Predicting Intervention Use in Youth with Rare Variants in Autism-Associated Genes.

Specialized multidisciplinary supports are important for long-term outcomes for autistic youth. Although family and child factors predict service utilization in autism, little is known with respect to youth with rare, autism-associated genetic variants, who frequently have increased psychiatric, developmental, and behavioral needs. We investigate the impact of family factors on service utilization to determine whether caregiver (autistic features, education, income) and child (autistic features, sex, age, IQ, co-occurring conditions) factors predicted service type (e.g., speech, occupational, behavioral) and intensity (hours/year) among children with autism-associated variants (N = 125), some of whom also had a confirmed ASD diagnosis. Analyses revealed variability in the types of services used across a range of child demographic, behavioral, and mental health characteristics. Speech therapy was the most received service (87.2%). Importantly, behavior therapy was the least received service and post-hoc analyses revealed that use of this therapy was uniquely predicted by ASD diagnosis. However, once children received a particular service, there was largely comparable intensity of services, independent of caregiver and child factors. Findings suggest that demographic and clinical factors impact families' ability to obtain services, with less impact on the intensity of services received. The low receipt of therapies that specifically address core support needs in autism (i.e., behavior therapy) indicates more research is needed on the availability of these services for youth with autism-associated variants, particularly for those who do not meet criteria for an ASD diagnosis but do demonstrate elevated and impactful child autistic features as compared to the general population.

Shared and divergent mental health characteristics of ADNP-, CHD8- and DYRK1A-related neurodevelopmental conditions.

BACKGROUND: Neurodevelopmental conditions such as intellectual disability (ID) and autism spectrum disorder (ASD) can stem from a broad array of inherited and de novo genetic differences, with marked physiological and behavioral impacts. We currently know little about the psychiatric phenotypes of rare genetic variants associated with ASD, despite heightened risk of psychiatric concerns in ASD more broadly. Understanding behavioral features of these variants can identify shared versus specific phenotypes across gene groups, facilitate mechanistic models, and provide prognostic insights to inform clinical practice. In this paper, we evaluate behavioral features within three gene groups associated with ID and ASD - ADNP, CHD8, and DYRK1A - with two aims: (1) characterize phenotypes across behavioral domains of anxiety, depression, ADHD, and challenging behavior; and (2) understand whether age and early developmental milestones are associated with later mental health outcomes. METHODS: Phenotypic data were obtained for youth with disruptive variants in ADNP, CHD8, or DYRK1A (N = 65, mean age = 8.7 years, 40% female) within a long-running, genetics-first study. Standardized caregiver-report measures of mental health features (anxiety, depression, attention-deficit/hyperactivity, oppositional behavior) and developmental history were extracted and analyzed for effects of gene group, age, and early developmental milestones on mental health features. RESULTS: Patterns of mental health features varied by group, with anxiety most prominent for CHD8, oppositional features overrepresented among ADNP, and attentional and depressive features most prominent for DYRK1A. For the full sample, age was positively associated with anxiety features, such that elevations in anxiety relative to same-age and same-sex peers may worsen with increasing age. Predictive utility of early developmental milestones was limited, with evidence of early language delays predicting greater difficulties across behavioral domains only for the CHD8 group. CONCLUSIONS: Despite shared associations with autism and intellectual disability, disruptive variants in ADNP, CHD8, and DYRK1A may yield variable psychiatric phenotypes among children and adolescents. With replication in larger samples over time, efforts such as these may contribute to improved clinical care for affected children and adolescents, allow for earlier identification of emerging mental health difficulties, and promote early intervention to alleviate concerns and improve quality of life.

Detection of a novel gross deletion in the UNC13D gene ends the diagnostic odyssey for a family with familial hemophagocytic lymphohistiocytosis 3.

BACKGROUND: Familial hemophagocytic lymphohistiocytosis (FHL) is an immunological disorder characterized by overactivation of macrophages and T lymphocytes. This autosomal recessive condition has been characterized into multiple types depending on the genetic etiology. FHL type 3 is associated with bi-allelic pathogenic variants in the UNC13D gene. CASE PRESENTATION: We present a 12-year diagnostic odyssey for a family with FHL that signifies the advances of FHL genetic testing in a clinical genetic diagnostic laboratory setting. We describe the first case of a large UNC13D gross deletion in trans to a nonsense variant in a family with FHL3, which may have been mediated by Alu elements within introns 12 and 25 of the UNC13D gene. CONCLUSIONS: This case highlights the importance of re-evaluating past genetic testing for a patient and family as test technology evolves in order to end a diagnostic odyssey.

Pubertal maturation and timing effects on resting state electroencephalography in autistic and comparison youth.

Autistic and comparison individuals differ in resting-state electroencephalography (EEG), such that sex and age explain variability within and between groups. Pubertal maturation and timing may further explain variation, as previous work has suggested alterations in pubertal timing in autistic youth. In a sample from two studies of 181 autistic and 94 comparison youth (8 years to 17 years and 11 months), mixed-effects linear regressions were conducted to assess differences in EEG (midline power for theta, alpha, and beta frequency bands). Alpha power was analyzed as a mediator in the relation between pubertal maturation and timing with autistic traits in the autistic groups to understand the role of puberty in brain-based changes that contribute to functional outcomes. Individuals advanced in puberty exhibited decreased power in all bands. Those who experienced puberty relatively early showed decreased power in theta and beta bands, controlling for age, sex, and diagnosis. Autistic individuals further along in pubertal development exhibited lower social skills. Alpha mediated the relation between puberty and repetitive behaviors. Pubertal maturation and timing appear to play unique roles in the development of cognitive processes for autistic and comparison youth and should be considered in research on developmental variation in resting-state EEG.

Rhythmic attentional sampling in autism.

Individuals diagnosed with autism often display alterations in visual spatial attention toward visual stimuli, but the underlying cause of these differences remains unclear. Recent evidence has demonstrated that covert spatial attention, rather than remaining constant at a cued location, samples stimuli rhythmically at a frequency of 4-8 Hz (theta). Here we tested whether rhythmic sampling of attention is altered in autism. Participants were asked to monitor three locations to detect a brief target presented 300-1200 ms after a spatial cue. Visual attention was oriented to the cue and modified visual processing at the cued location, consistent with previous studies. We measured detection performance at different cue-target intervals when the target occurred at the cued location. Significant oscillations in detection performance were identified using both a traditional time-shuffled approach and a new autoregressive surrogate method developed by Brookshire in 2022. We found that attention enhances behavioral performance rhythmically at the same frequency in both autism and control group at the cued location. However, rhythmic temporal structure was not observed in a subgroup of autistic individuals with co-occurring attention-deficit/hyperactivity disorder (ADHD). Our results imply that intrinsic brain rhythms which organize neural activity into alternating attentional states is functional in autistic individuals, but may be altered in autistic participants who have a concurrent ADHD diagnosis.

Characterizing the autism spectrum phenotype in DYRK1A-related syndrome.

Likely gene-disrupting (LGD) variants in DYRK1A are causative of DYRK1A syndrome and associated with autism spectrum disorder (ASD) and intellectual disability (ID). While many individuals with DYRK1A syndrome are diagnosed with ASD, they may present with a unique profile of ASD traits. We present a comprehensive characterization of the ASD profile in children and young adults with LGDs in DYRK1A. Individuals with LGD variants in DYRK1A (n = 29) were compared to children who had ASD with no known genetic cause, either with low nonverbal IQ (n = 14) or average or above nonverbal IQ (n = 41). ASD was assessed using the ADOS-2, ADI-R, SRS-2, SCQ, and RBS-R. Quantitative score comparisons were conducted, as were qualitative analyses of clinicians' behavioral observations. Diagnosis of ASD was confirmed in 85% and ID was confirmed in 89% of participants with DYRK1A syndrome. Individuals with DYRK1A syndrome showed broadly similar social communication behaviors to children with idiopathic ASD and below-average nonverbal IQ, with specific challenges noted in social reciprocity and nonverbal communication. Children with DYRK1A syndrome also showed high rates of sensory-seeking behaviors. Phenotypic characterization of individuals with DYRK1A syndrome may provide additional information on mechanisms contributing to co-occurring ASD and ID and contribute to the identification of genetic predictors of specific ASD traits.

Sex Differences on the ADOS-2.

The sex difference in the prevalence of autism spectrum disorder (ASD) may be magnified by sex differences on diagnostic measures. The current study compared autistic males and females on items on the gold-standard diagnostic measure, the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2). In a sample of 8-to-17-year old autistic individuals from research (n = 229) and clinical settings (n = 238), females were less likely to show atypicalities on most items related to social-communication behaviors and on total and subscale scores. When controlling for overall intensity of symptomatology, no sex differences survived statistical corrections. Diagnostic criteria and/or gold-standard assessments may be less sensitive to female presentations of ASD and/or autistic females may exhibit fewer or less intense behaviors characteristic of ASD.

Examining Feasibility and Outcomes of the PEERS® for Preschoolers Program.

Social impairments characteristic of autism spectrum disorder (ASD) are evident in early childhood and often worsen. There is a paucity of evidence-based interventions explicitly targeting social skill development for young children with ASD and few actively integrate caregivers. The PEERS® program, an evidence-based caregiver-assisted social skills program, was extended for young children with ASD (i.e., PEERS® for Preschoolers (P4P)). This pilot study expands upon initial results by examining the feasibility of a briefer intervention period and the effectiveness in improving child social skills among 15 children with ASD. Results suggest P4P recruitment, participant retention, and implementation are feasible across clinicians and sites. Further, P4P appears to improve social skills, maintained post-intervention. Future research might examine mechanisms that lead to results.

An Initial Pilot Study Examining Child Social Skills, Caregiver Styles, and Family Functioning in the PEERS® for Preschoolers Program for Young Autistic Children and their Caregivers.

BACKGROUND: Social impairments characteristic of autism spectrum disorder (ASD) are evident in early childhood and worsen as the child matures. Though many interventions for young children exist, few specifically target social skills and involve caregivers. AIMS: This pilot study examined PEERS® for Preschoolers, focusing on temporal change in child social skills, caregiver style, and family functioning in the context of a caregiver-assisted social skills intervention. This extension of the PEERS® program builds on the success of the intervention for older children, presenting skills in a developmentally appropriate manner to young autistic children and their caregivers. METHODS AND PROCEDURES: The present pilot study used a non-concurrent multiple baseline design to examine the above variables with 15 autistic children (Mage = 4.87, SD = 1.25; 11 boys). Children and caregivers participated in PEERS® for Preschoolers groups, with each group randomly assigned three different baseline periods (1.5, 2, or 2.5 weeks) before beginning. OUTCOMES AND RESULTS: Simulation Modeling Analysis (SMA) revealed concurrent improvements in social and caregiving skills, with subsequent changes in family functioning occurring over the course of this 16-session intervention. CONCLUSIONS AND IMPLICATIONS: Future research will need to examine mechanisms of change in PEERS® for Preschoolers for children and caregivers. WHAT THIS PAPER ADDS: There is a dearth of research that specifically examines social skills interventions for young autistic children that incorporates caregivers and examines family functioning as well. This paper is one of the first to evaluate the PEERS® for Preschoolers (P4P) intervention by: 1) exploring changes in child social skills, caregiver efficacy, and family functioning, and 2) analyzing the sequence of improvements in the aforementioned variables to measure systematic change. This pilot study presents results using appropriate methodology for a small sample size of children and caregivers. Results suggested concurrent improvements in social and caregiving skills and subsequent changes in family functioning. These can be built upon for further research on the PEERS® for Preschoolers intervention. This study supports PEERS® for Preschoolers as a feasible intervention that likely contributes to improvements for the child, caregiver in their relationship with their child and parenting styles in general, as well as functioning of the entire family. In sum, this work is essential to furthering the provision of a much needed service of social skills interventions for young autistic children.

Feasibility of Group Parent Training for Children with Autism Spectrum Disorder and Disruptive Behavior: A Demonstration Pilot.

Delivery of interventions in a group format is a potential solution to limited access to specialized services for children with autism spectrum disorder (ASD). We conducted an open feasibility trial of group-based RUBI parent training in 18 children (mean age 6.12 ± 1.95 years) with ASD and disruptive behaviors. Parents participated in one of five groups (3 to 4 parents per group). Eighty-three percent of participants completed the 24-week trial. Session attendance was moderate (74.2%). All parents indicated that they would recommend the treatment. Therapists demonstrated 98.8% fidelity to the manual. Eleven of 18 (64.7%) participants were rated as much/very much improved by an independent evaluator at Week 24. Preliminary efficacy findings justify further study.

A Meta-analytic Review of the Five Minute Speech Sample as a Measure of Family Emotional Climate for Youth: Relations with Internalizing and Externalizing Symptomatology.

The Five Minute Speech Sample's (FMSS) measure of parental expressed emotion (EE), defined as criticism (CRIT) and emotional overinvolvement (EOI), has been increasingly used to measure family emotional climate in relation to youth psychopathological development. As CRIT and EOI were defined based on adults, a meta-analysis and systematic review was conducted to analyze the presence and strength of an effect among maternal CRIT and EOI with youth internalizing and externalizing problems. A random effects model was used to analyze the 42 studies on families of youth (aged 1.5 to 19). There was a small, significant relation among maternal CRIT with youth internalizing and externalizing problems and among EOI with youth internalizing problems. EOI was not significantly related to externalizing problems. The current study suggests that the FMSS measure of CRIT is a more robust correlate of youth internalizing and externalizing symptoms than EOI, but EOI does relate to internalizing behaviors. Few moderators emerged, highlighting a continued need to identify factors accounting for heterogeneity. The current results suggest that the FMSS measure of CRIT may be a valuable measure of the family emotional climate in families of youth, but care should be taken when including analyses on EOI.

A Multidisciplinary Educational Approach for Children With Chronic Illness: An Intervention Case Study.

Chronic illness requires frequent medical treatments and lifestyle restrictions that increase academic and socioemotional stressors for families. This paper presents academic intervention recommendations based on a hospital's approach to improving educational outcomes for children with chronic illness. A case study on an intervention for a girl with sickle cell disease (SCD) and a history of stroke. SCD is a relatively common chronic illness that has physical and psychosocial side effects that are central to other chronic illnesses (Platt, Eckman, & Hsu, 2016). A quality improvement approach resulted in five cycles of interventions that were assessed with both qualitative and quantitative measures. The initial strategy of improving academics through collaboration among the school, hospital, and family resulted in psychosocial, but not academic, improvements. Frequent tutoring, which was most achievable using online platforms, resulted in the greatest gains. The girl passed previously failed classes and advanced to the next grade. Recommendations for how to improve academic outcomes for children with chronic illness using the presented intervention strategies are discussed.

All in the Family: A Systematic Review of the Effect of Caregiver-Administered Autism Spectrum Disorder Interventions on Family Functioning and Relationships.

A number of intervention models aimed at addressing Autism Spectrum Disorder (ASD)-related behaviors require caregivers to perform intensive and oftentimes extended protocols (Bearss et al. in Clin Child Fam Psychol Rev 18(2):170-182, 2015). Though a number of research findings describe how characteristics of the child with ASD affect the mental health and stress experienced by caregivers and family members (Davis and Carter in J Autism Dev Disord 38(7):1278-1291, 2008; Tomanik et al. in J Intellect Dev Disabil 29(1):16-26, 2004), few studies investigate effects on overall family functioning and relationships among other family members. This review aimed to examine caregiver-delivered interventions as they relate to ASD, the impact of these caregiver-administered interventions on the family unit and family relationships, and potential future targets of treatments and treatment structures that include family members. The results of the review illustrate the nature of caregiver-administered interventions, which largely benefit family functioning and relationships.

The Association of the Broader Autism Phenotype with Emotion-Related Behaviors in Mothers of Children With and Without Autism Spectrum Traits.

Broader autism phenotype (BAP) characteristics (pragmatic language deficits, aloofness, and rigidity) are prevalent in families of individuals with autism spectrum disorder (ASD) and may influence emotion-related behaviors. The current study analyzed associations among BAP characteristics with emotion-related behaviors in mothers of children with and without ASD. Twenty-seven mothers completed BAP and emotion regulation (ER) questionnaires. Maternal affect was coded during an interaction task. BAP rigidity negatively correlated with the ER strategy reappraisal. BAP total and pragmatic scores positively correlated with observed negative affect. Associations remained significant in step-wise regressions that controlled for other BAPQ subscale scores. Findings suggest that pragmatic difficulties may interfere with positive mother-child interactions and mothers with high rigidity may benefit from learning adaptive ER strategies.