This study tested the feasibility and outcomes of an intensive summer social program (summerMAXyc) on the social functioning, ASD-traits, and behaviors of autistic children, ages 4–6 years (N = 12). The manualized 5-week group intervention was delivered 5 days per week, 6 h per day to groups of 6 children each, and it included skills instruction and therapeutic activities targeting social/social-communication skills, emotion recognition, and interest expansion. summerMAXyc utilized direct instruction, modeling, roleplay, feedback, repeated practice, and reinforcement, and parents also participated in weekly group parent training. High levels of fidelity and child and parent satisfaction, as well as no attrition or adverse events supported feasibility. Significant pretest–posttest improvements were found for the primary outcome of child social performance (rated by masked observers), and secondary outcomes of parent-rated ASD-traits, social skills, communication skills, and problem behaviors. The results from 2 main outcome measures were pooled with prior summerMAXyc pilot study results to explore child features potentially associated with pretest–posttest change scores. Findings suggested that change scores were not related to third variables. summerMAXyc was feasible and appeared to yield child benefits. Implications and recommendations for further study are provided.

This study assessed the feasibility and initial outcomes of an innovative group exercise-based social intervention (So Fit) on the social functioning, ASD-features, and physical performance of autistic children, ages 7-12 years (N = 28). The So Fit manualized intervention (prescribed content and instructional procedures) was delivered to groups of 8-11 autistic children, and it consisted of two 60-minute sessions per week over 10 weeks. Each session included a skills instruction component targeting social and physical performance skills (10-15 min) followed by an exercise-based activity (45-50 min) to promote social interactions, practice social skills, and receive feedback. A behavioral reinforcement system was also implemented to foster skills development and improve ASD-features. Lastly, parents participated in three psychoeducational parent training groups on the program, and strategies for teaching, reinforcing, and generalizing skills/behaviors outside the program setting. Fidelity was high, parent and child satisfaction were good, and there were no adverse events/injuries or withdrawals supporting feasibility. Preposttest comparisons indicated significant improvements in parent-rated social skills and ASDfeatures, and on objective observations/tests of child social performance, social knowledge, and physical performance. Additional testing of So Fit in a randomized trial appears warranted and recommendations are provided.

This study examined informant discrepancies for parent and teacher ratings of social skills and behavioral flexibility/regulation of 124 children with autism spectrum disorder (ASD), ages 6 to 11 years. Scores on the Adapted Skillstreaming Checklist (ASC) were examined for mean differences, level of agreement, and moderators of difference scores between informant groups. Results indicated no significant differences between parent and teacher ASC mean scores. Parent and teacher scores were low-to-moderately correlated (intraclass correlation coefficient = .30 and Pearson r = .18) and the Bland-Altman plot and regression analysis revealed no systematic differences in agreement across the range of scores. None of the variables moderated the parent-teacher difference scores. Overall, practitioners should not necessarily anticipate parent-teacher differences when using the ASC for group-level comparisons. However, ratings were less consistent (modest correlations) at the individual child level. Less agreement at the individual child level suggests that practitioners should be prepared to follow-up and clarify the reason(s) for the differences.

Research suggests autistic children learn and generalize visual family-resemblance categories atypically (e.g., Church, et al., 2010, 2015), particularly when learning incidentally from exposure. This may reflect differences in perceptual learning (Mercado et al., 2020). However, it is unknown whether perceptual discrimination learning is also atypical and if differences extend to other modalities. To address this, autistic children with normal language abilities and IQ and typically developing (TD) matched comparison children completed auditory and visual discrimination tasks, after either incidental exposure to or direct training with stimuli presented in either progressive (easy-to-hard) or random orders of difficulty. In the visual task, both autistic and TD children only performed well after progressive training, suggesting limited perceptual learning from incidental visual exposure. In the auditory task, autistic children showed a progressive learning advantage after both exposure and training, but TD children only showed this advantage after training. They also had significantly better auditory discrimination than TD children after progressive training. These findings suggest typical visual discrimination learning after progressive training and enhanced auditory discrimination learning after progressive training and exposure. This enhanced auditory perceptual learning may help explain why these autistic children are socially impaired while retaining the capacity to learn language.

A prior randomized trial found a school social intervention yielded significantly better outcomes (social and autism features) immediately following intervention compared to typical school programming (services-as-usual [SAU]) for children on the autism spectrum. In that study, children in the SAU condition subsequently completed a summer social intervention. This study tested longer-term maintenance of effects for children who completed both interventions. A total of 103 children (ages 6–12 years) on the autism spectrum enrolled and 102 completed the initial RCT. Following the summer social intervention, 90 children from the original RCT completed the longer-term follow-up study. In addition to baseline and posttest in the initial RCT, children from both groups were tested at three follow-up points (five total testing points). At the time of first longitudinal follow-up testing, the children were 1.25–4.25 years post-intervention (ages 8–15 years). Longitudinal multilevel model analyses (and follow-up contrasts) revealed significant improvements for both groups post-intervention on measures of emotion recognition, autism features, and social skills, indicating maintenance of post-intervention improvements over the three follow-up testing points. No between-group differences were found for autism features or social skills over time; however, the school social intervention may have yielded somewhat better emotion recognition skills. Exploratory tests found that child IQ, language level, and length of time since completing the intervention did not moderate outcomes. Both social interventions yielded positive and durable longer-term improvements for children on the autism spectrum. [ClinicalTrials.gov, NCT03338530; November 8, 2017; original retrospectively registered trial]

Tay-Sachs disease is a neurodegenerative disorder characterized by progressive neurologic impairment due to pathogenic variants in the HEXA gene that codes for the alpha subunit of beta-hexosaminidase. We report 2 cases of adult-onset progressive weakness, ataxia, and neuropsychiatric symptoms in a 30-year-old man and 37-year-old woman. Both patients had compound heterozygosity in the HEXA gene with 4 distinct variants. The first patient had subsequent confirmatory functional enzyme testing displaying reduced hexosaminidase concentration, and the second patient had functional enzyme testing before genetic testing, exemplifying alternative avenues for the diagnosis of late-onset Tay-Sachs (LOTS) disease.

A 33-year-old man presented with acute dyspnoea and profound hypoxaemia, and had clubbing, greying of hair, orthodeoxia and fine inspiratory crackles. CT chest showed established pulmonary fibrosis in a usual interstitial pneumonia pattern. Additional investigations revealed a small patent foramen ovale, pancytopenia, and oesophageal varices and portal hypertensive gastropathy from liver cirrhosis. Telomere length testing demonstrated short telomeres (<1st percentile), confirming the diagnosis of a telomere biology disorder. An interstitial lung disease gene panel identified a pathogenic variant in TERT (c.1700C>T, p.(Thr567Met)) and a variant of uncertain significance in PARN (c.1159G>A, p.(Gly387Arg)). Combined lung and liver transplantation was deemed not suitable due to frailty and severe hepatopulmonary syndrome, and he died 56 days after presentation. Early recognition of the short telomere syndrome is important, and its multi-organ involvement poses challenges to management. Genetic screening may be important in younger patients with pulmonary fibrosis or in unexplained liver cirrhosis.

Although evidence has suggested that social skills interventions yield social and symptom benefits for autistic children, significant variability in outcomes between studies has raised important questions regarding efficacy and moderators of intervention outcomes (i.e., which interventions yield positive effects and which autistic children are most likely to benefit). The efficacy of a comprehensive psychosocial program for autistic children, ages 7–12 years ( N = 88) was tested in a prior randomized controlled trial (RCT). Significant effects favoring the program group (versus waitlist controls) were found at posttest on measures of autism-feature severity, social/social-communication skills, social-cognitive understanding (nonliteral language), and global social skills, and these were maintained at 4–6 week follow-up. In this exploratory study, demographic and clinical variables were tested as potential moderators of outcomes from the prior RCT. Moderation effects were not evident for demographics, or child IQ, expressive language, autistic diagnostic symptoms, or baseline co-occurring externalizing or internalizing symptoms. Child receptive language appeared to moderate the outcome of nonliteral language only. Overall, program effects were, with one exception, unrelated to third variables.

PURPOSE: This study assessed the feasibility and effectiveness of a 10-wk high intensity exercise program offered after-school for children with autism spectrum disorder (ASD) without intellectual disability. METHODS: Children with ASD (n = 11, M age: 9.53 ± 2.1 yr) engaged in a 1 hr after-school high intensity functional training exercise session, 2 d/wk for 10 wks that targeted social skills, ASD symptoms, and physical performance. Each group exercise session included an instruction period, warm-up, high intensity workout, related game, and cool-down. Social skill and symptom outcome measures included the Adapted Skillstreaming Checklist (ASC) and Social Responsiveness Scale 2nd Edition, School Age Form (SRS-2). Physical performance data (i.e., strength, flexibility, PACER aerobic fitness, power) were also collected. Paired t-tests were used to assess pre to post program performance differences. Participant and parent/guardian satisfaction surveys (7-point Likert scale) were administered following completion of the program. RESULTS: Feasibility and safety were supported in high levels of fidelity (96%), participant and parental satisfaction (4.66, 6.53 out of 7, respectively), and attendance (90% of all sessions), and there were no adverse events or injuries. Pre-post comparisons indicated significant improvements and large effects in social skills (ASC = 87.5 to 118.73; d = 1.95) and ASD symptoms (SRS-2 = 83.6 to 71.36; d = .98) and medium-to-large effects on tests of physical performance (PACER [6.9 to 9.9 laps; d = .86], 60 sec max sit-ups [13.3 to 23.5 reps, d = .58], 60 sec max body weight squats [19.5 to 29.6; d = .61]). CONCLUSION: This after-school high intensity exercise program for children with ASD without intellectual disability was feasible (high fidelity, satisfaction) and improved social functioning, ASD symptoms and physical performance.

Pathogenic variants in CCDC22 were initially described in 2012 in a large Australian family with intellectual disability and were subsequently noted to cause a phenotype consistent with the previously described Ritscher-Schinzel syndrome (RSS). The phenotypes of the original family were not described in detail and remains limited phenotypic data reported in medical literature. We detail the phenotypes of the original family, including newly diagnosed family members. With these eight phenotypic descriptions, more than triple the number of individuals for whom detailed clinical information is available. In addition to typical facies, common phenotypic features included intellectual disability, congenital heart disease and posterior fossa malformations, postnatal short stature, ectodermal abnormalities, and digital anomalies as previously described. Spinal curvature and genital anomalies were seen in most patients, while gastrointestinal features and disturbed sleep were also recurrently seen. We propose a possible mechanism linking the familial variant to a diagnosis of sarcoidosis in one individual. Given the clinical and genetic heterogeneity of RSS, we suggest a dyadic naming convention.

The Social Competence Observation Scale (SCOS) is an objective observational measure developed to assess the social performance of children with autism spectrum disorder (ASD). This paper describes development of the SCOS and results of initial testing of reliability and treatment sensitivity for a sample of 12 children, ages 4–6 years, with ASD. Based on observations, the measure can yield three scores including a social impairment severity, change, and responder status score. Results suggested good-to-excellent reliability (inter-observer agreement and test–retest) and the SCOS was treatment sensitive to changes resulting from the intervention (at the social impairment severity score, change score, and responder status levels). Lastly, the effect size based on the SCOS social impairment severity score improvements (baseline-to-post-treatment) for the coders was large and was comparable to parent ratings on a standardized measure of ASD social impairment symptom severity. Implications and suggestions for future study are discussed.

Heterozygous single nucleotide variants (SNVs) or copy-number variant deletions involving FOXF1 or its distant lung-specific enhancer on chromosome 16q24.1 have been identified in 80–90% of patients with Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV), a lethal neonatal lung developmental disorder. We describe a four-generation family with a deceased ACDMPV neonate, her sibling from the electively terminated pregnancy, healthy mother with a history of pulmonary arterial hypertension (PAH), an unaffected aunt, an aunt deceased due to findings consistent with ACDMPV, and a reportedly unaffected grandmother, all with the frameshifting variant c.881_902dup (p.Gly302Profs*46) in FOXF1 , and a deceased great-grandmother with a history of PAH. Genome sequencing analyses in the proband’s unaffected mother revealed a non-coding putative regulatory SNV rs560517434-A within the lung-specific distant FOXF1 enhancer in trans to the FOXF1 frameshift mutation. Functional testing of this variant using an in vitro luciferase reporter assay showed that it increased FOXF1 promoter activity 10-fold. Our studies further demonstrate that non-coding SNVs in the FOXF1 enhancer region can rescue the lethal ACDMPV phenotype and support the compound inheritance gene dosage model.

Children with ASD are more likely to be involved in bullying compared to typically developing peers; however, studies rarely examine bullying perpetration and the contributing factors among this population. The primary aim of this study was to examine the extent to which parent-reported ASD symptoms, social skills, and comorbid externalizing and internalizing symptoms predicted bullying perpetration in a sample of 390 children with ASD without intellectual disability. Findings from hierarchical regression analyses indicated that social skill deficits, externalizing symptoms (i.e., hyperactivity, aggression, and conduct problems), and depressive symptoms were associated with higher likelihood of bullying perpetration, while severity of ASD symptoms and anxiety were not significant predictors. Further research is needed to better understand bullying perpetration among children with ASD.

This study reports on two pilot studies developing a telemedicine parent-delivered social skills intervention (PDSSI) for school-aged children with ASD. Pilot study 1 involved initial development, training, and feasibility testing for six parent–child pairs using in-person training and fidelity monitoring. Findings from study 1 supported the intervention procedures through high satisfaction and parent implementation fidelity. Pilot study 2 tested the intervention with 11 parent–child pairs using telemedicine for parent training, fidelity monitoring, and child outcome testing. Findings from study 2 supported feasibility using telemedicine. Study 2 also provided initial data indicating improvements in child social skills knowledge (d = 1.15), social skills (d = 1.75), and ASD characteristics (d = 0.92). Parents reported improvements in their own empowerment (d = 1.09) and stress (d = 0.44). Some outcomes were assessed and maintained at a 16-week follow-up. Overall, results support ongoing testing of this telemedicine PDSSI.

Telomere biology disorders (TBDs) are a spectrum of multisystem inherited disorders characterized by bone marrow failure, resulting from mutations in the genes encoding telomerase or other proteins involved in maintaining telomere length and integrity. Pathogenicity of variants in these genes can be hard to evaluate, because TBD mutations show highly variable penetrance and genetic anticipation related to inheritance of shorter telomeres with each generation. Thus, detailed functional analysis of newly identified variants is often essential. Herein, we describe a patient with compound heterozygous variants in the TERT gene, which encodes the catalytic subunit of telomerase, hTERT. This patient had the extremely severe Hoyeraal-Hreidarsson form of TBD, although his heterozygous parents were clinically unaffected. Molecular dynamic modeling and detailed biochemical analyses demonstrate that one allele (L557P) affects association of hTERT with its cognate RNA component hTR, whereas the other (K1050E) affects the binding of telomerase to its DNA substrate and enzyme processivity. Unexpectedly, the data demonstrate a functional interaction between the proteins encoded by the two alleles, with wild-type hTERT rescuing the effect of K1050E on processivity, whereas L557P hTERT does not. These data contribute to the mechanistic understanding of telomerase, indicating that RNA binding in one hTERT molecule affects the processivity of telomere addition by the other molecule. This work emphasizes the importance of functional characterization of TERT variants to reach a definitive molecular diagnosis for patients with TBD, and, in particular, it illustrates the importance of analyzing the effects of compound heterozygous variants in combination, to reveal interallelic effects.

Yoga is a common exercise modality, ranking in the top 20 fitness trends for the last decade. Recent research has suggested that participating in yoga may provide supplemental benefits to muscular strength, when partnered with resistance training, in young adults. However, previous research has methodological limitations that impact the ability to properly understand the effects of yoga on muscular strength. PURPOSE: To determine the effects of a 6-week Hatha yoga intervention on total body muscular strength in healthy, resistance-trained, young adults. METHODS: Resistance-trained adults (n = 18); age: 23.1 ± 2.0 y; 61% females) were randomized to either the yoga intervention (n = 10) or control group (n = 8). The yoga intervention involved 18 Hatha yoga sessions over 6 weeks, while the control group maintained normal activities. Both groups continued their resistance training programs. Muscular strength was assessed pre- and post-intervention using 1-RM for bench press, deadlift, and squat using standard procedures. Data were analyzed using a 2 (time) x 2 (group) repeated measures ANCOVA, controlling for sex, with an alpha level set at 0.05. RESULTS: There was a significant difference in bench press 1-RM due to time (p < 0.001) with an increase in 1-RM following the intervention (pre: 55.4 ± 9.9 kg vs. post: 59.2 ± 10.0 kg). Deadlift 1-RM also increased across the intervention (pre: 96.7 ± 19.0 kg vs. post: 103.0 ± 18.1 kg; p = 0.04). There were no differences in 1-RM for bench press (p = 0.08) or deadlift (p = 0.29) between the two groups. There was a significant increase in squat 1-RM across time (pre: 79.5 ± 15.2 kg vs. post: 86.3 ± 15.4 kg; p < 0.001). Further, the yoga group had a significantly higher squat 1-RM (90.8 ± 15.0 kg) compared to the control group (75.0 ± 15.0 kg; p = 0.04). CONCLUSIONS: A 6-week Hatha yoga intervention does not improve deadlift and bench press 1-RM differently than resistance training alone. However, yoga may provide beneficial improvements to the 1-RM for squat in resistance-trained, young adults. Future research would be beneficial to investigate alternate forms of yoga on muscular strength such as Vinyasa yoga. Research should also aim to determine whether supplementing resistance training with yoga is beneficial in other populations such as older individuals and those with musculoskeletal disorders.

Purpose: Genetic variants causing aberrant premessenger RNA splicing are increasingly being recognized as causal variants in genetic disorders. In this study, we devise standardized practices for polymerase chain reaction (PCR)-based RNA diagnostics using clinically accessible specimens (blood, fibroblasts, urothelia, biopsy). Methods: A total of 74 families with diverse monogenic conditions (31% prenatal-congenital onset, 47% early childhood, and 22% teenage-adult onset) were triaged into PCR-based RNA testing, with comparative RNA sequencing for 19 cases. Results: Informative RNA assay data were obtained for 96% of cases, enabling variant reclassification for 75% variants that can be used for genetic counseling (71%), to inform clinical care (32%) and prenatal counseling (41%). Variant-associated mis-splicing was highly reproducible for 28 cases with samples from >= 2 affected individuals or heterozygotes and 10 cases with >= 2 biospecimens. PCR amplicons encompassing another segregated heterozygous variant was vital for clinical interpretation of 22 of 79 variants to phase RNA splicing events and discern complete from partial mis-splicing. Conclusion: RNA diagnostics enabled provision of a genetic diagnosis for 64% of recruited cases. PCR-based RNA diagnostics has capacity to analyze 81.3% of clinically significant genes, with long amplicons providing an advantage over RNA sequencing to phase RNA splicing events. The Australasian Consortium for RNA Diagnostics (SpliceACORD) provide clinically-endorsed, standardized protocols and recommendations for interpreting RNA assay data. (C) 2021 Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics.

BACKGROUND:The genomic era has led to enormous progress in clinical care and a multi-disciplinary team (MDT) approach is imperative for integration of genomics into epilepsy patient care.METHODS:The MDT approach involved patient selection, genomic testing choice, variant discussions and return of results. Genomics analysis included cytogenomic testing and whole exome sequencing (WES). Neurologist surveys were undertaken at baseline and after genomic testing to determine if genomic diagnoses would alter their management, and if there was a change in confidence in genomic testing and neurologist perceptions of the MDT approach.RESULTS:The total diagnostic yield from all genomic testing was 17% (11/66), with four diagnoses from cytogenomic analyses. All chromosomal microarray (CMA) diagnoses were in patients seen by adult neurologists. Diagnostic yield for WES was 11% (7/62). The most common gene with pathogenic variants was DCX, reported in three patients, of which two were mosaic. The genomic diagnosis impacted management in 82% (9/11). There was increased confidence with integrating genomics into clinical care (Pearson chi square = 83, p = 0.004) and qualitative comments were highly supportive of the MDT approach.CONCLUSIONS:We demonstrated diagnostic yield from genomic testing, and the impact on management in a cohort with drug-resistant epilepsy. The MDT approach increased confidence in genomic testing and neurologists valued the input from this approach. The utility of CMA was demonstrated in epilepsy patients seen by adult neurologists as was the importance of considering mosaicism for previously undiagnosed patients.

Pathogenic variants in ARX lead to a variety of phenotypes with intellectual disability being a uniform feature. Other features can include severe epilepsy, spasticity, movement disorders, agenesis of the corpus callosum, lissencephaly, hydranencephaly and ambiguous genitalia in males. We present the first report of monozygotic female twins with a de novo ARX pathogenic variant (c.1406_1415del; p. Ala469Aspfs*20), predicted to result in a truncated ARX protein missing the important regulatory Aristaless domain. The twins presented with profound developmental delay and seizures, consistent with the known genotype-phenotype correlation. Twin 2's features were significantly more severe. She also developed chorea; the first time this movement disorder has been seen in an ARX variant other than an expansion of the first polyalanine tract. Differential X-chromosome inactivation was the most likely explanation for the differing severities but could not be conclusively proven.