to their unaffected relatives, while affected relatives fall in-between the two.

Associations between autism symptom severity and mealtime behaviors in young children presented with an unfamiliar food

BackgroundFeeding problems are common in children with Autism Spectrum Disorder (ASD), and there are associations between parent reports of child ASD symptom severity and feeding problems. The current study further explores this association between ASD severity and family mealtime behaviors using directly observed naturalistic mealtime interactions. Methods and proceduresSeventy-three children (Mage = 5.42 years) were presented an unfamiliar food during a videotaped but otherwise typical home meal. Mealtime behavior was assessed through coding of the videotaped meal using the Dyadic Interaction Nomenclature for Eating (DINE) and parent report (Brief ASD Mealtime Behavior Inventory; BAMBI). ASD severity was assessed with the clinician-completed Childhood Autism Rating Scale-Second Edition (CARS-2). Outcomes and resultsGreater ASD severity was associated with fewer bites of the unfamiliar food, greater disruptive behavior during meals, and greater parental commands to take bites during meals. We found negative associations between limited food variety and food refusal (BAMBI subscales) and child bites of the unfamiliar food, with higher levels of limited food variety and food refusal associated with fewer bites of the unfamiliar food. Conclusions and implicationsChildren with more severe ASD may eat less and be more disruptive during meals, despite parent redirection. We also found associations between the BAMBI and DINE which suggest the BAMBI may be a sensitive measure of mealtime behaviors such as food flexibility and food refusal.

Study protocol of the multi-centre, randomised controlled trial of the Frankfurt Early Intervention Programme A-FFIP versus early intervention as usual for toddlers and preschool children with Autism Spectrum Disorder (A-FFIP study)

BackgroundNaturalistic developmental behavioural interventions (NDBI) have been shown to improve autism-specific symptoms in young children with Autism Spectrum Disorder (ASD). NDBI approaches, such as the ASD-specific Frankfurt Early Intervention Programme for ASD (A-FFIP), are based on ASD-specific developmental and learning aspects. A-FFIP is a low-intensity intervention which can easily be implemented in the local health care/social welfare system. The aim of the present study is to establish 1-year efficacy of the manualised early intervention programme A-FFIP in toddlers and preschool children with ASD. It is hypothesised that A-FFIP will result in improved ASD-specific symptoms compared to early intervention as usual (EIAU). Child- and family-specific secondary outcomes, as well as moderators and mediators of outcome, will be explored.Methods/designA prospective, multi-centre, parallel-group, randomised controlled, phase-III trial comparing A-FFIP versus EIAU. A total of 134 children (A-FFIP: 67, EIAU: 67) aged 24–66 months at baseline assessment meeting the criteria for ASD (DSM-5) will be included. The primary outcome is the absolute change of the total score of the Brief Observation of Social Communication Change (BOSCC-AT) between baseline (T2) and 1-year follow-up (T6). The treatment effect will be tested, adjusted for relevant covariates applying a mixed model for repeated measures. Secondary outcomes are BOSCC social communication and repetitive-behaviour scores, single ASD symptoms, language, cognition, psychopathology, parental well-being and family quality of life. Predictors, moderators and mediating mechanisms will be explored.DiscussionIf efficacy of the manualised A-FFIP early intervention is established, the current study has the potential to change clinical practice strongly towards the implementation of a low-intensity, evidence-based, natural early intervention in ASD. Early intervention in ASD requires specialist training, which subsequently needs to be developed or included into current training curricula.Trial registrationGerman Registry for Clinical Trials (Deutscher Register Klinischer Studien, DRKS); ID: 00016330. Retrospectively registered on 4 January 2019. URL: https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00016330.

Quantitative trait variation in ASD probands and toddler sibling outcomes at 24\u2009months

BackgroundYounger siblings of children with autism spectrum disorder (ASD) are at increased likelihood of receiving an ASD diagnosis and exhibiting other developmental concerns. It is unknown how quantitative variation in ASD traits and broader developmental domains in older siblings with ASD (probands) may inform outcomes in their younger siblings.MethodsParticipants included 385 pairs of toddler siblings and probands from the Infant Brain Imaging Study. ASD probands (mean age 5.5 years, range 1.7 to 15.5 years) were phenotyped using the Autism Diagnostic Interview-Revised (ADI-R), the Social Communication Questionnaire (SCQ), and the Vineland Adaptive Behavior Scales, Second Edition (VABS-II). Siblings were assessed using the ADI-R, VABS-II, Mullen Scales of Early Learning (MSEL), and Autism Diagnostic Observation Schedule (ADOS) and received a clinical best estimate diagnosis at 24 months using DSM-IV-TR criteria (n = 89 concordant for ASD; n = 296 discordant). We addressed two aims: (1) to determine whether proband characteristics are predictive of recurrence in siblings and (2) to assess associations between proband traits and sibling dimensional outcomes at 24 months.ResultsRegarding recurrence risk, proband SCQ scores were found to significantly predict sibling 24-month diagnostic outcome (OR for a 1-point increase in SCQ = 1.06; 95% CI = 1.01, 1.12). Regarding quantitative trait associations, we found no significant correlations in ASD traits among proband-sibling pairs. However, quantitative variation in proband adaptive behavior, communication, and expressive and receptive language was significantly associated with sibling outcomes in the same domains; proband scores explained 9–18% of the variation in cognition and behavior in siblings with ASD. Receptive language was particularly strongly associated in concordant pairs (ICC = 0.50, p < 0.001).ConclusionsProband ASD symptomology, indexed by the SCQ, is a predictor of familial ASD recurrence risk. While quantitative variation in social communication and restricted and repetitive behavior were not associated among sibling pairs, standardized ratings of proband language and communication explained significant variation in the same domains in the sibling at 24 months, especially among toddlers with an ASD diagnosis. These data suggest that proband characteristics can alert clinicians to areas of developmental concern for young children with familial risk for ASD.

Challenges of Autism Spectrum Disorders Families Towards Oral Health Care in Kingdom of Saudi Arabia

Objective: To assess the knowledge, attitudes, and practice regarding oral health care among parents of autistic children and also the challenges faced by them in providing dental care for their Autism Spectrum Disorders (ASD) children’s in four regions of Kingdom of Saudi Arabia. Material and Methods: In total, 263 parents of autistic children participated in this cross-sectional study who were enrolled from 4 major regions of Kingdom of Saudi Arabia. A self-administered questionnaire formulated in simple Arabic was distributed to parents of children diagnosed with autism or any form of ASD. The questionnaires consisted of demographic questions and also to assess their knowledge on oral health, child’s oral hygiene practices and visits to their dentist, oral hygiene, experience and challenges in waiting room area before the dental treatment, acceptance of treatment or rejection, accessibility to find non-dental centers either government or private for treatment and their recommendations . Results: All the parents brushed their child’s teeth using a toothbrush and fluoridated toothpaste. A total of 29.7% of the parents informed that their child never brushes teeth. A total of 41.4% of the parents visit the dental clinic when the child complains about dental problems and 54% find difficulty in locating appropriate dental clinic to deal with their ASD children. Most parents reported taking their child to a private office (38.8%). Only 3.8% of parents reported that their children had seizures during dental procedures. Conclusion: The knowledge toward oral health was found to be inadequate among the majority of the parents. Parents of ASD children need to be educated about the consequences of oral health neglect and the importance of regular check-ups.

ELMOD3‐SH2D6 gene fusion as a possible co‐star actor in autism spectrum disorder scenario

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by high heritability. It is known that genetic factors contribute to ASD pathogenesis. In particular, copy number variants (CNVs) are involved in ASD susceptibility and can affect gene expression regulation. 2p11.2 microdeletions encompassing ELMOD3, CAPG and SH2D6 genes have been described in four unrelated ASD families. The present study revealed that this microdeletion is responsible for the production of a chimeric transcript generated from the fusion between ELMOD3 and SH2D6. The identified transcript showed significantly higher expression levels in subjects carrying the deletion compared to control subjects, suggesting that it is not subjected to nonsense‐mediated decay and might encode for a chimeric protein. In conclusion, this study suggests the possible involvement of this gene fusion, together with the other previously identified variants, in ASD.

Reproductive stoppage in autism spectrum disorder in a population of 2.5 million individuals

BackgroundIt has been suggested that parents of children with autism spectrum disorder (ASD) curtail their reproduction, a phenomenon known as reproductive stoppage. To investigate the presence of reproductive stoppage, we followed the reproduction in mothers of children with or without an ASD diagnosis using Swedish population-based registries.MethodsWe followed all families with first child born in 1987 or later. In total 2,521,103 children, nested within 1,270,017 mothers, were included. Exposure was presence of ASD diagnosis in earlier born siblings, and outcome was considered as (1) inter-pregnancy interval and (2) number of subsequent children.ResultsAnalyses of inter-pregnancy intervals showed that the association differed across birth orders, with a lower rate of second children when first child had ASD diagnosis, but an increased rate of third and higher birth orders in families where a previous child had an ASD diagnosis. When all birth orders were simultaneously considered, families with a child with an ASD diagnosis were less likely to have another child (hazard ratio (HR), 0.79; 95% confidence interval [95% CI], 0.78–0.80). However, when adjusted for birth order, the association was close to null (HR, 0.97; 95% CI, 0.96–0.99), and after additional adjustments (maternal age, birth period, sex, paternal age, and maternal education), the association disappeared (HR, 1.00; 95% CI, 0.99–1.02). In analyses of subsequent children, after adjustment for covariates, families with an ASD diagnosis had 4% more subsequent children (rate ratio, 1.04; 95% CI, 1.03–1.05).LimitationsThe study was undertaken in a country with largely tax-funded healthcare; results may not generalize to other societies. Following the current dominating umbrella concept of ASD, we did not differentiate between the ASD sub-diagnoses; it is possible that reproductive patterns can be dependent on ASD subtypes and the severity and composition of ASD phenotypes and comorbidities.ConclusionsThis study does not support a universal reproductive stoppage effect in ASD families, when birth order and other factors are considered. Therefore, proper attention to birth order and other factors may alleviate potential bias in familial aggregation studies of ASD.

Predictive impact of rare genomic copy number variations in siblings of individuals with autism spectrum disorders

Identification of genetic biomarkers associated with autism spectrum disorders (ASDs) could improve recurrence prediction for families with a child with ASD. Here, we describe clinical microarray findings for 253 longitudinally phenotyped ASD families from the Baby Siblings Research Consortium (BSRC), encompassing 288 infant siblings. By age 3, 103 siblings (35.8%) were diagnosed with ASD and 54 (18.8%) were developing atypically. Thirteen siblings have copy number variants (CNVs) involving ASD-relevant genes: 6 with ASD, 5 atypically developing, and 2 typically developing. Within these families, an ASD-related CNV in a sibling has a positive predictive value (PPV) for ASD or atypical development of 0.83; the Simons Simplex Collection of ASD families shows similar PPVs. Polygenic risk analyses suggest that common genetic variants may also contribute to ASD. CNV findings would have been pre-symptomatically predictive of ASD or atypical development in 11 (7%) of the 157 BSRC siblings who were eventually diagnosed clinically.

Societal Perspective of Cost Analysis of an Early Intervention Programme for Autism Children and It’s Contributing Factors in Klang Valley Malaysia, 2019

Autism spectrum disorder (ASD) is a public health concern globally, characterized by impairments in cognitive process, social functioning, communication skills, behaviours and interests. These problems require a multidisciplinary approach through an early intervention programme (EIP) which is remarkably expensive. To date, the knowledge of EIP costs for ASD children in Malaysia remains unknown. This study estimated the annual average costs of EIP for ASD children from the societal perspective (total average costs, education costs, treatment costs, and living costs), the relationship between the total annual average costs of EIP and its predictors. A cross-sectional cost analysis study using simple random sampling according to proportion was conducted among 280 parents of ASD children receiving EIP services in Klang Valley. The data were collected using interview-based questionnaire and proforma. The Activity-based Costing Technique was used to estimate the EIP-related costs. The non-parametric test was used for bivariate analysis and multiple linear regression for the predictors. The result showed that the total annual average costs of EIP, average education costs, average treatment costs, and average living costs per ASD child were estimated at RM15,158; RM3,896; RM1,948; and RM4,409 respectively. There was a significant association (P = .05) between total annual average costs of EIP, and its contributing factors; family income, ASD level, programme characteristics, and family support. Multiple regression analysis showed that 27% of the total annual average costs of EIP can be predicted by the combination of these factors; EIP types, EIP frequency, centre-based type, ASD level and family income. In conclusion, the study determined the total annual average costs of EIP and its predictors. This information is beneficial as evidence to assist the decision on future resource allocation by the policy maker.

Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.

We performed a comprehensive assessment of rareinherited variation in autism spectrum disorder (ASD) by analyzing whole-genome sequences of 2,308 individuals from families with multiple affected children. We implicate 69 genes in ASD risk, including 24 passing genome-wide Bonferroni correction and 16 new ASD risk genes, most supported by rare inherited variants, a substantial extensionof previousfindings. Biological pathways enriched for genes harboring inherited variants represent cytoskeletal organization and ion transport, which are distinct from pathways implicated in previous studies. Nevertheless, the de novo and inherited genes contribute to a common protein-protein interaction network. We also identified structural variants (SVs) affecting non-coding regions, implicating recurrent deletions in the promoters of DLG2 and NR3C2. Loss of nr3c2 function in zebrafish disrupts sleep and social function, overlapping with human ASD-related phenotypes. These data support the utility of studying multiplex families in ASD and are available through the Hartwell Autism Research and Technology portal.

Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes

PurposeTo maximize the discovery of potentially pathogenic variants to better understand the diagnostic utility of genome sequencing (GS) and to assess how the presence of multiple risk events might affect the phenotypic severity in autism spectrum disorders (ASD). MethodsGS was applied to 180 simplex and multiplex ASD families (578 individuals, 213 patients) with exome sequencing and array comparative genomic hybridization further applied to a subset for validation and cross-platform comparisons. ResultsWe found that 40.8% of patients carried variants with evidence of disease risk, including a de novo frameshift variant in NR4A2 and two de novo missense variants in SYNCRIP, while 21.1% carried clinically relevant pathogenic or likely pathogenic variants. Patients with more than one risk variant (9.9%) were more severely affected with respect to cognitive ability compared with patients with a single or no-risk variant. We observed no instance among the 27 multiplex families where a pathogenic or likely pathogenic variant was transmitted to all affected members in the family. ConclusionThe study demonstrates the diagnostic utility of GS, especially for multiple risk variants that contribute to the phenotypic severity, shows the genetic heterogeneity in multiplex families, and provides evidence for new genes for follow up.