Early intervention has been established as efficacious in addressing developmental delays in young children with autism spectrum disorder. Evidence that caregiver-implemented interventions are feasible and effective for young children with autism spectrum disorder is emerging, yet research suggests there are barriers to enrollment in clinical trials of these interventions for infants at risk for autism. This study identifies factors associated with enrollment in a clinical trial of a caregiver-implemented intervention for 12-month-old infants at risk for autism spectrum disorder. As part of a large longitudinal study, fifty-seven infants were deemed eligible for intervention based on several converging indicators of autism risk. Of these eligible infants, 44% declined enrollment in the intervention study. Examination of factors associated with families who declined enrollment compared to those who agreed to enroll revealed maternal full-time work status, household income, and distance to the clinic as significant predictors. In contrast, autism red flags and parental concern were not significantly associated with enrollment. These results highlight the need for more research on how parental understanding of, and willingness to act on, early social-communication delays impacts intervention study enrollment. Future research can then examine how to address these barriers to enrollment in caregiver-implemented intervention studies. Lay abstract: Early intervention helps to address developmental delays in young children with autism spectrum disorder. Yet, research suggests there are barriers to enrollment into research studies that test the effectiveness of these interventions for infants at risk. This study identifies family characteristics that were associated with agreement to enroll in a clinical trial of early intervention for 12-month-old infants at risk for autism spectrum disorder. As part of a large longitudinal study, infants were evaluated for early signs of autism spectrum disorder at 1 year of age. Of the fifty-seven infants who were showing signs of autism and deemed eligible for the early intervention trial, 44% declined enrollment. Results suggest that families were more likely to decline enrolling into the intervention study if the mother was working full time, the total household income was between US$60,000 and US$100,000, and they lived further from the clinic. In contrast, infant autism symptoms and parental concern at 12 months were not significantly associated with enrollment. These findings highlight the need for intervention studies that are more accessible to parents, for example, intervention that takes place in the home, in addition to more research on how parental understanding of, and willingness to act on, early social-communication delays impact intervention study enrollment. Future research can then examine how to address these barriers to enrollment in early intervention studies. Such findings will shed light on best practices for dissemination of early identification and intervention strategies.

Differential diagnosis of young children with suspected autism spectrum disorder (ASD) is challenging, and clinician uncertainty about a child’s diagnosis may contribute to misdiagnosis and subsequent delays in access to early treatment. The current study was designed to replicate and expand a recent report in this Journal (McDonnell et al. in J Autism Dev Disord 49:1391–1401, https://doi.org/10.1080/15374416.2020.1823850, 2019), in which only 60% of diagnoses were made with complete certainty by clinicians evaluating 478 toddlers and preschool children referred for possible ASD to specialized clinics. In this study, secondary analyses were performed on diagnostic, demographic and clinical data for 496 16–30-month-old children who were consecutive referrals to a 6-site clinical trial executed by specialized centers with experienced clinicians following best-practice procedures for the diagnosis of ASD. Overall, 70.2% of diagnoses were made with complete certainty. The most important factor associated with clinician uncertainty was mid-level autism-related symptomatology. Mid-level verbal age equivalents were also associated with clinician uncertainty, but measures of symptomatology were stronger predictors. None of the socio-demographic variables, including sex of the child, was significantly associated with clinician certainty. Close to one third of early diagnoses of ASD are made with a degree of uncertainty. The delineation of specific ranges on the ADOS-2 most likely to result in clinician uncertainty identified in this study may provide an opportunity to reduce random subjectivity in diagnostic decision-making via calibration of young-child diagnostic thresholds based on later-age longitudinal diagnostic outcome data, and via standardization of decision-making in regard to clinical scenarios frequently encountered by clinicians.

To capture the full spectrum of genetic risk for autism, we performed a two-stage analysis of rare de novo and inherited coding variants in 42,607 autism cases, including 35,130 new cases recruited online by SPARK. We identified 60 genes with exome-wide significance (P < 2.5 × 10−6), including five new risk genes (NAV3, ITSN1, MARK2, SCAF1 and HNRNPUL2). The association of NAV3 with autism risk is primarily driven by rare inherited loss-of-function (LoF) variants, with an estimated relative risk of 4, consistent with moderate effect. Autistic individuals with LoF variants in the four moderate-risk genes (NAV3, ITSN1, SCAF1 and HNRNPUL2; n = 95) have less cognitive impairment than 129 autistic individuals with LoF variants in highly penetrant genes (CHD8, SCN2A, ADNP, FOXP1 and SHANK3) (59% vs 88%, P = 1.9 × 10−6). Power calculations suggest that much larger numbers of autism cases are needed to identify additional moderate-risk genes.

Infants show shifting patterns of visual engagement to faces over the first years of life. To explore the adaptive implications of this engagement, we collected eye-tracking measures on cross-sectional samples of 10–25-month-old typically developing toddlers (TD;N = 28) and those with autism spectrum disorder (ASD;N = 54). Concurrent language assessments were conducted and relationships between visual engagement and expressive and receptive language were analyzed between groups, and within ASD subgroups. TD and ASD toddlers exhibited greater mouth- than eye-looking, with TD exhibiting higher levels of mouth-looking than ASD. Mouth-looking was positively associated with expressive language in TD toddlers, and in ASD toddlers who had acquired first words. Mouth-looking was unrelated to expressive language in ASD toddlers who had not yet acquired first words.

Purpose To understand the consequences of the 3q29 deletion on medical, neurodevelopmental, psychiatric, brain structural, and neurological sequalae by systematic evaluation of affected individuals. To develop evidence-based recommendations using these data for effective clinical care. Methods Thirty-two individuals with the 3q29 deletion were evaluated using a defined phenotyping protocol and standardized data collection instruments. Results Medical manifestations were varied and reported across nearly every organ system. The most severe manifestations were congenital heart defects (25%) and the most common were gastrointestinal symptoms (81%). Physical examination revealed a high proportion of musculoskeletal findings (81%). Neurodevelopmental phenotypes represent a significant burden and include intellectual disability (34%), autism spectrum disorder (38%), executive function deficits (46%), and graphomotor weakness (78%). Psychiatric illness manifests across the lifespan with psychosis prodrome (15%), psychosis (20%), anxiety disorders (40%), and attention deficit–hyperactivity disorder (ADHD) (63%). Neuroimaging revealed structural anomalies of the posterior fossa, but on neurological exam study subjects displayed only mild or moderate motor vulnerabilities. Conclusion By direct evaluation of 3q29 deletion study subjects, we document common features of the syndrome, including a high burden of neurodevelopmental and neuropsychiatric phenotypes. Evidence-based recommendations for evaluation, referral, and management are provided to help guide clinicians in the care of 3q29 deletion patients.

Background: The 1.6 Mb 3q29 deletion is associated with neurodevelopmental and psychiatric phenotypes, including increased risk for autism spectrum disorder (ASD) and a 20 to 40-fold increased risk for schizophrenia. However, the phenotypic spectrum of the deletion, particularly with respect to ASD, remains poorly described. Methods: We ascertained individuals with 3q29 deletion syndrome (3q29Del, "cases," n = 93, 58.1% male) and typically developing controls (n = 64, 51.6% male) through the 3q29 registry (https://3q29deletion.patientcrossroads.org). Self-report of neuropsychiatric illness was evaluated for 93 cases. Subsets of participants were evaluated with the Social Responsiveness Scale (SRS, n = 48 cases, 56 controls), Social Communication Questionnaire (n = 33 cases, 46 controls), Autism Spectrum Screening Questionnaire (n = 24 cases, 35 controls), and Achenbach Behavior Checklists (n = 48 cases, 57 controls). Results: 3q29Del cases report a higher prevalence of autism diagnoses versus the general population (29.0% vs. 1.47%, p < 2.2E- 16). Notably, 3q29 deletion confers a greater influence on risk for ASD in females (OR = 41.8, p = 4.78E- 05) than in males (OR = 24.6, p = 6.06E- 09); this is aligned with the reduced male:female bias from 4:1 in the general population to 2:1 in our study sample. Although 71% of cases do not report a diagnosis of ASD, there is evidence of significant social disability (3q29Del SRS T-score = 71.8, control SRS T-score = 45.9, p = 2.16E- 13). Cases also report increased frequency of generalized anxiety disorder compared to controls (28.0% vs. 6.2%, p = 0.001), which is mirrored by elevated mean scores on the Achenbach diagnostic and statistical manual-oriented sub-scales (p < 0.001). Finally, cases show a distinct constellation of ASD features on the SRS as compared to idiopathic ASD, with substantially elevated Restricted Interests and Repetitive Behaviors, but only mild impairment in Social Motivation. Conclusions: Our sample of 3q29Del is significantly enriched for ASD diagnosis, especially among females, and features of autism may be present even when an ASD diagnosis is not reported. Further, the constellation of ASD features in this population is distinct from idiopathic ASD, with substantially less impaired social motivation. Our study implies that ASD evaluation should be the standard of care for individuals with 3q29Del. From a research perspective, the distinct ASD subtype present in 3q29Del is an ideal entry point for expanding understanding of ASD.

The burdens faced by military families who have a child with autism are unique. The usual challenges of securing diagnostic, treatment, and educational services are compounded by life circumstances that include the anxieties of war, frequent relocation and separation, and a demand structure that emphasizes mission readiness and service. Recently established military autism-specific health care benefits set the stage for community-viable and cost-effective solutions that can achieve better outcomes for children and greater well-being for families. Here we argue for implementation of evidence-based solutions focused on reducing age of diagnosis and improving access to early intervention, as well as establishment of a tiered menu of services, individualized to the child and family, that fit with the military ethos and system of health care. Absence of this new model of care could compromise the utility and sustainability of the autism-specific benefit.

Long before infants reach, crawl or walk, they explore the world by looking: they look to learn and to engage, giving preferential attention to social stimuli, including faces, face-like stimuli and biological motion. This capacity - social visual engagement - shapes typical infant development from birth and is pathognomonically impaired in children affected by autism. Here we show that variation in viewing of social scenes, including levels of preferential attention and the timing, direction and targeting of individual eye movements, is strongly influenced by genetic factors, with effects directly traceable to the active seeking of social information. In a series of eye-tracking experiments conducted with 338 toddlers, including 166 epidemiologically ascertained twins (enrolled by representative sampling from the general population), 88 non-twins with autism and 84 singleton controls, we find high monozygotic twin-twin concordance (0.91) and relatively low dizygotic concordance (0.35). Moreover, the characteristics that are the most highly heritable, preferential attention to eye and mouth regions of the face, are also those that are differentially decreased in children with autism (χ 2 = 64.03, P < 0.0001). These results implicate social visual engagement as a neurodevelopmental endophenotype not only for autism, but also for population-wide variation in social-information seeking. In addition, these results reveal a means of human biological niche construction, with phenotypic differences emerging from the interaction of individual genotypes with early life experience.

A global pandemic has significantly impacted the ability to conduct diagnostic evaluations for autism spectrum disorder (ASD). In the wake of the coronavirus, autism centers and providers quickly needed to implement innovative diagnostic processes to adapt in order to continue serve patient needs while minimizing the spread of the virus. The International Collaborative for Diagnostic Evaluation of Autism (IDEA) is a grassroots organization that came together to discuss standards of care during the pandemic and to provide a forum wherein providers communicated decisions. This white paper is intended to provide examples of how different centers adjusted their standard approaches to conduct diagnostic evaluations for ASD during the pandemic and to provide insight to other centers as they go through similar challenges.

Social-communication skills emerge within the context of rich social interactions, facilitated by an infant's capacity to attend to people and objects in the environment. Disruption in this early neurobehavioral process may decrease the frequency and quality of social interactions and learning opportunities, potentially leading to downstream deleterious effects on social development. This study examined early attention in infant siblings of children with autism spectrum disorder (ASD) who are at risk for social and communication delays. Visual and auditory attention was mapped from age 1 week to 5 months in infants at familial risk for ASD (high risk; N = 41) and low-risk typically developing infants (low risk; N = 39). At 12 months, a subset of participants (N = 40) was administered assessments of social communication and nonverbal cognitive skills. Results revealed that high-risk infants performed lower on attention tasks at 2 and 3 months of age compared to low-risk infants. A significant association between overall attention at 3 months and developmental outcome at 12 months was observed for both groups. These results provide evidence for early vulnerabilities in visual attention for infants at risk for ASD during a period of important neurodevelopmental transition (between 2 and 3 months) when attention has significant implications for social communication and cognitive development.