Journal of Autism and Developmental Disorders

Abstract Background & Aims: Language development in autism is heterogeneous and strongly predicts later functioning. The balance between receptive and expressive abilities and their developmental trajectories, however, remains poorly understood. While some autistic children exhibit a relative expressive advantage (ExpAdv), others show receptive advantage (RecAdv) or a balanced profile. Prior studies report inconsistent findings and are often limited by cross-sectional designs and small samples. The present study aimed to (1) describe longitudinal trajectories of receptive and expressive language in autistic and typically developing (TD) children; (2) classify children into ExpAdv, Balanced, and RecAdv profiles across early childhood; and (3) examine the stability and transitions of these profiles over time, including associated clinical features. Methods: We analyzed 1,174 longitudinal time points from 318 autistic children and 294 time points from 108 TD children (1.2-5.8 years) from the Geneva Autism Cohort. Receptive and expressive language were assessed with the Mullen Scales of Early Learning. Receptive-expressive balance was quantified as the ratio of receptive to expressive age equivalent scores, classifying children into ExpAdv, Balanced, and RecAdv profiles using adapted cut-offs. Mixed-effects models examined developmental trajectories, and Sankey diagrams visualized profile transitions. Autism features and adaptive behavior were compared across profiles. Results: Autistic children displayed lower expressive and receptive language than TD peers, with receptive abilities exceeding expressive skills in both groups. Overall, 30-35% of autistic children were classified as ExpAdv at 18-36 months, declining to ~12% by 48-54 months, while Balanced and RecAdv profiles became more prevalent with age. ExpAdv was associated with slower verbal and non-verbal developmental gains. Stability was highest for Balanced and RecAdv profiles (50-60%), whereas ExpAdv often transitioned to Balanced. Autistic children with stable ExpAdv profiles were more often female, less likely to receive early intervention, and showed weaker adaptive communication. Conclusions: Receptive-expressive language profiles in autistic children are dynamic. ExpAdv profile is more frequent in younger autistic children, less stable, and linked to slower verbal and non-verbal development and higher autism severity. Implications: ExpAdv may represent an early marker of autism associated with slower expressive and receptive language growth. Longitudinal monitoring of receptive and expressive skills is essential, as transitions toward Balanced or RecAdv profiles are associated with improved developmental outcomes. Early intervention before age three may facilitate transitions toward Balanced or RecAdv profiles, supporting more favorable language development and long-term outcomes. Keywords: autism; early childhood; longitudinal design; expressive language; receptive language; language profile; early intervention; language gap; discrepant profiles

Background: Female individuals tend to be diagnosed with autism later. One factor suggested to contribute to diagnostic timing is verbal ability, in which autistic females may show strengths relative to male peers. Social drivers of health (SDOH) predict higher verbal skills, yet access to resources may facilitate diagnosis; thus, SDOH likely contributes to diagnostic timing in complex ways. We use data from two autism cohorts with substantial representation of those assigned female at birth (AFAB) to examine interactions among assigned sex at birth (sex), verbal IQ (VIQ), and SDOH in predicting autism diagnostic timing. Methods: We used multiple linear regression to examine sex assigned at birth and VIQ as predictors of diagnostic timing in an assigned-sex-balanced research sample (N=164, AFAB: 71) and an independent clinical sample (N=641, AFAB: 177). We hypothesized VIQ would positively predict diagnostic age, particularly among AFAB. Available data in the clinical sample also permitted us to explore the contributions of SDOH and inclusion criteria to model fit in this cohort. Results: In the research sample, VIQ, but not sex, positively predicted diagnostic age. In the clinical sample, VIQ and VIQ x SDOH, but not sex, predicted diagnostic age. Fitting the same model in a subsample of the clinical cohort formed by applying exclusion criteria used in the research sample (N=484, AFAB: 110), VIQ x SDOH x Sex became significant. For AFAB, higher VIQ and lower SDOH together were associated with later diagnosis in the clinical subsample, while for AMAB the opposite was true. Conclusions: Autistic youth with strong verbal ability may experience diagnostic delays. SDOH interacts with VIQ in a complex fashion, with lower SDOH generally exacerbating the tendency for VIQ to be associated with later diagnosis across a large clinical sample. However, among autistic youth without complicating medical factors or intellectual disability, this relationship is dependent upon sex.

Genetic counselling outcome measures are increasingly adapted for diverse clinical contexts. While the Genetic Counselling Outcome Scale (GCOS-24) is available in Swedish, no autism-specific version has been developed. Therefore, we adapted the Swedish GCOS-24 using the English version of the modified GCOS-24 (mGCSOS-24) to create a Swedish autism-specific mGCOS-24. Thereafter, we evaluated both the Swedish autism mGCOS-24 and the Swedish general GCOS-24 using Rasch analysis to assess their psychometric properties. Both instruments exhibited structural challenges, including multidimensionality, disordered thresholds, local item dependence, and invariance issues. For the Swedish autism mGCOS-24, we were able to identify subscales with acceptable measurement properties. However, applying the same structure to the Swedish general GCOS-24 did not resolve its broader limitations. This study introduces the first Swedish autism-specific mGCOS-24 and represents the first Rasch-based evaluation of any GCOS-24 or mGCOS-24 in Swedish. Our findings highlight important opportunities for measure refinement but also indicate that new or more substantially adapted tools may be needed to capture outcomes of genetic counselling in autistic populations.

Abstract Parental depression and early child neurodevelopment are closely interconnected, yet few population-based studies have examined both maternal and paternal depression in relation to early neurodevelopmental risk. This study aimed to examine the association between child neurodevelopmental risk and parental depression in the French national birth cohort Etude Longitudinale Francaise depuis l'Enfance (ELFE). We conducted a cross-sectional analysis of 12,953 children and their parents who participated in the 2-year follow-up. Child neurodevelopmental risk was assessed at age 2 years using the Modified Checklist for Autism in Toddlers and categorized as low, intermediate, or high risk. Parental depression was assessed using the Kessler Psychological Distress Scale and defined as maternal depression, paternal depression, or depression in at least one parent. Multivariable logistic regression models were adjusted for sociodemographic, pregnancy-related, and child characteristics. Compared with low child neurodevelopmental risk, intermediate risk was associated with higher odds of maternal depression and depression in at least one parent. High child neurodevelopmental risk was associated with substantially higher odds of maternal depression and depression in at least one parent. Associations with paternal depression were weaker and were no longer statistically significant after adjustment. These findings suggest that parental depression, particularly maternal depression, is associated with early child neurodevelopmental risk from the stage of initial developmental concerns. They support an integrated, family-centred approach combining early identification of child developmental vulnerability with attention to parental mental health.

AimAutistic children have a high but varied prevalence of internalizing and externalizing problems. This study aimed to identify the subtypes of internalizing and externalizing problems among autistic preschool children in Japan, examine their temporal stability, and investigate differences in participation in daily life and family outcomes across these subtypes. MethodsA prospective cohort study was conducted with 275 caregivers of autistic children aged 51-75 months. Internalizing and externalizing problems were assessed using the Strengths and Difficulties Questionnaire. ResultsLatent transition analysis identified five subtypes: Low-symptom, High-emotional, Externalizing, Comorbid, and Peer-difficulty groups. Membership in the High-emotional and Externalizing groups was relatively stable over time, whereas the Peer-difficulty group showed frequent transitions to subtypes with higher levels of internalizing or externalizing problems. Significant differences in participation in daily life and family outcomes were observed across subtypes, but these patterns were inconsistent with a simple gradient of symptom levels. ConclusionsThe novel findings that the temporal stability of subtype membership varied and that differences in participation in daily life and family outcomes were observed across the subtypes suggest that the heterogeneity of internalizing and externalizing problems may be associated with variations in childrens participation in daily life and family outcomes over time. Plain Language SummaryAutistic preschool children often experience emotional and behavioral difficulties, but the way these difficulties manifest varies widely across individuals. This study aimed to identify the patterns of these difficulties, examine how they change over time, and investigate how participation in daily life and family outcomes differ across autistic preschool children. We conducted a study with 275 caregivers of autistic children aged 4-6 years in Japan. From caregiver reports of childrens emotional and behavioral difficulties, five distinct patterns were identified: a group with mainly emotional difficulties, a group with mainly behavioral difficulties, a group with both types of difficulties, a group with relatively low levels of difficulties, and a group characterized primarily by peer-related difficulties. Our findings suggest that different patterns of emotional and behavioral difficulties are associated with differences in childrens participation in daily life and family outcomes. These differences could not be explained simply by the overall severity of difficulties but rather reflect distinct patterns based on the type of difficulty. The results indicate that autistic children face diverse difficulties that change over time.

PurposeNavigational ability develops throughout childhood alongside the maturation of brain regions supporting egocentric and allocentric processing. In Autism Spectrum Disorder (ASD), atypical hippocampal development may impact flexible spatial memory; however, findings on navigational ability in autistic children remain inconsistent. This study aimed to compare both objective and perceived navigation ability in children with ASD and typically developing (TD) peers. MethodTwenty-six children with high-functioning ASD and twenty-five age- and gender-matched TD children (M_age = 12.04 years, SD = 1.64) completed a battery of navigational tasks from the Spatial Performance Assessment for Cognitive Evaluation (SPACE), including Path Integration, Egocentric Pointing, Mapping, Associative Memory, and Perspective Taking. Perceived navigation ability was assessed using the Santa Barbara Sense of Direction (SBSOD) scale. ResultsNo significant group differences were observed across any objective navigation tasks. However, children with ASD reported significantly lower perceived navigation ability compared to TD peers. ConclusionThese findings suggest a dissociation between perceived and actual navigational ability in ASD. By early adolescence, objective navigation performance appears intact, potentially reflecting sufficient maturation of underlying neural systems or the presence of compensatory mechanisms. The results underscore the importance of incorporating objective, task-based measures when assessing cognitive abilities in autistic populations.

Objective: To understand if sociodemographic and neuropsychiatric characteristics of people diagnosed with autism in the United Kingdom (UK) and Sweden have changed since 2010. Design: Cross-context population-based cohort studies. Setting: UK primary care records from 2010-2023 and Swedish population-wide register linkages from 2010-2021 Participants: 24,537,039 individuals age 16 or over, registered with general practices in the UK, including 141,119 with an autism diagnosis. 9,096,874 people age 16 or over in the Swedish Total Population Register, including over 100,817 with an autism diagnosis. Main outcome measures: Annual age-standardised incidence and prevalence of adult autism diagnoses within different sociodemographic groups. Annual age-standardised proportion of adults with new autism diagnoses, lifetime autism diagnoses, and no autism diagnoses, with prior records of other neuropsychiatric conditions or medications. Results: Incident adult autism diagnoses were consistently higher in Sweden than the UK, however incidence increased rapidly in the UK after 2020. Incident diagnoses increased fastest for 16-25-year-olds and females in both nations, as well as people in White ethnic groups in the UK and people with Swedish-born parents in Sweden. For example, in the UK in 2023 the age-standardised incidence of autism diagnoses among 16-65 years olds was 11 diagnoses per 10,000 person-years (95%CI: 10.7, 11.3) in the White ethnic group and 2.2 diagnoses per 10,000 person-years (95%CI: 1.9, 2.5) in the South Asian ethnic group. Over time there has been a consistent decline in the proportion of autistic adults with a prior diagnosis of epilepsy, psychosis and intellectual disability and an increase in the proportion with a prior diagnosis of ADHD, anxiety, depression and several other mental illnesses. For example, in the UK between 2010 and 2023 the age-standardised proportions of newly diagnosed autistic adults with prior records of epilepsy decreased from 10% (95%CI: 7.6, 13) to 4% (95%CI: 3.6, 4.5), while the proportion with records of anxiety increased from 28.7% (95%CI: 24.4, 33.6) to 58.3% (95%CI: 56.6, 60.1). Mental health conditions were generally more common in females and the reduction over time in intellectual disability was greater in females than males. Conclusions: The socio-demographic and neuro-psychiatric characteristics of individuals diagnosed as autistic have changed dramatically since 2010, a phenomenon observed both in the UK and Sweden. The extent to which these changes indicate nuanced recognition of autism or broadening of diagnostic practice needs investigation.

Atypical social functioning is a core feature of autism, yet findings remain fragmented across components and development. We aimed to systematically integrate this literature and characterize the organization, development, and moderators of social functioning in autism. We conducted a systematic review and meta-analysis of behavioral studies published between January 1990 and August 2025, identified through PubMed, Web of Science, and prior reviews, including studies with clinically diagnosed autistic individuals and neurotypical controls. A qualitative synthesis and two complementary quantitative meta-analyses were performed, with risk of bias evaluated through study-level characteristics. A total of 2,622 studies (94,114 autistic and 172,847 neurotypical individuals across 32 countries) were included, covering 22 social components that clustered into five domains. Overall group differences were substantial (Hedges g = -0.744, 95% CI [-0.797, -0.690]). Differences emerged earliest in motivation-based processes ([~]6 months), followed by motor, emotion, and inference domains, and showed age-related divergence alongside improvement in some skills. Cross-domain analyses revealed stronger interdependencies in autism and an organizational pattern most consistent with serial relationships among domains. These findings should be interpreted in light of methodological heterogeneity, underpowered samples, and uneven cultural representation. Together, the results provide an integrative framework for understanding the organization and development of social functioning in autism, with implications for precision subtyping, developmentally timed interventions, and neurodiversity-informed research and policy. This study was pre-registered (PROSPERO: CRD42024566141).

Excessive screen use is associated with childhood behavioral problems, but whether associations differ between typically developing (TD) children and those with autism spectrum disorder (ASD) is unclear. Our cross-sectional study included 108 children aged 5-9 years (61 TD, 47 ASD). ASD was diagnosed using standardized clinical instruments. Measures included parent-reported screen time (excluding TV/DVD), cognitive ability (K-ABC), and behavioral problems (Vineland-II). Screen time and externalizing problems were associated in the TD group (Spearmans {rho} = 0.361, p < 0.01), but not in the ASD group. In the regression model, screen time ({beta} = 0.40, t = 2.60, p < 0.05), ASD status ({beta} = 0.70, t = 8.30, p < 0.001), and their interaction ({beta} = -0.34, t = -2.06, p < 0.05) significantly predicted externalizing problems. Considering the diversity within the autism spectrum, future studies with larger sample sizes should consider individual heterogeneity when examining the association between behavioral outcomes and screen time.

Background: Adult autism services research is hampered by a lack of accessible self-reported outcome measures. The AASPIRE Outcomes Project used a community-based participatory research (CBPR) approach to create and test the AASPIRE Measurement Toolkit, a set of accessible survey instruments for use in real-world settings. The core toolkit contains 12 characteristics modules and 19 outcome measures, each with self-reported and caregiver-reported versions. Methods: In a prior phase of the project, we collaboratively adapted, revised, or co-created all instruments. We used our CBPR-nested Delphi process, our collaborative adaptation/creation process, and cognitive interviews to ensure accessibility and content validity. We then conducted a longitudinal survey to validate the 19 outcome measures in a pragmatic sample of 870 autistic adults from two healthcare systems, two disability service systems, and the larger autistic community in the United States. Participants completed surveys at 3 time points over 12-18 months. A 15% random subset completed an additional retest survey 2 weeks after the second time point. We assessed 1) accessibility using completion rates and perceived ease of use; 2) internal consistency using Cronbach's alphas and omegas; 3) convergent validity using Pearson's correlations; 4) two-week test-retest reliability using interclass correlation coefficients; and 5) six-month responsiveness to change by comparing self-perceived change with change in scores. Results: Over 90% of participants reported the survey items were easy to understand; over 90% of participants who started the survey completed all applicable sections at each time point; and participants answered 99% of items on each instrument. The outcome measures and their pre-determined subscales demonstrated strong accessibility, content validity, internal consistency reliability, test-retest reliability, convergent and discriminant validity, and responsiveness to change. Conclusion: The AASPIRE Measurement Toolkit is accessible and includes 19 outcome measures with strong initial psychometric properties. We will report in-depth assessments of construct and structural validity separately for each measure. All instruments are available for free and can help clinicians, service providers, advocacy organizations, and researchers assess the effectiveness of interventions and follow changes in outcomes over time.

Self-determination has been assessed as an internal psychological construct. External factors may also affect self-determination, but opportunities to make choices and decisions remain understudied. We developed and evaluated the AASPIRE-Choices and Decisions Scale (AASPIRE-CDS), a new measure of autistic adults opportunities to make choices and decisions, using a community-based participatory approach. We created and refined the AASPIRE-CDS through an iterative process. Data, from the AASPIRE Outcomes Project, included 839 autistic adults participating through direct report, supported direct report, and caregiver report (CR). Exploratory and confirmatory analyses supported a unidimensional structure. Measurement invariance analyses supported configural, metric, and partial scalar invariance across report type without CR, and across living status, with and without CR. The AASPIRE-CDS showed high internal consistency, test-retest reliability, and responsiveness to change over time. Convergent validity analyses showed that higher AASPIRE-CDS scores were associated with greater self-determination and communication fluency, more independent living, and fewer support needs. The AASPIRE-CDS showed weaker (albeit significant) associations with quality of life, overall health, and employment satisfaction than the self-determination measure showed with these variables. This pattern suggests that opportunities for choice-making are related to, but distinct from, commonly used measures of self-determination. Findings support the AASPIRE-CDS as a valid and reliable measure of choice-making opportunities in autistic adults across support needs but suggest caution interpreting CR. They underscore the importance of supporting autistic adults choice-making and evaluating opportunities for choice alongside internal self-determination. Future research should use larger CR samples to examine the validity of caregiver-reported choice-making opportunities.

ObjectiveTo characterize the familial patterns of misophonia and other commonly co-occurring neuropsychiatric conditions. MethodsWe examined cross-sectional survey responses from 101 probands with misophonia and their biological parents enrolled in a genetics study. ResultsProbands had a mean age of 24.6 {+/-} 11.6 years (8-64 years), were predominantly female (88%), and had high rates of co-occurring neuropsychiatric conditions, including anxiety (70%), depression (38%), ADHD (31%), and OCD (25%). Among probands, 39% had a first-degree relative with misophonia, and 48% had at least one any-degree relative with misophonia. In addition, many probands had at least one first-degree relative with anxiety (65%), depression (57%), ADHD (40%), OCD (20%), and autism (13%). Comparing rates of neuropsychiatric conditions reported by parents, mothers had significantly higher rates of misophonia (29% maternal vs. 9% paternal, p = 0.001) and anxiety (44% maternal vs. 26% paternal, p = 0.02) than fathers. ConclusionThese findings provide new insight into the familial patterns of misophonia and co-occurring neuropsychiatric conditions. Future research on underlying genetic and environmental factors is needed to shed light on the observed shared predispositions for misophonia and other neuropsychiatric conditions in families.

BackgroundGrowing numbers of people with a borderline personality disorder (BPD) diagnosis are realising they may have undiagnosed autism. Previous qualitative research has not focused on identifying barriers and facilitators to this diagnostic journey, did not explore the perspectives of clinicians, and did not include the experiences of people who are unsure whether they are autistic or not. We aimed to understand lived experience and clinician perspectives on facilitators and barriers to recognising undiagnosed autism, in women and people assigned female at birth (PAFAB) with a diagnosis of personality disorder. MethodsWe carried out in-depth qualitative interviews with 15 mental health clinicians, and 15 women/PAFAB who had a current or prior diagnosis of BPD and identified as definitely or possibly autistic, from across the United Kingdom. We analysed the interview data using reflexive thematic analysis. ResultsBoth clinician and lived experience participants identified many barriers to recognising autism in women and PAFAB with a BPD diagnosis: BPD diagnoses being made with minimal assessment during mental health crises, systemic incentivisation to diagnose BPD in order to access psychological therapies, siloed service pathways, clinician reluctance to question pre-existing BPD diagnoses, pathologizing of patients for questioning their BPD diagnosis, and lack of clinician knowledge about different presentations of autism or about ways that autism presents similarly and differently to BPD. Participants identified numerous ways in which autistic characteristics could be misattributed as symptomatic of BPD, further contributing to missed or misdiagnosis. ConclusionOur findings suggest that improving clinician awareness of different presentations of autism, and of differential diagnosis from BPD is likely to reduce misdiagnosis, alongside avoiding rapid diagnostic decisions during mental health crises. Our study further highlights the value of being open to questioning pre-existing diagnoses, joint working across autism and personality disorder services, and improving transdiagnostic access to psychological interventions. Community BriefO_ST_ABSWhy is this an important issue?C_ST_ABSAutism in adults may be missed, or mis-diagnosed as a mental health condition. Borderline personality disorder (BPD) is the most common perceived misdiagnosis held by autistic people. Unrecognised autism may lead to worsened mental health in BPD-diagnosed people. What was the purpose of this study?We aimed to understand lived experience and clinician perspectives on what gets in the way of recognising undiagnosed autism, in people with a diagnosis of BPD. What did the researchers do?We interviewed 15 mental health clinicians, and 15 women/people assigned female at birth (AFAB), who had a current or prior diagnosis of BPD and identified as definitely or possibly autistic. We asked lived experience participants about their experiences of realising that they may be autistic. We asked clinicians to share their experiences of differentiating autism and personality disorder in clinical practice. We asked all participants to discuss their experiences of what makes it challenging to recognise autism in BPD-diagnosed people, and what helps. What were the results and conclusions of the study?Both clinician and lived experience participants identified many barriers to recognising autism in women and AFAB people with a BPD diagnosis. They said BPD diagnoses are made with minimal assessment during mental health crises. They said clinicians feel that they have to diagnose BPD in order to help people access psychological therapies. They said service pathways separate out autism and BPD rather than considering them together. They said clinicians are reluctant to question pre- existing BPD diagnoses, and that patients questioning of their BPD diagnosis is sometimes seen as symptomatic of mental health difficulties. They said clinicians lack knowledge about how autism can look different in women and AFAB people, and about ways that autism can look similar and different to BPD. Participants identified numerous ways in which autistic characteristics could be misattributed as symptomatic of BPD, further contributing to missed or misdiagnosis. We concluded that improving mental health clinicians understanding of autism, and how it is different from BPD, may help to improve recognition of autism in BPD-diagnosed people. We also concluded its important for clinicians to be open to questioning pre-existing diagnoses, to establish joint working across autism and personality disorder services, and to improve transdiagnostic access to psychological interventions. What is new or controversial about these findings?Its the first time clinician and lived experience perspectives on this issue have been brought together. Its controversial because it suggests that mental health services are sometimes not good at recognising autism in BPD- diagnosed people, and that people are potentially being harmed by this. What are potential weaknesses in the study?We would have liked to understand more about the experiences of ethnically diverse people. Our study may have attracted people who disagree with the idea of BPD and who believe autism is underdiagnosed. How will these findings help autistic adults now or in the future?We hope it will help BPD-diagnosed people with undiagnosed autism to be better recognised and understood by mental health services.

Neuroligin-3 (NLGN3) was first identified as a risk gene associated with autism spectrum disorder (ASD). The initial variant, p.R451C, associating NLGN3 with ASD has been heavily investigated, yet little is known about the functional consequences of other NLGN3 variants. Furthermore, while most of the identified variants are present in males with maternally inherited variants from unaffected mothers, several de novo variants were observed in females, suggesting a possible functional difference between de novo and maternally inherited variants. To address the functional consequences of NLGN3 variants in vivo, we generated transgenic Drosophila models corresponding to one de novo variant (p.R175W) identified in one female proband, and two maternally inherited variants (p.R451C and p.R597W) identified in male probands. In Drosophila, loss of the fly homolog, Nlg3, altered sleep patterns, synaptic architecture, and vesicle dynamics, which were rescued by the expression of the human NLGN3Ref allele. When comparing the variants, the de novo p.R175W variant and the maternally inherited p.R451C variant altered synapse morphology and sleep patterns, with minimal effects on vesicle dynamics, and the p.R597W variant altered sleep and vesicle dynamics with minimal impact on synapse morphology. Using overexpression models, human NLGN3Ref altered sleep patterns and synaptic morphology. Moreover, the p.R175W variant exacerbated sleep phenotypes, and the p.R175W and p.R451C variants exacerbated synapse morphology phenotypes. Together, our findings suggest that de novo NLGN3 variants identified in females are likely gain-of-function, while maternally inherited variants have mixed loss-and gain-of-function effects. Moreover, the location of the variants may contribute to the distinct functional differences we observed. Some NLGN3 variants disrupt synaptic development, while other variants alter synaptic function, suggesting that NLGN3 variants have differential effects. These functional differences may provide insight into the heterogeneity of individuals with ASD. Author SummaryAutism spectrum disorder (ASD) is a common neurodevelopmental disorder. Mutations in the Neuroligin-3 (NLGN3) gene are associated with ASD but very few of these mutations have been characterized in animal models. Most of these mutations affect male individuals who maternally inherited their genetic mutation; however, more rarely female individuals may present with a genetic mutation that was not identified in either of the parents. Here, we utilized the fruit fly model to investigate how three different mutations, one mutation identified in a female and two mutations identified in males, affect the flys behavior and synapse development. We identified altered sleep patterns in some of our mutants which is consistent with sleep disturbances being highly comorbid with ASD. Additionally, we identified alterations in synapse development and function which is consistent with the role of NLGN3 in synapse formation and maturation. Together, our findings support that NLGN3 is important for regulating the synapse and mutations in this gene can alter its function. However, different mutations can have differential effects. This demonstrates the need to assess multiple variants simultaneously because each variant may have distinct functional significances.

The causes of severe neuropsychiatric deteriorations among patients with previously stable autism spectrum disorder (ASD) are poorly understood and present substantial challenges for care. We aimed to characterize the prevalence of autoimmune and inflammatory conditions and markers, as well as musculoskeletal findings, among youth with ASD experiencing a suspected post-infectious neuropsychiatric deterioration. The Stanford Immune Behavioral Health (IBH) Clinic is a specialty program for youth with neuropsychiatric deteriorations that are suspected to be post-infectious (non-psychosocial). We report findings for 43 consecutive patients with ASD (70% male [30 of 43]) evaluated in the IBH Clinic. The average (SD) age at clinical presentation was 12.0 (4.0) years. Juvenile arthritis was diagnosed in 15 patients (35%), predominantly enthesitis-related arthritis (ERA) and psoriatic arthritis (PsA). Seven patients had ultrasonographic evidence of joint effusions and/or synovitis without meeting juvenile idiopathic arthritis (JIA) criteria. Autoimmune conditions other than arthritis were observed in 9 patients (21%). The mean (SD) age at arthritis and other autoimmune condition diagnoses were 16.2 (5.5) and 12.7 (4.9) years, respectively. We observe markers of immune activation during neuropsychiatric deteriorations in over half of patients (60% [26 of 43]), including markers of autoimmunity (33% [12 of 36]), complement activation (41% [13 of 32]), immune dysregulation/inflammation (11% [4 of 37]), and vasculopathy (30% [13 of 43]). One-third (37% [16 of 43]) demonstrated two or more markers. These data underscore the importance of targeted immune evaluation--including musculoskeletal imaging and inflammatory marker screening--in ASD patients who have had a suspected post-infectious behavioral regression. Lay SummaryIn this cohort study of 43 patients with autism spectrum disorder (ASD) and suspected post-infectious deteriorations, more than half had laboratory markers of immune activation (using a limited panel), one-third had joint inflammation (confirmed by ultrasound), and additional autoimmune conditions were observed in 21%. From this, we conclude that patients with ASD who experience a suspected post-infectious neuropsychiatric deterioration may have underlying inflammation which may contribute to neuropsychiatric and behavioral regressions, highlighting the importance of immunologic and rheumatologic evaluation in clinical assessment.

Background Phonemic awareness deficits are a core feature of Specific Learning Disorder-Reading (SLD-R). How task- and language-specific factors influence these deficits in alphasyllabary languages may help clarify the cognitive mechanisms underlying reading impairment in SLD-R. Methods Thirty children with a DSM-5 diagnosis of SLD-R (mean age 11.4 years) and 29 age-matched typically developing children were given phoneme blending (words and pseudowords) and segmentation tasks in Malayalam. The effects of age and consonant clusters on task performance were evaluated. Results Children with SLD-R performed significantly worse than controls across most phonemic awareness tasks, with the largest deficits observed in pseudoword blending and word blending, and smaller deficits in segmentation. No significant difference was observed for initial phoneme deletion. In typically developing children, age showed strong positive correlations with phonemic performance across most tasks, whereas the SLD-R group showed weak or absent correlations, except in word blending and initial phoneme deletion. Consonant clusters significantly affected performance in both groups, with SLD-R showing more severe deficits. Conclusions Phonemic awareness deficits observed in SLD-R in alphasyllabary languages like Malayalam are more prominent in tasks where lexical support is absent, like pseudoword blending. These deficits vary across task types and linguistic complexity. Phonemic awareness improves with age in typically developing children, while improvement is uneven in children with SLD-R. The findings suggest that phonemic awareness deficits are a core feature of SLD-R across languages, but their manifestation is shaped by orthographic and linguistic characteristics of the writing system.

Objective: Autistic individuals may face elevated risk for PTSD, yet the degree to which this risk differs by sex remains unknown. We examined the association between autism and incident PTSD, characterized sex differences in risk, identified high-risk subgroups, and described post-diagnosis clinical trajectories. Method: We conducted a population-based matched cohort study using Swedish national registers. Individuals born 1990 through 2010 were followed from age 6 years through December 31, 2017. Autistic individuals (N=42,862) were matched 1:10 to controls (N=412,251) on sex and birth year. Cox proportional hazards regression estimated hazard ratios (HRs) for incident PTSD. Among those who developed PTSD, we compared care utilization, hospitalization rates, and persistence of care contacts. Results: During mean follow-up of 5.1 years, 401 autistic individuals (0.9%) and 903 controls (0.2%) developed PTSD (incidence rates: 18.3 vs 4.2 per 10,000 person-years). Autism was associated with 4.4-fold increased PTSD risk (HR=4.37; 95% CI, 3.93-4.86). Risk was higher among females (HR=4.79) than males (HR=3.39; P interaction=.006). Among autistic individuals, comorbid ADHD conferred additional risk (HR=1.38; 95% CI, 1.14-1.68). Ten-year cumulative incidence reached 6.0% among autistic females with ADHD. Autistic individuals with PTSD had higher care utilization (mean visits: 5.0 vs 3.9; P<.001), more psychiatric hospitalizations (27.9% vs 19.8%; P=.002), and more persistent courses (24.8% vs 12.3% with contacts in all 3 post-diagnosis years; P=.001). Conclusion: Autism is associated with substantially elevated PTSD risk, particularly among females with comorbid ADHD. When PTSD occurs, autistic individuals experience more severe and persistent clinical courses, supporting targeted screening and sustained follow-up.

BackgroundAutism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) share substantial clinical and physiological overlap. While naturalistic and sensory-driven paradigms increasingly capture evoked neurophysiological responses, the intrinsic baseline physiology of these conditions remains poorly defined. We aimed to characterize resting-state autonomic arousal and oculomotor stability across the ASD-ADHD spectrum using both continuous (RDoC) and categorical (DSM-5) analytical frameworks. MethodsWe analyzed resting-state eye-tracking data from a large pediatric cohort (N = 2,640) from the Healthy Brain Network. During an unconstrained baseline, we extracted Pupil Relative Volatility (Coefficient of Variation [CV]) to index intrinsic autonomic arousal, and the Bivariate Contour Ellipse Area (BCEA) to index spatial gaze instability. Data were evaluated using continuous dimensional regressions against the Social Responsiveness Scale (SRS) and SWAN inventories, followed by 2x2 factorial ANCOVAs based on clinical diagnoses. Sensitivity analyses accounted for clinical collinearity, spatial outliers, and psychostimulant medication. ResultsDimensional models revealed that Pupil CV was significantly and uniquely associated with continuous autistic traits (q = 0.0043, joint model), exhibiting a strong statistical suppression effect when controlling for ADHD trait covariance. However, this pupillary biomarker lost significance in binary categorical models. Conversely, spatial gaze instability (BCEA) demonstrated robust categorical threshold effects; isolated ASD and ADHD diagnoses significantly impaired baseline gaze stability. Furthermore, comorbid ASD+ADHD produced a distinct, sub-additive interaction for BCEA (q = 0.005) that remained robust to extreme spatial outliers. Both physiological phenotypes were independent of active psychostimulant use. LimitationsWhile this study included a large and diverse group of children, the eye-tracking data were collected during a brief resting period -- watching a simple cross on a screen -- which may not capture how children behave in everyday, real-world situations. Because holding still for eye-tracking can be difficult, particularly for children with more severe symptoms, some data were lost; however, we statistically accounted for how much data each child contributed. Finally, while we confirmed that ADHD medication taken on the day of testing did not explain our findings, complete medication records were not available for every participant in this large observational study. ConclusionsPupillary dynamics and oculomotor stability associate with the ASD-ADHD spectrum through differing analytical patterns during resting states. Baseline autonomic volatility is more strongly captured by dimensional models of autistic trait severity, whereas baseline gaze instability is more clearly differentiated across categorical diagnostic groups, exhibiting a sub-additive interaction in comorbidity. Integrating both dimensional and categorical frameworks provides a more comprehensive understanding of these physiological variations, establishing a necessary foundation for future naturalistic and sensory-evoked research.

Adult ADHD is increasingly recognized across the lifespan, yet the psychometric equivalence of the Adult ADHD Self-Report Scale (ASRS) remains unverified for older populations. This study examined age-related Differential Item Functioning (DIF) in 600 adults (n = 100 per decade, ages 20-80) who completed the 18-item ASRS. Using a bi-factor Graded Response Model, we extracted latent ADHD trait scores ({omega}H = .895) and assessed DIF via ordinal logistic regression with adaptive age modeling. Five of 18 items exhibited significant uniform DIF. At equivalent latent severity, older adults were less likely to endorse hyperactivity symptoms in Part A (fidgeting, feeling "driven by a motor") but more likely to endorse specific symptoms in Part B (careless mistakes, misplacing items, interrupting). From ages 20 to 80, expected Part A scores decreased by 1.36 points (~0.27 per decade), while Part B scores increased by 1.15 points (~0.23 per decade). These findings indicate a phenotypic redistribution of ADHD symptoms as individuals age. Because the 6-item Part A screener serves as the primary clinical gatekeeper, its concentration of negative DIF suggests standard screening practice may systematically underestimate ADHD severity in older adults. We recommend using the full 18-item ASRS when screening older populations and suggest that developing age-adjusted norms would improve diagnostic accuracy.

Abstract Background Gene dosage disorders impact cognition and psychopathology, but outcomes vary widely amongst carriers of the same variant. Recent work has sought to better predict proband outcomes using measures of corresponding traits in family members. However, family-based models have not yet been prospectively quantified across several traits in different genetic disorders, nor evaluated for the precision they afford: both crucial issues for clinical implementation. Methods In a first test case for these questions, we apply regression analyses to quantify and compare family-based prediction of 12 traits (including IQ, autism- and ADHD-related traits) in 433 individuals from families including a proband with XXY or XYY syndrome (N=93 and 58, respectively). Results The 12 traits vary substantially in their proband-family associations (0.001<|r|<0.55) - with differences emerging between XXY and XYY syndrome. Only two traits also show significant and similar proband-family associations in both aneuploidies, with the greatest concordance found for IQ. A family-based model for IQ prediction in male sex chromosome trisomies significantly reduces error vs. a group mean IQ model (F = 7.4, p = 0.006), but only in 65% of probands, and with mean error reduction of ~2 IQ points. Conclusions Family-based prediction of neuropsychiatric traits in genetic syndromes likely requires trait- and syndrome- specific models. Family models can significantly improve outcome prediction for IQ, but to variable degrees across individuals and with a small mean improvement. By mapping and quantifying these limits, our work helps draft a roadmap for refinement of family-based prediction of proband outcomes in gene dosage disorders.