Autism Spectrum Disorder Families Research Articles

Narrative Ability in Autism and First-Degree Relatives.

Narrative is an important communication skill for sharing personal experiences and connecting with others. Narrative skills are often impacted in autism spectrum disorder (ASD) and have important consequences for social interactions and relationships. Subtle differences in narrative have also been reported among first-degree relatives of autistic individuals, suggesting that narrative may also be an etiologically important language-related skill that is influenced by genes associated with ASD. This study examined narrative ability and related visual attention during narration in ASD and first-degree relatives of individuals with ASD (siblings and parents) to understand how narrative and related attentional styles may be variably impacted across the spectrum of ASD genetic influence. Participants included 56 autistic individuals, 42 siblings of autistic individuals, 49 controls, 161 parents of autistic individuals, and 61 parent controls. Narratives were elicited using a wordless picture book presented on an eye tracker to record concurrent gaze. Findings revealed parallel patterns of narrative differences among ASD and sibling groups in the use of causal language to connect story elements and the use of cognitive and affective language. More subtle differences within the domain of causal language were evident in ASD parents. Parallel patterns in the ASD and sibling groups were also found for gaze during narration. Findings implicate causal language as a critical narrative skill that is impacted in ASD and may be reflective of ASD genetic influence in relatives. Gaze patterns during narration suggest similar attentional mechanisms associated with narrative among ASD families.

Familial Recurrence of Autism: Updates From the Baby Siblings Research Consortium.

Autism spectrum disorder (ASD) is estimated to be ∼10 times higher in children with versus without an autistic sibling in population-based studies. Prospective studies of infant siblings have revealed even higher familial recurrence rates. In the current prospective longitudinal study, we provide updated estimates of familial ASD recurrence using a multinational database of infants with older autistic siblings. Data were collated across 18 sites of the Baby Siblings Research Consortium, an international network studying the earliest manifestations of ASD. A total of 1605 infants with an older autistic sibling were followed from early in life to 3 years, when they were classified as ASD or non-ASD. Hierarchical generalized linear modeling, with site as a random effect, was used to examine predictors of recurrence in families and calculate likelihood ratios. A total of 20.2% of siblings developed ASD, which is not significantly higher than the previously reported rate of 18.7%. Male infant sex and >1 older affected sibling were significant predictors of familial recurrence. Proband sex also influenced recurrence rates, with siblings of female probands significantly more likely to develop ASD than siblings of male probands. Race and maternal education were also associated with recurrence in families. The familial recurrence rate of ASD, as measured in infant sibling studies, has not changed appreciably since previous estimates were made in 2011. Younger siblings of autistic children, particularly those who are male, have an affected female sibling, multiple affected siblings, or are impacted by social inequities, should be closely monitored and promptly referred for diagnostic evaluation.

Novel splicing variant and gonadal mosaicism in DYRK1A gene identified by whole-genome sequencing in multiplex autism spectrum disorder families.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with considerable genetic heterogeneity. The disorder is clinically diagnosed based on DSM-5 criteria, featuring deficits in social communication and interaction, along with restricted and repetitive behaviours. Here, we performed whole-genome sequencing (WGS) on four individuals with ASD from two multiplex families (MPX), where more than one individual is affected, to identify potential single nucleotide variants (SNVs) and structural variants (SVs) in coding and non-coding regions. A rigorous bioinformatics pipeline was employed for variant detection, followed by segregation analysis. Our investigation revealed an unreported splicing variant in the DYRK1A gene (c.-77 + 2T > C; IVS1 + 2T > C; NM_001396.5), in heterozygote form in two affected children in one of the families (family B), which was absent in the healthy parents and siblings. This finding suggests the presence of gonadal mosaicism in one of the parents, representing the first documented instance of such inheritance for a variant in the DYRK1A gene associated with ASD. Furthermore, we identified a 50bp deletion in intron 9 of the DLG2 gene in two affected patients from the same family, confirmed by PCR and Sanger sequencing. In Family A, we identified potential candidate variants associated with ASD shared by the two patients. These findings enhance our understanding of the genetic landscape of ASD, particularly in MPX families, and highlight the utility of WGS in uncovering novel genetic contributions to neurodevelopmental disorders.

Short tandem repeat expansions in cortical layer-specific genes implicate in phenotypic severity and adaptability of autism spectrum disorder.

Short tandem repeats (STRs) are repetitive DNA sequences and highly mutable in various human disorders. While the involvement of STRs in various genetic disorders has been extensively studied, their role in autism spectrum disorder (ASD) remains largely unexplored. In this study, we aimed to investigate genetic association of STR expansions with ASD using whole genome sequencing (WGS) and identify risk loci associated with ASD phenotypes. We analyzed WGS data of 634 ASD families and performed genome-wide evaluation for 12,929 STR loci. We found rare STR expansions that exceeded normal repeat lengths in autism cases compared to unaffected controls. By integrating single cell RNA and ATAC sequencing datasets of human postmortem brains, we prioritized STR loci in genes specifically expressed in cortical development stages. A deep learning method was used to predict functionality of ASD-associated STR loci. In ASD cases, rare STR expansions predominantly occurred in early cortical layer-specific genes involved in neurodevelopment, highlighting the cellular specificity of STR-associated genes in ASD risk. Leveraging deep learning prediction models, we demonstrated that these STR expansions disrupted the regulatory activity of enhancers and promoters, suggesting a potential mechanism through which they contribute to ASD pathogenesis. We found that individuals with ASD-associated STR expansions exhibited more severe ASD phenotypes and diminished adaptability compared to non-carriers. Short tandem repeat expansions in cortical layer-specific genes are associated with ASD and could potentially be a risk genetic factor for ASD. Our study is the first to show evidence of STR expansion associated with ASD in an under-investigated population.

NASP gene contributes to autism by epigenetic dysregulation of neural and immune pathways

BackgroundEpigenetics makes substantial contribution to the aetiology of autism spectrum disorder (ASD) and may harbour a unique opportunity to prevent the development of ASD. We aimed to identify novel epigenetic...

Identification of novel driver risk genes in CNV loci associated with neurodevelopmental disorders

Copy number variants (CNVs) are genome-wide structural variations involving the duplication or deletion of large nucleotide sequences. While these types of variations can be commonly found in humans, large and rare CNVs are known to contribute to the development of various neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD). Nevertheless, given that these NDD-risk CNVs cover broad regions of the genome, it is particularly challenging to pinpoint the critical gene(s) responsible for the manifestation of the phenotype. In this study, we performed a meta-analysis of CNV data from 11,614 patients with NDDs and 4,031 controls from SFARI database to identify 41 NDD-risk CNV loci, including 24 novel regions. We also found evidence for dosage-sensitive genes within these regions being significantly enriched for known NDD-risk genes and pathways. In addition, a significant proportion of these genes was found to i) converge in protein-protein interaction networks; ii) be among most expressed genes in the brain across all developmental stages; and iii) be hit by deletions that are significantly over-transmitted to individuals with ASD within multiplex ASD families from the iHART cohort. Finally, we conducted a burden analysis using 4,281 NDD cases from Decipher and iHART cohorts, and 2,504 neurotypical controls from 1,000 Genomes and iHART, that resulted in the validation of the association of 162 dosage sensitive genes driving risk for NDDs, including 22 novel NDD-risk genes. Importantly, most NDD-risk CNV loci entail multiple NDD-risk genes in agreement with a polygenic model associated with the majority of NDD cases.

Differences in caregiver and child factors within families of autistic youth across birth order groups

BackgroundResearch has highlighted the ways that birth order relates to autism spectrum disorder (ASD) prevalence rates. However, little research has focused on how birth order relates to the wellbeing of the family once a child is diagnosed with ASD. Additionally, many family factors (such as measures of parental wellbeing) and elements of child emotional/behavioral symptoms have not yet been investigated when evaluating the potential effects of birth order. The current study aimed to investigate how family birth order may impact caregiver reporting of parental wellbeing/competency and child symptoms. MethodThree groups were created based on caregivers (N = 155) who have (1) a first-born child with ASD and then child(ren) without ASD, (2) child(ren) without ASD and then a child with ASD, and (3) an only child with ASD. Caregivers completed questionnaires measuring family resources, child symptoms, and parental factors. ResultsDespite comparable ratings on family resources and ASD severity, significant differences based on birth order emerged. Having one or multiple children without ASD before having a child with ASD may enhance feelings of satisfaction and competency as a parent. Parents with an only child with ASD also reported higher ratings of competency, had significantly less ASD knowledge, and demonstrated a significant negative correlation between efficacy and knowledge. ConclusionFamilies with an only child with ASD may require further support to augment their knowledge of ASD. Caregivers who have a first-born child with ASD may benefit from interventions focusing on their feelings of parental competency.

Association between parental psychiatric disorders and risk of offspring autism spectrum disorder: a Swedish and Finnish population-based cohort study

Roughly more than one in six adults worldwide suffer from psychiatric conditions. Sporadic studies have associated parental psychiatric disorders with autism spectrum disorder in offspring. Comprehensively examining the association between parental psychiatric disorders and offspring autism spectrum disorder is needed to guide health policies, and to inform etiologic studies. We included all children born in Sweden and Finland 1997-2016. Diagnoses were clinically ascertained from National Registers through 2017. We calculated adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for autism spectrum disorder in offspring of fathers and mothers with psychiatric disorders, in both parents jointly and across co-occurring conditions. Among 2,505,842 children, 33,612 were diagnosed with autism spectrum disorder, of which 20% had a parent with psychiatric disorders. The risk of autism spectrum disorder was increased across all psychiatric disorders in fathers (Sweden: aHR=2.02, 95% CI=1.92-2.12; Finland: aHR=1.63, 95% CI=1.50-1.77), mothers (Sweden: aHR=2.34, 95% CI=2.24-2.43; Finland aHR=2.12, 95% CI=1.92-2.28), or both parents (Sweden: aHR=3.76, 95% CI=3.48-4.07; Finland aHR=3.61, 95% CI=3.20-4.07), compared to neither parents. Co-occurrence of parental psychiatric disorders further increased risk (e.g., Sweden: for one, two or≥three different diagnostic categories compared to no diagnosis, in fathers aHR=1.81, 2.07, 2.52; in mothers aHR=2.05, 2.63, 3.57). Psychiatric disorders in both parents conveyed the highest risk of offspring autism spectrum disorder, followed by mothers and then fathers. The risk increased with number of co-occurring disorders. All parental psychiatric disorders were associated with increased the risk of autism spectrum disorder. To reliably assess the risk of autism spectrum disorder in children, a comprehensive history incorporating the full range of parental psychiatric disorders is needed beyond solely focusing on familial autism spectrum disorder. Swedish-Research-Council-2021-0214.

Genomic analysis of 116 autism families strengthens known risk genes and highlights promising candidates

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with a strong genetic component in which rare variants contribute significantly to risk. We performed whole genome and/or exome sequencing (WGS and WES) and SNP-array analysis to identify both rare sequence and copy number variants (SNVs and CNVs) in 435 individuals from 116 ASD families. We identified 37 rare potentially damaging de novo SNVs (pdSNVs) in the cases (n = 144). Interestingly, two of them (one stop-gain and one missense variant) occurred in the same gene, BRSK2. Moreover, the identification of 8 severe de novo pdSNVs in genes not previously implicated in ASD (AGPAT3, IRX5, MGAT5B, RAB8B, RAP1A, RASAL2, SLC9A1, YME1L1) highlighted promising candidates. Potentially damaging CNVs (pdCNVs) provided support to the involvement of inherited variants in PHF3, NEGR1, TIAM1 and HOMER1 in neurodevelopmental disorders (NDD), although mostly acting as susceptibility factors with incomplete penetrance. Interpretation of identified pdSNVs/pdCNVs according to the ACMG guidelines led to a molecular diagnosis in 19/144 cases, although this figure represents a lower limit and is expected to increase thanks to further clarification of the role of likely pathogenic variants in ASD/NDD candidate genes not yet established. In conclusion, our study highlights promising ASD candidate genes and contributes to characterize the allelic diversity, mode of inheritance and phenotypic impact of de novo and inherited risk variants in ASD/NDD genes.

Lamotrigine‐associated macular phototoxicity in Asperger syndrome

Purpose: Asperger's syndrome is a neurodevelopmental disorder that falls within the autism spectrum disorder family. Comorbid conditions such as depression and anxiety are commonly associated, and lamotrigine is often prescribed off‐label for treatment. It has the capacity to absorb ultraviolet (UV) light and generate free oxygen radicals, which can potentially cause cellular damage. In this case report, we present multimodal imaging findings in a patient diagnosed with solar maculopathy.Methods: A young patient was referred to our department for bilateral visual decline and central scotoma. The patient was examined with multimodal imaging including fundus photography, fundus autofluorescence (FAF), swept‐source optical coherence tomography (SS‐OCT) and multifocal electroretinogram.Results: A 25‐year‐old patient with Asperger's syndrome treated with lamotrigine was referred to our department for bilateral visual decline and central scotoma. Best corrected visual acuity (BCVA) was 0.40 in both eyes. Dilated fundus examination revealed a bilateral yellow foveal lesion. Fundus autofluorescence (FAF) imaging showed foveal hyperautofluorescence. SS‐OCT in the macular region of both eyes showed a disruption of the ellipsoid zone and the external limiting membrane. Upon further questioning, the patient disclosed history of repeatedly gazing at the sun. The diagnosis of solar maculopathy associated with lamotrigine was established.Conclusion: This is the second report of lamotrigine associated retinal phototoxicity. Lamotrigine, recognized as a photosensitizer, may induce a photochemical response, with retinal phototoxicity. Caution must be exercised to educate patients about the importance of not gazing directly at the sun, as it van cause irreversible retinal impairment.

Rare X-linked variants carry predominantly male risk in autism, Tourette syndrome, and ADHD

Autism spectrum disorder (ASD), Tourette syndrome (TS), and attention-deficit/hyperactivity disorder (ADHD) display strong male sex bias, due to a combination of genetic and biological factors, as well as selective ascertainment. While the hemizygous nature of chromosome X (Chr X) in males has long been postulated as a key point of “male vulnerability”, rare genetic variation on this chromosome has not been systematically characterized in large-scale whole exome sequencing studies of “idiopathic” ASD, TS, and ADHD. Here, we take advantage of informative recombinations in simplex ASD families to pinpoint risk-enriched regions on Chr X, within which rare maternally-inherited damaging variants carry substantial risk in males with ASD. We then apply a modified transmission disequilibrium test to 13,052 ASD probands and identify a novel high confidence ASD risk gene at exome-wide significance (MAGEC3). Finally, we observe that rare damaging variants within these risk regions carry similar effect sizes in males with TS or ADHD, further clarifying genetic mechanisms underlying male vulnerability in multiple neurodevelopmental disorders that can be exploited for systematic gene discovery.

Comparison of three bioinformatics tools in the detection of ASD candidate variants from whole exome sequencing data

Autism spectrum disorder (ASD) is a heterogenous multifactorial neurodevelopmental condition with a significant genetic susceptibility component. Thus, identifying genetic variations associated with ASD is a complex task. Whole-exome sequencing (WES) is an effective approach for detecting extremely rare protein-coding single-nucleotide variants (SNVs) and short insertions/deletions (INDELs). However, interpreting these variants' functional and clinical consequences requires integrating multifaceted genomic information. We compared the concordance and effectiveness of three bioinformatics tools in detecting ASD candidate variants (SNVs and short INDELs) from WES data of 220 ASD family trios registered in the National Autism Database of Israel. We studied only rare (< 1% population frequency) proband-specific variants. According to the American College of Medical Genetics (ACMG) guidelines, the pathogenicity of variants was evaluated by the InterVar and TAPES tools. In addition, likely gene-disrupting (LGD) variants were detected based on an in-house bioinformatics tool, Psi-Variant, that integrates results from seven in-silico prediction tools. Overall, 372 variants in 311 genes distributed in 168 probands were detected by these tools. The overlap between the tools was 64.1, 22.9, and 23.1% for InterVar–TAPES, InterVar–Psi-Variant, and TAPES–Psi-Variant, respectively. The intersection between InterVar and Psi-Variant (I ∩ P) was the most effective approach in detecting variants in known ASD genes (PPV = 0.274; OR = 7.09, 95% CI = 3.92–12.22), while the union of InterVar and Psi Variant (I U P) achieved the highest diagnostic yield (20.5%).Our results suggest that integrating different variant interpretation approaches in detecting ASD candidate variants from WES data is superior to each approach alone. The inclusion of additional criteria could further improve the detection of ASD candidate variants.

The contributions of rare inherited and polygenic risk to ASD in multiplex families

Autism spectrum disorder (ASD) has a complex genetic architecture involving contributions from both de novo and inherited variation. Few studies have been designed to address the role of rare inherited variation or its interaction with common polygenic risk in ASD. Here, we performed whole-genome sequencing of the largest cohort of multiplex families to date, consisting of 4,551 individuals in 1,004 families having two or more autistic children. Using this study design, we identify seven previously unrecognized ASD risk genes supported by a majority of rare inherited variants, finding support for a total of 74 genes in our cohort and a total of 152 genes after combined analysis with other studies. Autistic children from multiplex families demonstrate an increased burden of rare inherited protein-truncating variants in known ASD risk genes. We also find that ASD polygenic score (PGS) is overtransmitted from nonautistic parents to autistic children who also harbor rare inherited variants, consistent with combinatorial effects in the offspring, which may explain the reduced penetrance of these rare variants in parents. We also observe that in addition to social dysfunction, language delay is associated with ASD PGS overtransmission. These results are consistent with an additive complex genetic risk architecture of ASD involving rare and common variation and further suggest that language delay is a core biological feature of ASD.

Large-Scale Whole Genome Sequence Analysis of >22,000 Subjects Provides no Evidence of FMR1 Premutation Allele Involvement in Autism Spectrum Disorder.

Expansion of a CGG repeat in the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene on the X chromosome is the cause of Fragile X Syndrome (FXS). The repeat length of unaffected individuals varies between 5-40 repeats, whereas >200 repeats are observed in cases of FXS. The intermediate range between 55-200 repeats is considered the premutation range and is observed in roughly 1:300 females and 1:900 males in the general population. With the availability of large-scale whole genome sequence (WGS) data and the development of computational tools to detect repeat expansions, we systematically examined the role of FMR1 premutation alleles in autism spectrum disorder (ASD) susceptibility, assess the prevalence, and consider the allelic stability between parents and offspring. We analyzed the WGS data of 22,053 subjects, including 32 FXS positive controls, 1359 population controls, and 5467 ASD families. We observed no FMR1 full mutation range repeats among the ASD parent-offspring families but identified 180 family members with premutation range alleles, which represents a higher prevalence compared to the independent WGS control sample and previous reports in the literature. A sex-specific analysis between probands and unaffected siblings did not reveal a significant increase in the burden of premutation alleles in either males or females with ASD. PCR validation, however, suggests an overestimation of the frequency of FMR1 premutation range alleles through computational analysis of WGS data. Overall, we show the utility of large-scale repeat expansion screening in WGS data and conclude that there is no apparent evidence of FMR1 premutation alleles contributing to ASD susceptibility.

A framework for measuring the cost to families of caring for children’s health: the design, methodology, and study population of the r-Kids study

BackgroundAll families experience financial and time costs related to caring for their children’s health. Understanding the economic burden faced by families of children with chronic health conditions (CHC) is crucial for designing effective policies to support families.MethodsIn this prospective study we used electronic health records to identify children between 3 and 17 years old with autism spectrum disorder (ASD), asthma, or neither (control) from three Kaiser Permanente regions and several community health centers in the OCHIN network. We oversampled children from racial and ethnic minority groups. Parent/guardian respondents completed surveys three times, approximately four months apart. The surveys included the Family Economic Impact Inventory (measuring financial, time, and employment costs of caring for a child’s health), and standardized measures of children’s quality of life, behavioral problems, and symptom severity for children with ASD or asthma. We also assessed parenting stress and parent physical and mental health. All materials were provided in English and Spanish.ResultsOf the 1,461 families that enrolled (564 ASD, 468 asthma, 429 control), children were predominantly male (79%), with a mean age of 9.0 years, and racially and ethnically diverse (43% non-Hispanic white; 22% Hispanic; 35% Asian, Black, Native Hawaiian, or another race/ethnicity). The majority of survey respondents were female (86%), had a college degree (62%), and were married/partnered (79%). ASD group respondents were less likely to be employed (73%) than those in the asthma or control groups (both 80%; p = .023). Only 32% of the control group reported a household income ≤ $4,000/month compared with 41% of asthma and 38% of ASD families (p = .006).ConclusionsUtilizing a novel measure assessing family economic burden, we successfully collected survey responses from a large and diverse sample of families. Drawing upon the conceptual framework, survey measures, and self-report data described herein we will conduct future analyses to examine the economic burdens related to CHC and the incremental differences in these burdens between health groups. This information will help policy makers to design more equitable health and social policies that could reduce the burden on families.

Noncoding de novo mutations contribute to autism via long-range chromatin interactions

IntroductionThree-dimensional chromatin interactions regulate gene expressions. The significance of de novo mutations (DNMs) in chromatin interactions remains poorly understood for autism spectrum disorder (ASD).ObjectivesTo investigate the genomic architecture of ASD in terms of non-coding de novo mutations and 3-dimensional chromatin interactionsMethodsWe generated 813 whole-genome sequences from 242 Korean simplex families to detect DNMs, and identified target genes which were putatively affected by non-coding DNMs in chromatin interactions.ResultsNon-coding DNMs in chromatin interactions were significantly involved in transcriptional dysregulations related to ASD risk. Correspondingly, target genes showed spatiotemporal expressions relevant to ASD in developing brains and enrichment in biological pathways implicated in ASD, such as histone modification. Regarding clinical features of ASD, non-coding DNMs in chromatin interactions particularly contributed to low intelligence quotient levels in ASD probands. We further validated our findings using two replication cohorts, Simons Simplex Collection (SSC) and MSSNG, and showed the consistent enrichment of non-coding DNM-disrupted chromatin interactions in ASD probands. Generating human induced pluripotent stem cells in two ASD families, we were able to demonstrate that non-coding DNMs in chromatin interactions alter the expression of target genes at the stage of early neural development.ConclusionsTaken together, our findings indicate that non-coding DNMs in ASD probands lead to early neurodevelopmental disruption implicated in ASD risk via chromatin interactions.Disclosure of InterestNone Declared

Prenatal maternal stress and the severity of autism spectrum disorder: A cross-sectional study.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder linked to several genetic and environmental factors including antenatal stress. Hence, we aimed to examine whether a mother's stress during pregnancy is associated with the severity of autism spectrum disorder in children. The study was conducted with 459 mothers of children with autism (aged 2-14 years) who were attending rehabilitation and educational centers in the two major cities of Makkah and Jeddah in Saudi Arabia. Environmental factors, consanguinity, and ASD family history were assessed using a validated questionnaire. The Prenatal Life Events Scale questionnaire was used to assess whether the mothers were exposed to stress during pregnancy. Two models of ordinal regression analysis were conducted including gender, child age maternal age, parental age, maternal education, parental education, income nicotine exposure, mother taking medication during pregnancy, family history of ASD, gestation, consanguinity, exposure of prenatal life events (in model 1), and severity of prenatal life events (in model 2). Family history of ASD showed a statistically significant association with the severity of ASD in both regression models (p = .015, odds ratio [OR]: 4.261 in Model 1, and p = .014, OR: 4.901 in model 2). In model 2, the moderate severity prenatal life events showed higher statistically significant adjusted odds ratio for ASD severity compared to no stress (p = .031; OR: 3.82). Within the limitations of this study, prenatal stressors showed some potential contribution to ASD severity. Family history of ASD was the only factor that showed a persistent association with ASD severity. A study that assesses the effect of COVID-19 stress on ASD prevalence and severity is recommended.

Structural variants identified using non-Mendelian inheritance patterns advance the mechanistic understanding of autism spectrum disorder.

The heritability of autism spectrum disorder (ASD), based on 680,000 families and five countries, is estimated to be nearly 80%, yet heritability reported from SNP-based studies are consistently lower, and few significant loci have been identified with genome-wide association studies. This gap in genomic information may reside in rare variants, interaction among variants (epistasis), or cryptic structural variation (SV) and may provide mechanisms that underlie ASD. Here we use a method to identify potential SVs based on non-Mendelian inheritance patterns in pedigrees using parent-child genotypes from ASD families and demonstrate that they are enriched in ASD-risk genes. Most are in non-coding genic space and are over-represented in expression quantitative trait loci, suggesting that they affect gene regulation, which we confirm with their overlap of differentially expressed genes in postmortem brain tissue of ASD individuals. We then identify an SV in the GRIK2 gene that alters RNA splicing and a regulatory region of the ACMSD gene in the kynurenine pathway as significantly associated with a non-verbal ASD phenotype, supporting our hypothesis that these currently excluded loci can provide a clearer mechanistic understanding of ASD. Finally, we use an explainable artificial intelligence approach to define subgroups demonstrating their use in the context of precision medicine.

Age of Diagnosis and Demographic Factors Associated with Autism Spectrum Disorders in Chinese Children: A Multi-Center Survey.

The present study investigated the age of diagnosis, treatment and demographic factors of Chinese children with autism spectrum disorders (ASD), to provide a scientific basis for the early detection, diagnosis, and intervention of ASD. A total of 1500 ASD children aged 2-7 years old from 13 cities in China were administered questionnaires to examine their diagnosis, treatment, and basic family information. The Childhood Autism Rating Scale (CARS) was used to measure the symptoms and severity of ASD children, and the Children Neuropsychological and Behavior Scale-Revision 2016 (CNBS-R2016) was utilized to measure neurodevelopmental levels of ASD children. We found that for children with ASD, the median (p25, p75) age for the initial detection of social behavioral developmental delay was 24 (18, 30) months, while the age for the initial diagnosis was 29 (24, 36) months and the age for the beginning of intervention was 33 (27, 42) months. Multiple linear regression (MLR) analysis suggested that in children with ASD whose parents were divorced, separated, or widowed, or whose mothers were engaged in physical work, the initial detection of social behavioral developmental delay happened later. For the children with ASD who lived in urban areas, had higher levels of ASD symptom severity or whose parents were not divorced or separated, the age for the initial diagnosis was earlier. For the children with ASD who lived in urban areas or whose mothers had received higher level of education, the earlier age for the beginning of intervention was observed, while for those with ASD whose mothers were engaged in physical work, the age for the beginning of training was later. It is recommended to actively carry out health education of ASD and strengthen the support for ASD families to enhance their rehabilitation level.

Social attention during object engagement: toward a cross-species measure of preferential social orienting

BackgroundA central challenge in preclinical research investigating the biology of autism spectrum disorder (ASD) is the translation of ASD-related social phenotypes across humans and animal models. Social orienting, an observable, evolutionarily conserved behavior, represents a promising cross-species ASD phenotype given that disrupted social orienting is an early-emerging ASD feature with evidence for predicting familial recurrence. Here, we adapt a competing-stimulus social orienting task from domesticated dogs to naturalistic play behavior in human toddlers and test whether this approach indexes decreased social orienting in ASD.MethodsPlay behavior was coded from the Autism Diagnostic Observation Schedule (ADOS) in two samples of toddlers, each with and without ASD. Sample 1 (n = 16) consisted of community-ascertained research participants, while Sample 2 involved a prospective study of infants at a high or low familial liability for ASD (n = 67). Coding quantified the child’s looks towards the experimenter and caregiver, a social stimulus, while playing with high-interest toys, a non-social stimulus. A competing-stimulus measure of “Social Attention During Object Engagement” (SADOE) was calculated by dividing the number of social looks by total time spent playing with toys. SADOE was compared based on ASD diagnosis and differing familial liability for ASD.ResultsIn both samples, toddlers with ASD exhibited significantly lower SADOE compared to toddlers without ASD, with large effect sizes (Hedges’ g ≥ 0.92) driven by a lower frequency of child-initiated spontaneous looks. Among toddlers at high familial likelihood of ASD, toddlers with ASD showed lower SADOE than toddlers without ASD, while SADOE did not differ based on presence or absence of familial ASD risk alone. SADOE correlated negatively with ADOS social affect calibrated severity scores and positively with the Communication and Symbolic Behavior Scales social subscale. In a binary logistic regression model, SADOE alone correctly classified 74.1% of cases, which rose to 85.2% when combined with cognitive development.ConclusionsThis work suggests that a brief behavioral measure pitting a high-interest nonsocial stimulus against the innate draw of social partners can serve as a feasible cross-species measure of social orienting, with implications for genetically informative behavioral phenotyping of social deficits in ASD and other neurodevelopmental disorders.