Autism Research

PurposeMany genes have been identified in autism spectrum disorder (ASD). Yet how many adults with ASD receive recommended genetic testing and their outcomes is unknown. We investigated the percentage of adults with ASD with documented genetic testing in our ASD specialty clinic and the percentage with positive findings. MethodsAdults were identified through search of our data repository and ASD diagnoses confirmed using record review by psychiatrists specializing in ASD. Patients were included (N=630) who had at least one visit with a qualifying clinician between 5/1/2010 and 12/15/2020. Data were collected through manual retrospective record review. ResultsOnly 41% of the adults with ASD (261/630) had a documented history of genetic testing. Genetic testing was declined by patients or families for 11% of records and not recorded in 47%. Mean (SD; range) age for the 261 adults was 28.5 (5.3; 22-58) years; 26% were female and 73% had intellectual disability (ID). The genetic testing method was recorded in 91% (238). Only 54% of these patients had testing using a recommended method (chromosomal array, autism/ID sequencing panel, or exome sequencing). Few adults received testing with sequencing technologies. A genetic cause of ASD was found in 28%. ConclusionASD-related genetic testing is underutilized in adults with ASD. Nearly half of the adults in our sample lacked documentation of genetic testing. Thus, the percentage who received testing may be even lower than reported. Adults with ASD may benefit from having their genetic testing history reviewed in the clinic and the recommended testing performed.

We investigated the relationship between parent-reported assessments and autism spectrum disorder (ASD) severity. Parents evaluated 9573 children with ASD on five subscales: combinatorial receptive language, expressive language, sociability, sensory awareness, and health using Autism Treatment Evaluation Checklist (ATEC) and Mental Synthesis Evaluation Checklist (MSEC). Scores in every subscale improved with age and there were clear differences between the three diagnostic categories. The differences between mild and moderate ASD as well as between moderate and severe ASD reached statistical significance in each subscale and in every age group in children 3 years of age and older. These findings demonstrate a consistent relationship between childrens diagnoses and their assessments.

The effect of pretend play in 2 to 5-year-old children with ASD was investigated in the largest and the longest observational study to-date. Parents assessed the development of 7,069 children quarterly for three years on five subscales: combinatorial receptive language, expressive language, sociability, sensory awareness, and health. Pretend play was associated with superior developmental trajectories: 1.9-fold faster improvement of combinatorial receptive language (p<0.0001), 1.4-fold faster improvement of expressive language (p<0.0001), and 1.3-fold faster improvement of sensory awareness (p=0.0009). Pretend play had little effect on sociability and health. The strong association of pretend play with combinatorial receptive language remained significant even when controlling for expressive language. Similarly, the effect of pretend play on expressive language remained significant even when controlling for combinatorial receptive language. The effect of pretend play on combinatorial receptive language (but not on the expressive language) was stronger than the effects of seizures, sleep problems or high-TV exposure. The strong effect of pretend-play supports earlier studies indicating that it is an important stepping stone for language acquisition, particularly, the acquisition of combinatorial language.

BackgroundEvidence supporting the association between breastfeeding patterns and ASD is inconsistent. This study examined sociodemographic and birth factors related to breastfeeding duration and ASD, compared to a typically developing (TD) cohort, using a data-driven approach based on electronic health and developmental records (EHR). MethodsDemographics, feeding preferences (breastfeeding, bottle or both), breastfeeding duration as reported by parents during routine baby wellness visits, were analyzed for a cohort of 11,766 (1.9%) children with ASD and a random subsample of 12,000 (2.03%) TD children. The designation of ASD versus TD was based on a national ASD registry and assigned after EHR were completed. Pre-term, very low birth weight, multiple births, and infants with complex medical comorbidities were excluded. ResultsInfants with ASD were breastfed for an average of 5.0 months, 1.5 months shorter than TD. Fewer ASD infants were exclusively breastfed in the first year of life. Two-way ANOVAs indicated a significant effect of socioeconomic status (SES) and ASD on breastfeeding duration, and a significant interaction with ASD. Post-hoc comparisons showed that the Low SES ASD and TD groups were breastfed longer than all other groups (p<.001). For the Low-Medium, Medium-High and High SES groups, infants with ASD were breastfed less than TD. ConclusionsShorter breastfeeding duration among ASD was confirmed in this representative cohort, calling for closer monitoring for ASD in infants with breastfeeding difficulties. These challenges were independent of birth parameters; however, influenced by socioeconomic factors.

RationaleNeurodevelopmental disorders (NDDs) are characterised by significant challenges in communication, social interaction, and adaptive function, often impacting quality of life. Previous studies support genetic influences on the communication abilities of individuals with NDD, but were either limited to single genetic conditions or to small cohorts with a limited selection of communication measures. MethodsWe analysed caregiver-reported communication abilities in 79,518 individuals with NDD from the Simons Searchlight and SPARK registries: 4,439 with a CNV-based or monogenic NDD and 75,079 with autism spectrum disorder (ASD) without a known genetic cause (idiopathic ASD) as controls. For analysis, we a priori selected 10 communication-related measures based on their availability in the study cohorts, coverage of distinct communication aspects, and their frequent use in neurodevelopmental phenotyping, yielding 177,328 data points across all study cohorts. The individuals in the Searchlight registry were divided into a Discovery cohort (the 15 most prevalent genetic NDD conditions) and a Confirmation cohort (all other genetic NDD conditions). A second Confirmation cohort was generated using all individuals with genetic ASD forms from the SPARK registry. We then tested each of the three case cohorts and each genetic condition represented in the Discovery cohort against the ASD control cohort. Developmental trajectories were assessed through testing of participants grouped by age at evaluation. ResultsMeasure-level analyses demonstrated significant associations between genetic status and communication abilities, differences in communication abilities between classes of genetic variants (monogenic vs. CNV-based NDDs), and variability between specific genetic NDD conditions. CNV-based NDDs showed milder communication impairment, outperforming idiopathic ASD controls in 9/10 communication measures, whereas monogenic NDD conditions had more pervasive impairments, especially in verbal communication. Although impaired in verbal communication, five monogenic NDD conditions showed at least suggestive strengths in nonverbal and social communication relative to idiopathic ASD controls (CSNK2A1, CTNNB1, SETBP1, MED13L, and PPP2R5D), specifically in using gestures. Developmental trajectory analyses revealed STXBP1 as the gene group at highest risk of developmental stagnation in communication abilities. ConclusionsThese findings underscore the potential of precision speech-language pathology (SLP) approaches tailored to the specific verbal and nonverbal communication strengths and weaknesses of genetic groups. We also provide evidence for measurable improvements and declines in communication abilities with age at the group level, highlighting the need for developmentally informed care. By integrating genetic insights into clinical practice, precision SLP approaches may enhance communication outcomes and developmental progress and improve quality of life for individuals with genetic NDDs.

The importance of extensive genetic testing of autism spectrum disorder (ASD) cases has been demonstrated repeatedly in research settings but such testing in clinical settings remains sporadic. Determining which individuals should be prioritized for expensive tests remains a challenge. Several guidelines have been released relating to clinical genetic evaluations and testing in the context of ASD and these guidelines may be informed by the results of genetic testing in large research cohorts. The current study summarizes findings from over 2,000 individuals with ASD who received genetic testing, including microarray and exome testing, through the Simons Simplex Consortium. A returnable genetic result is identified in 10% of cases, however, this yield increases based on four readily accessible phenotypes: female sex and the presence of intellectual disability, seizures or delayed walking. Combinations of these factors increase return rate further, with some combinations yielding a return rate over 50%. In conclusion, these four phenotypes provide a simple approach to prioritize genetic testing in a clinical setting and inform future clinical guidelines. Providing a systematic approach to decisions about who to test removes barriers for, and therefore decrease disparities in, reimbursable genetic testing for individuals diagnosed with ASD.

BackgroundDifferences in sensory processing are a core feature of autism spectrum disorder. Hyper- and hyporesponsivity to sensory stimuli have historically been conceptualized as separate constructs but may co-occur within individuals. Sensory processing may impact both lower and higher-level cognitive processes; thus, it is crucial to understand the relationships between hyper- and hyporesponsivity within and across modalities, as well as the relationship between sensory processing and other aspects of development in both autistic and typically developing (TD) children. MethodsIn 3-4-year-old children (n=41 autism; n=37 TD), we assessed relationships between sensory hyper- and hyporesponsivity both within and across visual, auditory, touch, and oral sensory modalities as measured by caregiver report. Secondary analyses evaluated relationships between sensory responsivity, social communication, and cognitive abilities. FindingsWe found a positive correlation between sensory hyper- and hyporesponsivity ({rho} = .788, p < .001). These associations persisted within groups and within and across modalities. There are positive associations between sensory responsivity and social interaction, communication, and nonverbal developmental quotient, with associations between sensory responsivity and social communication driven by associations within the autism group. InterpretationThe positive correlations between hyper- and hyporesponsivity both within and across sensory modalities, which we term the "Sensory Paradox," may provide key clues to understanding sensory processing in autism and other neurodevelopmental disorders by pointing towards neural circuit-level mechanisms that may underlie neurodevelopmental conditions. FundingThis study was funded by NIH/NINDS 1R01NS134948-01 (ARL), NIMH T32MH112510 (KDC), the Simons Foundation Autism Research Initiative (Award number 648277, ARL), and the Eagles Autism Foundation (ARL). Research in contextO_ST_ABSEvidence before this studyC_ST_ABSUp to 95% of autistic individuals are impacted by sensory processing differences. Across the full range of the autism spectrum, including individuals with profound ASD and self-advocates who speak publicly on issues of neurodiversity, improving sensory processing challenges is repeatedly noted as a common goal that would improve quality of life. Classical medical evaluation of sensory processing typically focuses on whether the structural pathways for transmission of sensory information are intact. The modulation of sensory information as it traverses these pathways, however, is a field ripe for further understanding. Initial reports have identified both hyper- and hyporesponsivity to sensory stimuli in autism, with some overlap between the two patterns of behavior. Added value of this studyThis study demonstrates the seemingly paradoxical finding that hyper- and hyporesponsivity are strongly positively correlated in both autistic and typically developing toddlers. This positive correlation persists within groups and within individual sensory modalities (sight, sound, touch, and oral), as well as across modalities. Implications of all of the available evidenceThe current findings, taken together with prior literature, support the Sensory Paradox - a framework for understanding sensory processing and the resulting sensory experience of autistic individuals which may also have key implications for a wider variety of neurological, psychiatric, and developmental conditions. Rather than considering hyper- and hyporesponsivity as static and opposing constructs, future work on the neurobiology, diagnosis, and management of sensory processing will benefit from considering the variable and context-dependent nature of sensory processing within individuals.

Autism is a highly heterogenous neurodevelopmental condition that, in some individuals, can significantly impair quality of life. Early identification followed by timely intervention is crucial for enhancing cognitive outcomes in children with developmental delay. Yet, marked variability in intervention response remains insufficiently understood. Characterizing this heterogeneity is essential for informing intervention strategies tailored to each childs developmental profile. Here, we aim to identify subgroups based on intervention response trajectories and investigate subgroup-specific predictors of intervention outcomes. We analyzed longitudinal data from 107 children (1.7-3.5 y.o.) receiving 1.5-2 years of Early Start Denver Model (ESDM) intervention. Children gained an average of 19 points in Developmental Quotient (DQ), significantly improved their adaptive skills and showed less autism features. Using latent class regression model, we identified 3 classes: Progressive Group A (35.5% of participants), which had the highest baseline cognitive scores (mean DQ: 78) and gained 27 DQ points in average throughout the intervention; Progressive Group B (34.6% of participants), which showed significant developmental delay at baseline (mean DQ: 62) and gained 25 DQ points; and the Stable Group (29.9% of participants), which also started with significant developmental delay (mean DQ: 47) and showed steady and modest improvement in cognitive scores throughout the intervention. Among the subgroup-specific predictors of better cognitive outcome were younger age for the Progressive Groups and fewer restrictive and repetitive behaviors for the Stable Group. Our results support previous findings of ESDMs efficacy, replicated in a larger sample of 107 children and reveal the association of subgroup-specific baseline factors with cognitive evolution, offering a first step towards personalizing interventions. Lay SummaryO_LIIn a group of 107 autistic children receiving Early Start Denver Model intervention we observed significant gain in cognitive and adaptive skills as well as reduced level of autism features. C_LIO_LIWe identified three subgroups of response with different developmental trajectories. Different factors at baseline were selected as predictors of the cognitive outcome for each subgroup. For two of the subgroups, younger age at the start of intervention was linked to better cognitive outcomes. C_LI

ImportanceASD diagnosis remains behavior-based and the median age of the first diagnosis remains unchanged at [~]52 months, which is nearly 5 years after its first trimester origin. Long delays between ASDs prenatal onset and eventual diagnosis likely is a missed opportunity. However, accurate and clinically-translatable early-age diagnostic methods do not exist due to ASD genetic and clinical heterogeneity. There is a need for early-age diagnostic biomarkers of ASD that is robust against its heterogeneity. ObjectiveTo develop a single blood-based molecular classifier that accurately diagnoses ASD at the age of first symptoms. Design, Setting, and ParticipantsN=264 ASD, typically developing (TD), and language delayed (LD) toddlers with their clinical, diagnostic, and leukocyte RNA data collected. Datasets included Discovery (n=175 ASD, TD subjects), Longitudinal (n=33 ASD, TD subjects), and Replication (n=89 ASD, TD, LD subjects). We developed an ensemble of ASD classifiers by testing 42,840 models composed of 3,570 feature selection sets and 12 classification methods. Models were trained on the Discovery dataset with 5-fold cross validation. Results were used to construct a Bayesian model averaging-based (BMA) ensemble classifier model that was tested in Discovery and Replication datasets. Data were collected from 2007 to 2012 and analyzed from August 2019 to April 2021. Main Outcomes and MeasuresPrimary outcomes were (1) comparisons of the performance of 42,840 classifier models in correctly identifying ASD vs TD and LD in Discovery and Replication datasets; and (2) performance of the ensemble model composed of 1,076 models and weighted by Bayesian model averaging technique. ResultsOf 42,840 models trained in the Discovery dataset, 1,076 averaged AUC-ROC>0.8. These 1,076 models used 191 different feature routes and 2,764 gene features. Using weighted BMA of these features and routes, an ensemble classifier model was constructed which demonstrated excellent performance in Discovery and Replication datasets with ASD classification AUC-ROC scores of 84% to 88%. ASD classification accuracy was comparable against LD and TD subjects and in the Longitudinal dataset. ASD toddlers with ensemble scores above and below the ASD ensemble mean had similar diagnostic and psychometric scores, but those below the ASD ensemble mean had more prenatal risk events than TD toddlers. Ensemble features include genes with immune/inflammation, response to cytokines, transcriptional regulation, mitotic cell cycle, and PI3K-AKT, RAS, and Wnt signaling pathways. Conclusions and RelevanceAn ensemble ASD molecular classifier has high and replicable accuracy across the spectrum of ASD clinical characteristics and across toddlers aged 1 to 4 years, which has potential for clinical translation. Key PointsO_ST_ABSQuestionC_ST_ABSSince ASD is genetically and clinical heterogeneous, can a single blood-based molecular classifier accurately diagnose ASD at the age of first symptoms? FindingsTo address heterogeneity, we developed an ASD classifier method testing 42,840 models. An ensemble of 1,076 models using 191 different feature routes and 2,764 gene features, weighted by Bayesian model averaging, demonstrated excellent performance in Discovery and Replication datasets producing ASD classification with the area under the receiver operating characteristic curve (AUC-ROC) scores of 84% to 88%. Features include genes with immune/inflammation, response to cytokines, transcriptional regulation, mitotic cell cycle, and PI3K-AKT, RAS and Wnt signaling pathways. MeaningAn ensemble gene expression ASD classifier has high accuracy across the spectrum of ASD clinical characteristics and across toddlers aged 1 to 4 years.

BackgroundAltered patterns of eye-movements during scene exploration, and atypical gaze preferences in social settings, have long been noted as features of the Autism phenotype. While these are typically attributed to differences in social engagement and interests (e.g., preferences for inanimate objects over face stimuli), there are also reports of differential saccade measures to non-social stimuli, raising the possibility that fundamental differences in visuo-sensorimotor processing may be at play. Here, we tested the plasticity of the eye-movement system using a classic saccade-adaptation paradigm to assess whether individuals with ASD make typical adjustments to their eye-movements in response to experimentally introduced errors. Saccade adaptation can be measured in infants as young as 10 months, raising the possibility that such measures could be useful as early neuromarkers of ASD risk. MethodsSaccade amplitudes were measured while children and adults with ASD (N=41) and age-matched typically developing (TD) individuals (N=68) made rapid eye-movements to peripherally presented targets. During adaptation trials, the target was relocated from 20-degrees to 15-degrees from fixation once a saccade to the original target location was initiated, a manipulation that leads to systematic reduction in saccade amplitudes in typical observers. ResultsNeither children nor adults with ASD showed any differences relative to TD peers in their abilities to appropriately adapt saccades in the face of persistently introduced errors. ConclusionsOf the three studies to date of saccade adaptation in ASD, none have shown frank deficits in saccade adaptation. Unlike prior studies, we found no evidence for a slower adaptation rate during the early adaptation phase, and no of evidence greater variance of saccade amplitudes in ASD. In post-hoc analysis, there was evidence for larger primary saccades to non-adapted targets, a finding requiring replication in future work.

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. Methods31 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 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 the 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.

PurposeSeveral clinical studies have shown correlations between certain physiological measurements and an autism spectrum disorder (ASD) diagnosis. Such findings, however, have generally not resulted in tangible progress towards practical translation. In fact, most studies have been retrospective in nature and compare biomarker profiles in children with an ASD diagnosis to those who are typically developing. A clinically meaningful test, however, requires an ASD diagnostic center to distinguish children from those with a developmental disorder pre-diagnosis. MethodsThis paper presents, for the first time, a double-blind case/control trial design in which metabolic profiles, collected at two developmental pediatric clinics, were collected from children on a diagnostic waitlist for the purpose of developing a blood-based test for ASD. Besides obtaining blood samples, the children underwent gold-standard clinical evaluations, including the Autism Diagnostic Observation Schedule (ADOS), Mullens Scale of Early Learning (MSEL), and Vineland Adaptive Behavior Scale (VABS). The analysis, together with a complete medical history and physical exam, allowed to confirm or rule-out suspected ASD using DSM-V criteria. The study was based on a cohort of 140 children between the ages 18-60 months, that were referred to a developmental pediatrician because of concerns in their development. Results114 of these children received an ASD diagnosis, while 26 were diagnosed with non-ASD related developmental delays. Based on the measured metabolites, artificial intelligence-based classification algorithms allowed for an over 80% accuracy in predicting whether a sample came from a child diagnosed with ASD or not. ConclusionWhile these results need to be replicated in a larger study, especially involving more children with non-ASD related developmental delays, this is the first work using physiological measurements, coupled with AI, to support ASD diagnoses in a clinically relevant setting.

Language development, a core pillar of social communication, has variable trajectories in autism that include a regression or loss of skills in roughly 20% of autistic individuals. Language regression is most frequently identified through parent report but can also be observed as a decrease in raw scores on a repeated language assessment (measure-defined). Later language outcomes after regression have been observed to be highly variable, but not lower than children without a language regression. The current study explores rates of parent-reported and measure-defined language regression in a large sample of infants at high familial likelihood of autism due to having an older autistic sibling. Among all participants at high familial likelihood for autism (n=428), parent-reported regression was observed in 2.8% (n=12) and was associated with 2.77 times higher odds of receiving an autism diagnosis. Measure-defined regression was observed in 8% (n=36) and was associated with 1.21 times higher odds of autism diagnosis. These rates of regression are expectedly lower than estimates collected in autistic samples. Neither of these elevated odds was statistically significant and there was low concordance between these groups with only one participant present in both. Nearest-neighbor comparison samples of non-autistic infants at high and low likelihood for autism without language regression were selected to assess differences in language growth trajectories associated with regression. Infants with parent-reported language regression showed comparable language development to a matched high-likelihood sample while infants with measure-defined language regression showed slower overall language development than matched peers. Taken together, our results show that parent-report and direct measurement of regression capture unique aspects of child language development that may not be predictive of an autism diagnosis but may indicate delayed language growth in early toddlerhood. These language outcomes support previous findings of wide heterogeneity among those with regression and continued language growth after loss of skills. Key PointsO_LILanguage regression can be captured through parent-report or decrease in raw scores on repeated language assessment and is reported in approximately 20% of autistic toddlers. C_LIO_LIMost research on language regression uses retrospective report of regression in autistic children, but this study prospectively examines regression in toddlers at high familial likelihood for autism who do and do not receive later diagnoses. C_LIO_LIParent-reported and measure-defined regression in this high-likelihood sample have low concordance indicating that these may be different events in language development. C_LIO_LIThe presence of language regression was not associated with significantly higher odds of receiving an autism diagnosis. C_LIO_LIChildren who exhibit language regression continue growing and developing language and those with parent-reported regression display comparable language skills to children without language regression at three years of age. C_LI

ImportanceMotor skill impairments affect up to 87% of children with autism spectrum disorder (ASD) and are associated with greater severity of repetitive behaviors. Yet, most research examining this relationship has treated ASD as a unitary condition. Understanding whether motor-behavior relationships differ by genetic etiology could inform stratified approaches to ASD research and clinical care. ObjectiveTo determine whether the relationship between motor function and restricted and repetitive behaviors (RRBs) differs between children with monogenic forms of ASD (SHANK3, DYRK1A, or SCN2A variants) and children with idiopathic ASD. Design, Setting, and ParticipantsMatched cohort cross-sectional study using data from the Simons Foundation Powering Autism Research for Knowledge (SPARK) database. Children with loss-of-function variants in SHANK3, DYRK1A, or SCN2A were matched to children with idiopathic autism and intellectual disability. Main Outcomes and MeasuresMotor function was assessed using the Developmental Coordination Disorder Questionnaire (DCDQ). Repetitive behaviors were assessed using the Repetitive Behavior Scale-Revised (RBS-R), with subscales categorized as lower-order (stereotyped, self-injurious) or higher-order (compulsive, ritualistic, sameness, restricted interests). The primary analysis compared motor-RRB correlations between groups. ResultsThe sample included 93 children with monogenic autism (SHANK3, n=34; DYRK1A, n=46; SCN2A, n=13) and 787 matched children with idiopathic ASD. In idiopathic ASD, motor function was negatively correlated with RRBs (r = -0.156); in monogenic ASD, this reversed to a positive correlation (r = +0.185; {Delta}r = 0.341, P = 0.002). This reversal was specific to higher-order RRBs (idiopathic r=-0.106; monogenic r=+0.234; {Delta}r=0.339, 95% CI 0.124-0.535, P=0.002) and was not observed for lower-order RRBs ({Delta}r=0.212, P=0.05). All three genes showed positive correlations (SHANK3 r=+0.033; DYRK1A r=+0.262; SCN2A r=+0.623) with no significant heterogeneity (P=0.153). Conclusions and RelevanceThe relationship between motor function and repetitive behaviors differs by genetic etiology, with children with monogenic ASD showing a positive motor-RRB correlation specific to higher-order behaviors, opposite to the negative correlation observed in idiopathic ASD. This reversal was consistent across three molecularly distinct genes. These findings support stratifying autism research and clinical care by genetic etiology. KEY POINTSO_ST_ABSQuestionC_ST_ABSDoes the relationship between motor function and restricted and repetitive behaviors (RRBs) differ between children with autism spectrum disorder (ASD) attributable to SHANK3, DYRK1A, or SCN2A variants and children with idiopathic ASD? FindingsWe conducted a matched cohort cross-sectional study comparing correlations between motor function and RRBs in children with monogenic ASD versus children with idiopathic ASD and intellectual disability. Motor function was negatively correlated with RRBs in children with idiopathic ASD but positively correlated in children with monogenic ASD. MeaningGenetic variants may alter behavioral organization, supporting the value of stratifying populations of individuals with ASD by genetic etiology in both research and clinical care.

PurposeThis study aimed to examine the association between age-specific sleep sufficiency and autism spectrum disorders (ASD) among U.S. children aged 6-17 years. MethodsData were gathered from the 2022-2023 National Survey of Childrens Health (NSCH), including 63,866 children. Sleep sufficiency was defined based on age-specific guidelines from the American Academy of Sleep Medicine. Descriptive statistics, incidence risk ratios (IRRs), and adjusted logistic regression models were used to assess associations between ASD and key predictors. Stratified models by sex and BMI were conducted to explore effect modification. Additionally, a machine learning model was developed to predict the adjusted probability of ASD risk. ResultsChildren with insufficient sleep had a significantly higher incidence of ASD (5.16%) compared to those with sufficient sleep (4.05%) (p < 0.001). In adjusted models, sufficient sleep was associated with lower odds of ASD (OR = 0.78; 95% CI: 0.72-0.85; p < 0.001). Stratified analyses showed a protective effect in both males (OR = 0.78; 95% CI: 0.71-0.86) and females (OR = 0.80; 95% CI: 0.68-0.93), more pronounced in males. Machine learning analysis revealed that females with sufficient sleep and age below 14 years exhibited the lowest probability of ASD, whereas males aged 8 to 14 years with insufficient sleep demonstrated the highest likelihood of ASD risk. ConclusionThese results suggest that sufficient age-specific sleep is significantly associated with reduced odds of ASD, particularly in male children. Findings highlight the importance of sleep as a potentially modifiable factor in ASD risk and support targeted public health interventions.

Differences in sensorimotor processing represent an important, yet underrecognized, feature of autism; typically assessed through subjective observations, which are susceptible to biases. A more objective approach to quantify sensorimotor function may be possible through reflex- based neurobehavioral evaluations. The clinical application of these assessments has, however, been confined largely to laboratory settings. Thus, small sample sizes and inconsistent findings have made it challenging to understand how sensorimotor function differs in autism and whether it can be used as an objective biomarker for diagnostics. Here we present a novel smartphone-based platform to conduct neurobehavioral evaluations by measuring facial and behavioral responses in at-home environments. Through a multi-centre study, we explored the platforms ability to distinguish between children with and without autism. We enrolled 536 children aged 3-12 years. BlinkLab smartphone-based assessments were successfully completed in 431 children (80.4%), including 275 with autism and 156 neurotypical children. We found that autistic children showed altered sensorimotor responses across multiple domains. These included reduced prepulse inhibition (PPI), stronger habituation over the course of a PPI test, more variable eyeblink responses to auditory stimuli and significant sensitization. Additionally, children with autism displayed more screen avoidance, postural instability, head movements, mouth openings, non-syllabic vocalizations, horizontal pupil shifts, "side-eyeing", and variation in baseline eyelid opening. Exploratory analyses showed that these effects were largely independent of co-occurring ADHD or intellectual disability. Notably, co-occurrence did influence certain subdomains (e.g., PPI, mouth openings). These findings illustrate that smartphone-based assessments can capture distinct sensorimotor profiles associated with autism in real-world environments.

The relationship between symbolic thinking and language abilities is a topic of intense debate. We have recently discovered three distinct phenotypes of language comprehension, which we defined as command, modifier and syntactic phenotypes (Vyshedskiy et al., 2024). Individuals in the command phenotype were limited to comprehension of simple commands, while those in the modifier phenotype showed additional comprehension of color, size, and number modifiers. Finally, individuals in the most-advanced syntactic phenotype added comprehension of spatial prepositions, verb tenses, flexible syntax, possessive pronouns, complex explanations, and fairytales. In this report we analyzed how these three language phenotypes differed in their symbolic thinking as exhibited through their drawing abilities. In a cohort of 39,654 autistic individuals 4- to 21-years-of-age, parents reported that drawing, coloring and art was manifested by 36.0% of participants. Among these individuals, representational drawing was manifested by 54.1% of individuals with syntactic-, 27.7% of those with modifier-, and 10.1% of those with command-phenotype (all pairwise differences between the phenotypes were statistically significant, p < 0.0001). The ability to draw a novel image per parents description (e.g. a three-headed horse) was reported by 34.6% of individuals with syntactic-, 7.9% of those with modifier-, and 1.9% of individuals with command-phenotype (all pairwise differences between the phenotypes were statistically significant, p < 0.0001). These results show strong association between the representational drawing ability and the syntactic-language-comprehension-phenotype, suggesting a potential benefit of drawing interventions in language therapy.

AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSBackgroundC_ST_ABSFragile X syndrome (FXS) is the most prevalent form of inherited intellectual disability and is the most common monogenetic cause of autism. Previous studies have linked the structural and functional alterations in FXS with impaired sensory processing and sensory hypersensitivity, which may hinder the early development of cognitive functions such as language comprehension. In this study, we compared the P1 response in event-related potential (ERP) and its habituation to repeated auditory stimuli in male children (2-7 years old) with and without FXS, and examined their association with clinical measures in these two groups. MethodsWe collected high-density electroencephalography (EEG) data in an auditory oddball paradigm from 12 children with FXS and 11 age- and sex-matched typically developing (TD) children. After standardized EEG pre-processing, we conducted a spatial principal component (PC) analysis and identified two major PCs -- a frontal PC and a temporal PC. Within each PC, we compared the P1 amplitude and inter-trial phase coherence (ITPC) between the two groups, and performed a series of linear regression analysis to study the association between these EEG measures and several clinical measures, including assessment scores for language development, non-verbal skills, and sensory hypersensitivity. ResultsAt the temporal PC, both early and late standard stimuli evoked a larger P1 response (p = 0.0037, p<0.0001, respectively) and higher ITPC (p = 0.0402, p = 0.0027) in FXS than in TD. We observed habituation of ITPC in both groups at the frontal PC (p = 0.0149 for FXS; p = 0.0244 for TD). Linear regression analysis showed that within the FXS group reduced frontal P1 response to late standard stimuli and increased habituation were associated with better languages scores. No associations were observed with non-verbal skills or sensory hypersensitivity. ConclusionWe identified P1 amplitude and ITPC in the temporal region as a contrasting EEG phenotype between the FXS and the TD groups. P1 response and habituation in the frontal region may be reflective of the language outcome in male children with FXS. These EEG measures are potential biomarkers for early diagnosis and future language development in patients with FXS.

ImportanceHeterogeneous mental health outcomes during the COVID-19 pandemic are recognized in the general population, but it has not been systematically assessed in youth with neurodevelopmental disorders (NDD), including autism spectrum (ASD). ObjectiveIdentify subgroups of youth with ASD/NDD based on the pandemic impact on symptoms and service changes, as well as predictors of outcomes. Design, Setting, and ParticipantsThis is a naturalistic observational study conducted across 14 North American and European clinical and/or research sites. Parent responses on the Coronavirus Health and Impact Survey Initiative (CRISIS) adapted for Autism and Related Neurodevelopmental Conditions (AFAR) were cross-sectionally collected from April to October 2020. The sample included 1275, 5-21 year-old youth with ASD and/or NDD who were clinically well-characterized prior to the pandemic. Main Outcomes and MeasuresTo identify impact subgroups, hierarchical clustering analyzed eleven AFAR factors measuring pre- to pandemic changes in clinically relevant symptoms and service access. Random forest classification assessed the relative contribution in predicting subgroup membership of 20 features including socio-demographics, pre-pandemic service, and clinical severity along with indices of COVID-19 related experiences and environments empirically-derived from AFAR parent responses and global open sources. ResultsClustering analyses revealed four ASD/NDD impact subgroups. One subgroup - broad symptom worsening only (20% of the aggregate sample) - included youth with worsening symptoms that were above and beyond that of their ASD/NDD peers and with similar service disruptions as those in the aggregate average. The three other subgroups showed symptom changes similar to the aggregate average but differed in service access: primarily modified services (23%), primarily lost services (6%), and average services/symptom changes (53%). Pre-pandemic factors (e.g., number of services), pandemic environments and experiences (e.g., COVID-19 cases, related restrictions, COVID-19 Worries), and age emerged in unique combinations as distinct protective or risk factors for each subgroup. Together they highlighted the role of universal risk factors, such as risk perception, and the protective role of services before and during the pandemic, in middle childhood. Conclusions and RelevanceConcomitant assessment of changes in both symptoms and services access is critical to understand heterogeneous impact of the pandemic on ASD/NDD youth. It enabled the delineation of pathways to risk and resilience that include universal and ASD/NDD specific contributors.

Typically-developing children progress through three distinct language-comprehension phenotypes. 1) The Command Phenotype, emerging by age 2, is characterized by understanding single words and simple commands. 2) The Modifier Phenotype, observed around age 3, is characterized by understanding adjective-noun combinations. 3) The Syntactic Phenotype, reached by age 4, is characterized by understanding stories and complex syntactic structures. This study examined language-comprehension trajectories in autistic children using parent-submitted longitudinal assessments from 6,736 participants, with a mean observation period of 2.2 {+/-} 1.3 years, spanning ages 1.5-22 years. Autistic children advanced through the same three phenotypes as neurotypical children but showed systematic differences. Increasing autism severity both reduced the likelihood of attaining higher-level phenotypes and lengthened the time required to reach them. The Command Phenotype was retained by 11%, 19%, and 39% of individuals with mild, moderate, and severe autism. Among individuals who advanced, median ages for acquiring the Modifier Phenotype were 3.7, 4.6, and 5.7 years for those with mild, moderate, and severe autism. For the Syntactic Phenotype, median ages were 4.8, 5.9, and 6.5 years across the same groups. These findings provide the first large-scale quantification of language-comprehension trajectories in autism and underscore the importance of early intervention.