Among high-impact genomic variants associated with severe neurodevelopmental disorders, the 3q29 deletion (3q29Del) stands out, conferring a 40-100-fold elevated risk of schizophrenia, alongside a heightened susceptibility to autism, intellectual disability and ADHD. Despite growing knowledge of its clinical associations, its neurobiological consequences are largely unknown.

High-impact genetic variants associated with neurodevelopmental disorders provide biologically-defined entry points for mechanistic investigation. The 3q29 deletion (3q29Del) is one such variant, conferring a 40-100-fold increased risk for schizophrenia, as well as high risk for autism and intellectual disability. However, the mechanisms leading to neurodevelopmental disability remain largely unknown. Here, we report the first in vivo quantitative neuroimaging study in individuals with 3q29Del (N = 24) and neurotypical controls (N = 1608) using structural MRI. Given prior radiology reports of posterior fossa abnormalities in 3q29Del, we focused our investigation on the cerebellum and its tissue-types and lobules. Additionally, we compared the prevalence of cystic/cyst-like malformations of the posterior fossa between 3q29Del and controls and examined the association between neuroanatomical findings and quantitative traits to probe gene-brain-behavior relationships. 3q29Del participants had smaller cerebellar cortex volumes than controls, before and after correction for intracranial volume (ICV). An anterior-posterior gradient emerged in finer grained lobule-based and voxel-wise analyses. 3q29Del participants also had larger cerebellar white matter volumes than controls following ICV-correction and displayed elevated rates of posterior fossa arachnoid cysts and mega cisterna magna findings independent of cerebellar volume. Cerebellar white matter and subregional gray matter volumes were associated with visual-perception and visual-motor integration skills as well as IQ, while cystic/cyst-like malformations yielded no behavioral link. In summary, we find that abnormal development of cerebellar structures may represent neuroimaging-based biomarkers of cognitive and sensorimotor function in 3q29Del, adding to the growing evidence identifying cerebellar pathology as an intersection point between syndromic and idiopathic forms of neurodevelopmental disabilities.

BACKGROUND:3q29 deletion syndrome (3q29del) is a rare (~1:30 000) genomic disorder associated with a wide array of neurodevelopmental and psychiatric phenotypes. Prior work by our team identified clinically significant executive function (EF) deficits in 47% of individuals with 3q29del; however, the nuances of EF in this population have not been described. METHODS:We used the Behavior Rating Inventory of Executive Function (BRIEF) to perform the first in-depth assessment of real-world EF in a cohort of 32 individuals with 3q29del (62.5% male, mean age = 14.5 ± 8.3 years). All participants were also evaluated with gold-standard neuropsychiatric and cognitive assessments. High-resolution structural magnetic resonance imaging was performed on a subset of participants (n = 24). RESULTS:We found global deficits in EF; individuals with 3q29del scored higher than the population mean on the BRIEF global executive composite (GEC) and all subscales. In total, 81.3% of study subjects (n = 26) scored in the clinical range on at least one BRIEF subscale. BRIEF GEC T scores were higher among 3q29del participants with a diagnosis of attention deficit/hyperactivity disorder (ADHD), and BRIEF GEC T scores were associated with schizophrenia spectrum symptoms as measured by the Structured Interview for Psychosis-Risk Syndromes. BRIEF GEC T scores were not associated with cognitive ability. The BRIEF-2 ADHD form accurately (sensitivity = 86.7%) classified individuals with 3q29del based on ADHD diagnosis status. BRIEF GEC T scores were correlated with cerebellar white matter and subregional cerebellar cortex volumes. CONCLUSIONS:Together, these data expand our understanding of the phenotypic spectrum of 3q29del and identify EF as a core feature linked to both psychiatric and neuroanatomical features of the syndrome.

3q29 deletion syndrome (3q29del) is associated with neuropsychiatric and neurodevelopmental phenotypes. We previously reported that graphomotor weakness is present in up to 78% of individuals with 3q29del. We have now explored nuances of the graphomotor phenotype and its association with other comorbidities in this population. Participants were recruited from the online 3q29 registry (3q29deletion.org) for two days of deep phenotyping. 32 individuals with 3q29del (62.5% male) were evaluated with the Beery-Buktenica Developmental Test of Visual-Motor Integration (VMI) to assess visual-motor integration. Participants were also evaluated with measures of cognitive ability, executive function, adaptive behavior, and school function. Males with 3q29del performed significantly worse than females on the VMI and Motor Coordination subtest. VMI performance was significantly associated with ADHD diagnosis and cognitive ability. Compared to published data from individuals with 22q11.2 deletion syndrome, individuals with 3q29del showed significantly more impairment. The 3q29 deletion is associated with substantial deficits in visual-motor integration, Visual Perception, and Motor Coordination. Our data suggests that 3q29del may qualify as a nonverbal learning disability. Future studies should assess whether individuals with 3q29del would benefit from early interventions, including occupational therapy.

Emerging evidence suggests that the higher prevalence of autism in individuals who are assigned male than assigned female at birth results from both biological factors and identification biases. Autistic individuals who are assigned female at birth (AFAB) and those who are gender diverse experience health disparities and clinical inequity, including late or missed diagnosis and inadequate support. In this Viewpoint, an international panel of clinicians, scientists, and community members with lived experiences of autism reviewed the challenges in identifying autism in individuals who are AFAB and proposed clinical and research directions to promote the health, development, and wellbeing of autistic AFAB individuals. The recognition challenges stem from the interplay between cognitive differences and nuanced or different presentations of autism in some AFAB individuals; expectancy, gender-related, and autism-related biases held by clinicians; and social determinants. We recommend that professional development for clinicians be supported by health-care systems, professional societies, and governing bodies to improve equitable access to assessment and earlier identification of autism in AFAB individuals. Autistic AFAB individuals should receive tailored support in education, identity development, health care, and social and professional sense of belonging.

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.

Purpose of Review The goal of this paper is to provide an overview of profiles of adaptive behavior in autism spectrum disorder and highlight the importance of these everyday skills in optimizing self-sufficiency throughout life. Recent Findings Research has clearly confirmed that adaptive deficits exist in ASD, particularly in social skills. These impairments are highly associated with co-occurring conditions such as executive functioning impairments, psychiatric conditions, and even psychosis. There tends to be a discrepancy between intellectual capacity and adaptive functioning, particularly in autistic individuals without cognitive and language delays, with this gap widening between childhood and adulthood. Summary Although cognition and language skills are associated with good outcome in ASD, they are insufficient in the absence of intact adaptive behavior. There is a critical need to emphasize the importance of adaptive functioning in diagnostic evaluations and treatment/intervention programs to ensure that every autistic individual has the potential for success.

The 3q29 deletion is associated with psychiatric phenotypes including a 40-fold increased risk for schizophrenia. We conducted deep phenotyping on 3q29 deletion study subjects to describe the phenotype and identify possible schizophrenia endophenotypes.

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 31 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 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. 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.

OBJECTIVE:To evaluate the predictive relationship between early trajectories of postural and head control during a pull-to-sit task and later autism diagnostic and developmental outcomes. STUDY DESIGN:Using a prospective longitudinal design, postural skills of 100 infants at elevated and low familial likelihood of autism spectrum disorder (ASD) were evaluated using a pull-to-sit task monthly from age 1 month to 6 months. At age 24 months, infants were seen for a developmental and diagnostic evaluation completed by examiners masked to participant group. Latent growth curve models were used to compare early trajectories of pull-to-sit performance in infants later diagnosed with ASD and typically developing infants and to predict developmental outcomes. RESULTS:Pull-to-sit trajectories did not differ in infants with an elevated likelihood of ASD or infants with ASD compared with low-likelihood and typically developing infants, but infants with ASD were more likely to exhibit a head lag by age 4 months. In addition, pull-to-sit trajectories were predictive of social and speech skills 2 years later. CONCLUSIONS:These findings highlight the link between very early pull-to-sit skills and later social and language outcomes. Atypical postural development and persistent presence of head lag may be important early indicators of social and language vulnerabilities, including ASD.

The COVID-19 pandemic has posed unique challenges for families and caregivers, as well as for autism-focused clinicians, who are faced with providing a thorough and accurate evaluation of children's specific needs and diagnoses in the absence of in-person assessment tools. The shift to telehealth assessments has challenged clinicians to reconsider approaches and assumptions that underlie the diagnostic assessment process, and to adopt new ways of individualizing standard assessments according to family and child needs. Mandates for physical distancing have uncovered deficiencies in diagnostic practices for suspected autism and have illuminated biases that have posed obstacles preventing children and families from receiving the services that they truly need. This Commentary outlines several considerations for improving diagnostic practices as we move forward from the current pandemic and continue to strive to build an adaptable, sustainable, equitable, and family-centered system of care. LAY SUMMARY: Physical distancing and the abrupt end to in-person services for many children on the autism spectrum has forced clinicians to examine the existing challenges with autism spectrum disorder (ASD) diagnostic assessment and consider things they want to keep and things that should be changed in the years ahead. New approaches such as telehealth both alleviated and exacerbated existing disparities, and brought into stark focus the importance of equitable and timely access to family-centered care. This commentary suggests ways of improving clinical practices related to ASD assessment to continue along this path.

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.

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.

Recent research has demonstrated greater prevalence of gastrointestinal (GI) symptoms in children with autism spectrum disorder (ASD) as compared to their typically developing peers. While there is an existing body of research that examines behavioral correlates of ASD and GI symptoms, few specifically examine social and adaptive profiles in this context. The aim of the current study was to identify correlations between social and adaptive skills in children with ASD, with the endorsement of GI symptoms. Significant correlations were found between GI symptoms and overall adaptive functioning, socialization, and daily living skills. No significant correlations were found between GI symptoms and communication skills, motor skills, or ADOS-2 severity scores. Strengths, limitations, and directions for future research are discussed.

BACKGROUND: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.CASE PRESENTATION:Through the 3q29 registry at Emory University, a multiplex family was identified where three offspring had a paternally inherited 3q29 deletion. We evaluated all 4 3q29 deletion family members using our previously described standardized, systematic phenotyping protocol. The transmitting parent reported no psychiatric history, however upon evaluation he was discovered to meet criteria for multiple psychiatric diagnoses including previously undiagnosed schizoaffective disorder. All four 3q29 deletion individuals in the pedigree had multiple psychiatric diagnoses that interfered with quality of life and prohibited successful academic and occupational functioning. Cognitive ability for all individuals was average or below average, but within the normal range.CONCLUSIONS:This is the first case report of inherited 3q29 deletion syndrome where all affected individuals in the pedigree have been comprehensively and systematically evaluated for neurodevelopmental and psychiatric symptoms, using a standard battery of normed instruments administered by expert clinicians. Our investigation reveals that individuals with 3q29 deletion syndrome may have psychiatric morbidity that is debilitating, but only apparent through specialized evaluation by an expert. In the absence of appropriate evaluation, individuals with 3q29 deletion syndrome may suffer from psychiatric illness but lack avenues for access to care. The individuals evaluated here all have cognition in the normal range alongside multiple psychiatric diagnoses each, suggesting that cognitive ability alone is not a representative proxy for 3q29 deletion-associated disability. These results require replication in a larger cohort of individuals with 3q29 deletion syndrome.

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.

To explore racial disparities for African Americans with autism in diagnosis and access to care, and familial and socioeconomic correlates of elevated rates of comorbid ID. BrightcoveDefaultPlayer10.1542/6158618575001PEDS-VA_2019-3629Video AbstractOBJECTIVES:African American (AA) children affected by autism spectrum disorder (ASD) experience delays in diagnosis and obstacles to service access, as well as a disproportionate burden of intellectual disability (ID) as documented in surveillance data recently published by the US Centers for Disease Control and Prevention. Our objective in this study was to analyze data from the largest-available repository of diagnostic and phenotypic information on AA children with ASD, and to explore the wide variation in outcome within the cohort as a function of sociodemographic risk and specific obstacles to service access for the purpose of informing a national approach to resolution of these disparities.METHODS:Parents of 584 AA children with autism consecutively enrolled in the Autism Genetic Resource Exchange across 4 US data collection sites completed event history calendar interviews of the diagnostic odysseys for their children with ASD. These data were examined in relation to developmental outcomes of the children with autism and their unaffected siblings.RESULTS:The average age of ASD diagnosis was 64.9 months (49.6), on average 42.3 months (+/- 45.1) after parents' first concerns about their children's development. The relationship between timing of diagnosis and ASD severity was complex, and ID comorbidity was not predicted in a straightforward manner by familial factors associated with cognitive variation in the general population.CONCLUSIONS:These findings document significant opportunity to expedite diagnosis, the need to further understand causes of ID comorbidity, and the necessity to identify effective approaches to the resolution of disparities in severity-of-outcome for AA children with autism.