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Physical examinations are recommended as part of a comprehensive evaluation for individuals with neurodevelopmental disorders (NDDs), such as autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder. These examinations should include assessment for morphological variants. Previous studies have shown an increase in morphological variants in individuals with NDDs, particularly ASD, and that these variants may be present in greater amounts in individuals with genetic alterations. Unfortunately, assessment for morphological variants can be subjective and time-consuming, and require a high degree of clinical expertise. Therefore, objective, automated methods of morphological assessment are desirable. This study compared the use of Face2Gene, an automated tool to explore facial morphological variants, to clinical consensus assessment, using a cohort of N = 290 twins enriched for NDDs (n = 135 with NDD diagnoses). Agreement between automated and clinical assessments were satisfactory to complete (78.3-100%). In our twin sample, individuals with NDDs did not have greater numbers of facial morphological variants when compared to those with typical development, nor when controlling for shared genetic and environmental factors within twin pairs. Common facial morphological variants in those with and without NDDs were similar and included thick upper lip vermilion, abnormality of the nasal tip, long face, and upslanted palpebral fissure. We conclude that although facial morphological variants can be assessed reliably in NDDs with automated tools like Face2Gene, clinical utility is limited when just exploring the facial region. Therefore, currently, automated assessments may best complement, rather than replace, in-person clinical assessments., (© 2020 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals, Inc.)

Aim: Early intensive behavioural intervention (EIBI) for children with autism spectrum disorder (ASD) is often delivered using a community model. Behaviour modification experts train and supervise non-experts (e.g. preschool personnel) to teach children according to applied behaviour analysis principles in their natural environment. Several factors predict EIBI outcomes in ASD, for example, knowledge of EIBI and EIBI allegiance among trainers. The aim of the present study was to survey levels of knowledge about and allegiance towards EIBI., Methods: Formal knowledge of EIBI and EIBI allegiance was surveyed in supervised preschool staff conducting EIBI (n = 33), preschool staff not involved in EIBI (n = 26), behaviour modification experts (n = 60), school staff (n = 25) and parents of children with ASD (n = 150) [N = 294]. A 27-item (15 knowledge and 12 allegiance questions) online questionnaire was collected., Results: Supervised preschool staff conducting EIBI had more knowledge than preschool staff not using EIBI, but they were not more allegiant. Compared with behaviour modification experts, the supervised EIBI preschool staff group showed markedly less knowledge and allegiance., Conclusions: Findings indicate potential for improvement regarding formal knowledge levels of preschool staff delivering EIBI to children with ASD in real-world settings. In addition, fostering EIBI allegiance might be prioritized when teaching EIBI among non-experts. Broadly increased EIBI knowledge levels among all preschool teachers should be achieved by adding behaviour modification techniques to common university curricula in preschool education. Allegiance of preschool personnel might be accomplished by EIBI supervisors meeting skepticism in practice with conveyance of evidence-based principles and discussions of ethical issues., (© 2016 John Wiley & Sons Australia, Ltd.)

Background: Studies of infants with an elevated likelihood of autism spectrum disorder can identify basic developmental processes that are associated with subsequently emerging clinical symptoms. Atypical responsiveness to sounds in infancy is such a potential early marker of autism. Here, we used pupillometry to quantify reactivity to social and nonsocial sounds in infants with a subsequent diagnosis. Previous research suggest that pupil dilation reflects attentional alerting, and link it to the locus coeruleus norepinephrine system. Methods: We measured pupil dilation responses to child‐directed speech and the sound of running water; sounds infants often hear in their everyday life. The final sample consisted of 99 ten‐month‐old infants (52 girls), of whom 68 had an elevated likelihood of autism and 31 were typically developing low‐likelihood infants. At follow‐up (36 months of age), 18 children in the elevated‐likelihood group were diagnosed with autism. Results: Compared to infants without diagnosis, the infants who were subsequently diagnosed with autism had larger pupil dilation when listening to nonsocial sounds, while reactivity to speech was strikingly similar between groups. In the total sample, more pupil dilation to the nonsocial sound was associated with higher levels of autistic symptoms. We also found that on a trial‐by‐trial basis, across all conditions and groups, more pupil dilation was associated with making fewer gaze shifts. Conclusions: This study did not find evidence of atypical pupillary reactivity to child‐directed speech early in life in autism. Instead, the results suggest that certain nonsocial sounds elicit atypically strong alerting responses in infants with a subsequent autism diagnosis. These findings may have important theoretical and clinical implications. [ABSTRACT FROM AUTHOR]

Exome sequencing has been proposed as the first‐tier genetic testing in autism spectrum disorder (ASD). Here, we performed exome sequencing in autistic individuals with average to high intellectual abilities (N = 207) to identify molecular diagnoses and genetic modifiers of intervention outcomes of social skills group training (SSGT) or standard care. We prioritized variants of clinical significance (VCS), variants of uncertain significance (VUS) and generated a pilot scheme to calculate genetic scores of rare and common variants in ASD‐related gene pathways. Mixed linear models were used to test the association between the carrier status of VCS/VUS or the genetic scores with intervention outcomes measured by the social responsiveness scale. Additionally, we combined behavioral and genetic features using a machine learning (ML) model to predict the individual response. We showed a rate of 4.4% and 11.3% of VCS and VUS in the cohort, respectively. Individuals with VCS or VUS had improved significantly less after standard care than non‐carriers at post‐intervention (β = 9.35; p = 0.036), while no such association was observed for SSGT (β = −2.50; p = 0.65). Higher rare variant genetic scores for synaptic transmission and regulation of transcription from RNA polymerase II were separately associated with less beneficial (β = 8.30, p = 0.0044) or more beneficial (β = −6.79, p = 0.014) effects after SSGT compared with standard care at follow‐up, respectively. Our ML model showed the importance of rare variants for outcome prediction. Further studies are needed to understand genetic predisposition to intervention outcomes in ASD. Lay Summary: Social skills group training is one of the most common behavior interventions aiming at autistic children and adolescents, but the outcome varies between individuals. In this study, we showed that rare variants identified by exome sequencing were associated with intervention outcomes. The results may guide future studies on underlying biological mechanisms and help shape more precise intervention plans for autistic individuals. [ABSTRACT FROM AUTHOR]

No robust biomarkers have yet been identified for autism spectrum disorder (ASD) or autistic traits. Familial factors likely influence biomarkers such as protein concentrations. Comparing twins with ASD or high autistic traits to the less affected co‐twin allows estimating the impact of familial confounding. We measured 203 proteins in cerebrospinal fluid (n = 86) and serum (n = 127) in twins (mean age 14.2 years, 44.9% females) enriched for ASD and other neurodevelopmental conditions. Autistic traits were assessed by using the parent‐report version of the Social Responsiveness Scale‐2. In cerebrospinal fluid, autistic traits correlated negatively with three proteins and positively with one. In serum, autistic traits correlated positively with 15 and negatively with one. Also in serum, six were positively—and one negatively—associated with ASD. A pathway analysis of these proteins revealed immune system enrichment. In within twin pair analyses, autistic traits were associated with serum B‐cell activating factor (BAFF) only, whereas Cystatin B (CSTB) remained significantly associated with ASD. These associations did not remain significant when only considering monozygotic twins. For the remainder, the within‐pair analysis indicated familial confounding, including shared environment and genes, influencing both autism and protein levels. Our findings indicate proteins involved in immunity as putative biomarkers of autistic traits and ASD with partial genetic confounding. Although some results are in line with previous studies in general, further studies are needed for replication. [ABSTRACT FROM AUTHOR]

This study aimed to describe concept of social competence as a theoretical background for social skills group intervention for children with autism spectrum disorder (ASD). A model of social competence comprised of three components: social skills, social performance, and social adjustment. We also examined the feasibility and preliminary efficacy of the manualized Social Competence group intervention for children with autism spectrum disorder (SOCO) using a variety of outcome measures. The nine‐month intervention included children groups, parental support groups and co‐operation with teachers. A pilot study involved 23 children aged 7 to 12 years (n = 16 intervention, n = 7 control) and intervention outcomes were measured with questionnaires for parents and teachers, neuropsychological tests, and observations. The parents of the intervention group reported improvements in social skills and social adjustment, whereas the teachers reported increases in social performance. Findings also indicated that affect recognition skills, social overtures, and reactions to peers were improved in the intervention group. Although the evidence of the pilot study should be considered as preliminary, it gives some indication of the feasibility of the SOCO group intervention and supports the usability of the theoretical background and approach for multiple outcome measures. [ABSTRACT FROM AUTHOR]

Summary: Background: Associations between parental asthma and prenatal exposure to asthma medications with offspring autism spectrum disorder (ASD) have been reported. However, the associations might be confounded by unmeasured (genetic and shared environmental) familial factors. Objective: We investigated the association between (a) maternal/paternal asthma and offspring ASD, and (b) prenatal exposures to β2‐agonists, other asthma medications and offspring ASD using cases and controls selected from the population as well as biological relatives with different degrees of relatedness. Methods: We included all children (N = 1 579 263) born in Sweden 1992‐2007. A nested case‐control design was used to compare 22 894 ASD cases identified from the National Patient Register to (a) 228 940 age‐, county‐ and sex‐matched controls randomly selected from the population, (b) their eligible full‐siblings (n = 1267), (c) half‐siblings (n = 1323), (d) full‐cousins (n = 11 477) and (e) half‐cousins (n = 3337). Conditional logistic regression was used to estimate the odds ratios (OR) and 95% confidence intervals (CI) for ASD in children differentially exposed to parental asthma or prenatal asthma medications. Results: Maternal asthma was associated with increased risk of offspring ASD (OR 1.43, 95% CI 1.38‐1.49); there was a weaker association for paternal asthma (OR 1.17, 95% CI 1.11‐1.23). The risk of offspring ASD in mothers with asthma showed similar estimates when adjusting for shared familial factors among paternal half‐siblings (OR 1.20, 95% CI 0.80‐1.81), full‐cousins (OR 1.28, 95% CI 1.16‐1.41) and half‐cousins (OR 1.30, 95% CI 1.10‐1.54), albeit with wider confidence intervals. Prenatal exposure to asthma medications among subjects whose mothers had asthma was not associated with subsequent ASD. Conclusions and Clinical Relevance: In this large observational study, parental asthma was associated with slightly elevated risk of ASD in offspring. More specifically, the increased risk by maternal asthma did not seem to be confounded by familial factors. There was no evidence of an association between asthma medications during pregnancy and offspring ASD. [ABSTRACT FROM AUTHOR]

Individuals with autism spectrum disorder (ASD) exhibit significant impairments in adaptive functioning that impact on their ability to meet the demands of everyday life. A recurrent finding is that there is a pronounced discrepancy between level of cognitive ability and adaptive functioning, and this is particularly prominent among higher‐ability individuals. However, the key clinical and demographic associations of these discrepancies remain unclear. This study included a sample of 417 children, adolescents, and adults with ASD as part of the EU‐AIMS LEAP cohort. We examined how age, sex, IQ, levels of ASD symptom and autistic trait severity and psychiatric symptomatology are associated with adaptive functioning as measured by the Vineland Adaptive Behavior Scales‐Second Edition and IQ‐adaptive functioning discrepancies. Older age, lower IQ and higher social‐communication symptoms were associated with lower adaptive functioning. Results also demonstrate that older age, higher IQ and higher social‐communication symptoms are associated with greater IQ‐adaptive functioning discrepancy scores. By contrast, sensory ASD symptoms, repetitive and restricted behaviors, as well as symptoms of attention deficit/hyperactivity disorder (ADHD), anxiety and depression, were not associated with adaptive functioning or IQ‐adaptive functioning discrepancy scores. These findings suggest that it is the core social communication problems that define ASD that contribute to adaptive function impairments that people with ASD experience. They show for the first time that sensory symptoms, repetitive behavior and associated psychiatric symptoms do not independently contribute to adaptive function impairments. Individuals with ASD require supportive interventions across the lifespan that take account of social‐communicative ASD symptom severity. Autism Res 2019, 12: 645–657. © 2019 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc. Lay summary: This study investigated key clinical and demographic associations of adaptive functioning impairments in individuals with autism. We found that older age, lower IQ and more severe social‐communicative symptoms, but not sensory or repetitive symptoms or co‐occurring psychiatric symptoms, are associated with lower adaptive functioning and greater ability‐adaptive function discrepancies. This suggests that interventions targeting adaptive skills acquisition should be flexible in their timing and intensity across developmental periods, levels of cognitive ability and take account of social‐communicative ASD symptom severity. [ABSTRACT FROM AUTHOR]

Background: Effective multisensory processing develops in infancy and is thought to be important for the perception of unified and multimodal objects and events. Previous research suggests impaired multisensory processing in autism, but its role in the early development of the disorder is yet uncertain. Here, using a prospective longitudinal design, we tested whether reduced visual attention to audiovisual synchrony is an infant marker of later‐emerging autism diagnosis. Methods: We studied 10‐month‐old siblings of children with autism using an eye tracking task previously used in studies of preschoolers. The task assessed the effect of manipulations of audiovisual synchrony on viewing patterns while the infants were observing point light displays of biological motion. We analyzed the gaze data recorded in infancy according to diagnostic status at 3 years of age (DSM‐5). Results: Ten‐month‐old infants who later received an autism diagnosis did not orient to audiovisual synchrony expressed within biological motion. In contrast, both infants at low‐risk and high‐risk siblings without autism at follow‐up had a strong preference for this type of information. No group differences were observed in terms of orienting to upright biological motion. Conclusions: This study suggests that reduced orienting to audiovisual synchrony within biological motion is an early sign of autism. The findings support the view that poor multisensory processing could be an important antecedent marker of this neurodevelopmental condition. [ABSTRACT FROM AUTHOR]

This is the third in a series of four empirical studies designed to develop International Classification of Functioning, Disability and Health (ICF) Core Sets for Autism Spectrum Disorder (ASD). The present study aimed to describe functioning in ASD (as operationalized by the ICF) derived from the perspectives of diagnosed individuals, family members, and professionals. A qualitative study using focus groups and semi‐structured interviews were conducted with 19 stakeholder groups (N = 90) from Canada, India, Saudi Arabia, South Africa, and Sweden. Meaningful concepts from the focus groups and individual interviews were linked to ICF categories using a deductive qualitative approach with standardized linking procedures. The deductive qualitative content analysis yielded meaningful functioning concepts that were linked to 110 ICF categories across all four ICF components. Broad variation of environmental factors and activities and participation categories were identified in this study, while body functions consisted mainly of mental functions. Body structures were sparsely mentioned by the participants. Positive aspects of ASD included honesty, attention to detail, and memory. The experiences provided by international stakeholders support the need to understand individuals with ASD in a broader perspective, extending beyond diagnostic criteria into many areas of functioning and environmental domains. This study is part of a larger systematic effort that will provide the basis to define ICF Core Sets for ASD, from which assessment tools can be generated for use in clinical practice, research, and health care policy making. Autism Res2018, 11: 463–475. © 2017 The Authors Autism Research published by International Society for Autism Research and Wiley Periodicals, Inc. Lay Summary: The study findings support the need to understand the living experiences of individuals with Autism Spectrum Disorder (ASD) from a broader perspective, taking into account many areas of an individual's functioning and environment. The ICF can serve as foundation for exploring these living experiences more extensively by offering tools that enable wide variety of individual difficulties and strengths to be captured along with important environmental influences. As such, these tools can facilitate interventions that meet the needs and goals of the individual. [ABSTRACT FROM AUTHOR]

Background: Variable size deletions affecting 12q12 have been found in individuals with neurodevelopmental disorders (NDDs) and distinct facial and physical features. For many genetic loci affected by deletions in individuals with NDDs, reciprocal duplications have been described. However, for the 12q12 region, there are no detailed descriptions of duplication cases in the literature. Methods: We report a phenotypic description of a family with monozygotic twins diagnosed with NDDs, carrying a 9 Mb duplication at 12q12, and five other individuals with overlapping duplications ranging from 4.54 Mb up to 15.16 Mb. Results: The duplication carriers had language delays, cognitive delays, and were diagnosed with autism spectrum disorder. Additionally, distinct facial features (e.g., high foreheads, deeply set eyes, short palpebral fissures, small ears, high nasal bridges, abnormalities of the nose tip, thin lips), large feet, and abnormalities in the digits were noted. We also describe incomplete penetrance of the NDD phenotypes among the individuals with 12q12 duplication. Conclusion: This case series expands our knowledge on this rare genetic aberration and suggests that large 12q12 duplications may increase the risk for developing NDDs. [ABSTRACT FROM AUTHOR]

Hypogonadotrophic hypogonadism (HH) is a rare disorder that manifests absent puberty and infertility. Genetic syndromes with hypogonadism, such as Klinefelter syndrome, are associated with an increased risk of neurodevelopmental disorders (NDDs). However, it is not clear whether patients with HH or transient delayed puberty in general, have an increased risk of NDDs. We performed a register‐based study on a national cohort of 264 patients with HH and 7447 patients diagnosed with delayed puberty that was matched with 2640 and 74 470 controls, respectively. The outcome was defined as having any of the following NDD diagnoses: (i) autism spectrum disorder (ASD); (ii) attention deficit hyperactivity disorder (ADHD); or (iii) intellectual disability (ID). Additional sensitivity analyses were performed to control for different parental and birth variables, as well as diagnosed malformation syndromes and chromosomal anomalies (ie, Down's and Turner syndromes). Patients with HH had increased risk for being diagnosed with ASD (odds ratio [OR] = 5.7; 95% confidence interval [CI] = 2.6‐12.6), ADHD (OR = 3.0; 95% CI = 1.8‐5.1) and ID (OR = 18.0; 95% CI = 8.9‐36.3) compared to controls. Patients with delayed puberty also had a significantly increased risk of being diagnosed with an NDD. These associations remained significant after adjustments. This is the first study to demonstrate a significant association between HH, delayed puberty and NDDs in a population‐based cohort. Clinicians should be aware of the overlap between these disorders. Further studies should explore the mechanisms behind these associations. [ABSTRACT FROM AUTHOR]