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.
Individuals with autism spectrum disorder and average IQ exhibit a widening discrepancy between lagging adaptive skills relative to their cognitive potential, but it is unknown when this discrepancy emerges in development. To address this important question, we measured adaptive and cognitive skills longitudinally, from 12–36 months, in 96 low-risk typically developing infants and 69 high-risk siblings of children with autism spectrum disorder who at 36 months were diagnosed with autism spectrum disorder (N = 21), the broader autism phenotype (N = 19), or showed no concerns (unaffected; N = 29). Results indicate that both cognitive and adaptive communication skills remained stable over time for all four groups, but toddlers with autism spectrum disorder and the broader autism phenotype failed to keep pace with unaffected and typically developing toddlers with regard to adaptive socialization skills and, to a lesser extent, daily living skills. The odds of having a discrepant developmental profile, with average cognitive skills and below average adaptive skills, was significantly greater for socialization and daily living skills in toddlers with autism spectrum disorder or the broader autism phenotype and increased over time from 12 to 36 months. The discrepancy between adaptive skills and cognition emerges early and widens over time for infants with autism spectrum disorder symptomology, supporting early assessment and intervention of adaptive socialization and daily living skills.
3q29 deletion syndrome is associated with a range of medical, neurodevelopmental, and psychiatric phenotypes. The deletion is usually de novo but cases have been reported where the deletion is inherited from apparently unaffected parents. The presence of these unaffected or mildly affected individuals suggests there may be an ascertainment bias for severely affected cases of 3q29 deletion syndrome, thus the more deleterious consequence of the 3q29 deletion may be overestimated. However, a substantial fraction of 3q29 deletion syndrome morbidity is due to psychiatric illness. In many case reports, probands and transmitting parents are not systematically evaluated for psychiatric traits. Here we report results from a systematic phenotyping protocol for neurodevelopmental and neuropsychiatric traits applied to all 3q29 deletion carriers in a multiplex family.
Aim: To investigate neurobehavioral maturation for neonates who are later diagnosed with autism spectrum disorder (ASD). Method: In a prospective longitudinal design, neonatal neurobehavior was examined monthly in 1- to 3-month-old infants at elevated and low familial likelihood of ASD (n=60). At 2 years, infants were seen for a clinical best-estimate evaluation, resulting in 18 infants with ASD and 36 typically developing infants. Repeated-measures analysis of variance models were conducted to examine the effects of age, diagnostic group, and their interactions. Results: Neurobehavioral maturation of infants diagnosed with ASD was largely comparable to typically developing infants from 1 to 3 months, with the exception of the development of attention. Object-focused attention was significantly attenuated for infants with ASD beginning at 2 to 3 months and was predictive of social-communication skills 2 years later. Interpretation: This is the first study to prospectively examine neonatal neurobehavior of infants at an elevated familial likelihood of ASD who later received a diagnosis. Despite relatively intact neurological and behavioral maturation in the neonatal period, attention to objects emerged as a key early indicator of ASD. This suggests a complex attentional vulnerability within the first 3 months of life that may be associated with cascading sequelae of social-communication challenges and the emergence of ASD.
Background: 3q29 deletion syndrome is caused by a recurrent hemizygous 1.6Mb deletion on the long arm of chromosome 3. The syndrome is rare (1 in 30,000 individuals) and is associated with mild to moderate intellectual disability, increased risk for autism and anxiety, and a 40-fold increased risk for schizophrenia, along with a host of physical manifestations. However, the disorder is poorly characterized, the range of manifestations is not well described, and the underlying molecular mechanism is not understood. We designed the Emory 3q29 Project to document the range of neurodevelopmental and psychiatric manifestations associated with 3q29 deletion syndrome. We will also create a biobank of samples from our 3q29 deletion carriers for mechanistic studies, which will be a publicly-available resource for qualified investigators. The ultimate goals of our study are three-fold: first, to improve management and treatment of 3q29 deletion syndrome. Second, to uncover the molecular mechanism of the disorder. Third, to enable cross-disorder comparison with other rare genetic syndromes associated with neuropsychiatric phenotypes. Methods: We will ascertain study subjects, age 6 and older, from our existing registry ( 3q29deletion.org ). Participants and their families will travel to Atlanta, GA for phenotypic assessments, with particular emphasis on evaluation of anxiety, cognitive ability, autism symptomatology, and risk for psychosis via prodromal symptoms and syndromes. Evaluations will be performed using standardized instruments. Structural, diffusion, and resting-state functional MRI data will be collected from eligible study participants. We will also collect blood from the 3q29 deletion carrier and participating family members, to be banked at the NIMH Repository and Genomics Resource (NRGR). Discussion: The study of3q29 deletion has the potential to transform our understanding of complex disease. Study of individuals with the deletion may provide insights into long term care and management of the disorder. Our project describes the protocol for a prospective study of the behavioral and clinical phenotype associated with 3q29 deletion syndrome. The paradigm described here could easily be adapted to study additional CNV or single gene disorders with high risk for neuropsychiatric phenotypes, and/or transferred to other study sites, providing a means for data harmonization and cross-disorder analysis.
Background: The 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. Methods: Thirty-one 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. Results: Subjects 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 the 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 improved nonverbal communication in 3q29del + ASD. Limitations: There 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. Conclusions: 3q29del 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.
Social-communication differences are a robust and defining feature of autism spectrum disorder (ASD) but identifying early points of divergence in infancy has been a challenge. The current study examines social communication in 9- to 12-month-old infants who develop ASD (N = 30; 23% female; 70% white) compared to typically developing (TD) infants (N = 94, 38% female; 88% white). Results demonstrate that infants later diagnosed with ASD were already exhibiting fewer social-communication skills using eye gaze, facial expression, gestures, and sounds at 9 months (effect size: 0.42–0.89). Moreover, three unique patterns of change across distinct social-communication skills were observed within the ASD group. This study documents that observable social-communication differences for infants with ASD are unfolding by 9 months, pointing to a critical window for targeted intervention.
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.
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.