De novo missense variants in the E3 ubiquitin ligase adaptor KLHL20 cause a developmental disorder with intellectual disability, epilepsy, and autism spectrum disorder.

PURPOSE: KLHL20 is part of a CUL3-RING E3 ubiquitin ligase involved in protein ubiquitination. KLHL20 functions as the substrate adaptor that recognizes substrates and mediates the transfer of ubiquitin to the substrates. Although KLHL20 regulates neurite outgrowth and synaptic development in animal models, a role in human neurodevelopment has not yet been described. We report on a neurodevelopmental disorder caused by de novo missense variants in KLHL20. METHODS: Patients were ascertained by the investigators through Matchmaker Exchange. Phenotyping of patients with de novo missense variants in KLHL20 was performed. RESULTS: We studied 14 patients with de novo missense variants in KLHL20, delineating a genetic syndrome with patients having mild to severe intellectual disability, febrile seizures or epilepsy, autism spectrum disorder, hyperactivity, and subtle dysmorphic facial features. We observed a recurrent de novo missense variant in 11 patients (NM_014458.4:c.1069G>A p.[Gly357Arg]). The recurrent missense and the 3 other missense variants all clustered in the Kelch-type ß-propeller domain of the KLHL20 protein, which shapes the substrate binding surface. CONCLUSION: Our findings implicate KLHL20 in a neurodevelopmental disorder characterized by intellectual disability, febrile seizures or epilepsy, autism spectrum disorder, and hyperactivity.

Conceptualization of quality of life in autistic individuals.

The present study examines to what extent two core characteristics of the quality of life (QoL) construct were incorporated in the field of autism: (1) its subjective nature; and (2) its multidimensionality. Therefore, we reviewed 174 articles examining QoL in individuals with autism. The review showed parents reporting a lower QoL compared with autistic individuals themselves, especially on internal domains. This may suggest different expectations about what a good QoL may entail. Such an underestimation of QoL by others is commonly observed in individuals with disabilities (the so-called 'disability paradox'). For the multidimensionality of the QoL construct, our findings suggest that the narrower (and more unidimensional) construct of health-related QoL is often measured instead of QoL. Additionally, a substantial proportion of items did not measure QoL, but they evaluated characteristics that may or may not have an impact on QoL. Researchers and clinicians should be aware that QoL domains are selected and operationalized differently by different instruments. QoL may benefit from an exclusive focus on subjective aspects, which can be measured alongside more normative, objective characteristics of individuals or their environment.

8p21.3 deletions are rare causes of non-syndromic autism spectrum disorder.

A de novo 0.95 Mb 8p21.3 deletion had been identified in an individual with non-syndromic autism spectrum disorder (ASD) through high-resolution copy number variant analysis. Subsequent screening of in-house and publicly available databases resulted in the identification of six additional individuals with 8p21.3 deletions. Through case-based reasoning, we conclude that 8p21.3 deletions are rare causes of non-syndromic neurodevelopmental and neuropsychiatric disorders. Based on literature data, we highlight six genes within the region of minimal overlap as potential ASD genes or genes for neuropsychiatric disorders: DMTN, EGR3, FGF17, LGI3, PHYHIP, and PPP3CC.

How well are DSM-5 diagnostic criteria for ASD represented in standardized diagnostic instruments?

Five years after the publication of DSM-5 in 2013, three widely used diagnostic instruments have published algorithms designed to represent its (sub-)criteria for Autism Spectrum Disorder (ASD) in children and adolescents. This study aimed to: (1) establish the content validity of these three DSM-5-adapted algorithms, and (2) identify problems with the operationalization of DSM-5 diagnostic criteria in measurable and observable behaviors. Algorithm items of the Autism Diagnostic Observation Schedule-Second Edition (ADOS-2), Developmental, Dimensional and Diagnostic Interview (3di) and Diagnostic Interview for Social and Communication Disorders-11th edition (DISCO-11) were mapped onto DSM-5 sub-criteria. The development and decision-making rules integrated in their algorithms were then compared with DSM-5. Results demonstrated significant variability in the number and nature of sub-criteria covered by the ADOS-2, 3di and DISCO-11. In addition to differences in the development of algorithms and cut-off scores, instruments also differed in the extent to which they follow DSM-5 decision-making rules for diagnostic classification. We conclude that such differences in interpretation of DSM-5 criteria provide a challenge for symptom operationalization which will be most effectively overcome by consensus, testing and reformulation.

Does adapting a self-report instrument to improve its cognitive accessibility for people with intellectual disability result in a better measure? - A cognitive interview study.

BACKGROUND AND AIMS: We investigated whether improving the cognitive accessibility of a widely used self-report measure leads to better understanding and more accurate answers in a sample of adults with mild intellectual disability and borderline intellectual functioning. METHODS AND PROCEDURES: We undertook a series of cognitive interviews before and after adaptation of the instructions and selected items of an existing self-report measure of adaptive functioning. Interview results and participant feedback were supplemented with quantitative comparisons between participant and carer scores. OUTCOMES AND RESULTS: Adaptation based on participant experiences and preferences combined with evidence-informed guidelines improved understanding and accuracy. Self-report and carer-report scores showed greater convergence after adaptation; this occurred because people with intellectual disabilities appeared to understand the self-report measure more effectively. CONCLUSIONS AND IMPLICATIONS: The results show that adaptation of the self-report instrument to suit the needs and preferences of people with mild intellectual disability or borderline intellectual functioning leads to a more accessible measure and more reliable and valid results. Results also highlight the importance of complementing proxy reports with a first-person perspective in assessment as clients and informants may differ in their assessment of behavior and skills.

Diagnosing autism spectrum disorder: who will get a DSM-5 diagnosis?

BACKGROUND: Introduction of proposed criteria for DSM-5 Autism Spectrum Disorder (ASD) has raised concerns that some individuals currently meeting diagnostic criteria for Pervasive Developmental Disorder (PDD; DSM-IV-TR/ICD-10) will not qualify for a diagnosis under the proposed changes. To date, reports of sensitivity and specificity of the new criteria have been inconsistent across studies. No study has yet considered how changes at the 'sub domain' level might affect overall sensitivity and specificity, and few have included individuals of different ages and ability levels. METHODS: A set of DSM-5 ASD algorithms were developed using items from the Diagnostic Interview for Social and Communication Disorders (DISCO). The number of items required for each DSM-5 subdomain was defined either according to criteria specified by DSM-5 (Initial Algorithm), a statistical approach (Youden J Algorithm), or to minimise the number of false positives while maximising sensitivity (Modified Algorithm). The algorithms were designed, tested and compared in two independent samples (Sample 1, N = 82; Sample 2, N = 115), while sensitivity was assessed across age and ability levels in an additional dataset of individuals with an ICD-10 PDD diagnosis (Sample 3, N = 190). RESULTS: Sensitivity was highest in the Initial Algorithm, which had the poorest specificity. Although Youden J had excellent specificity, sensitivity was significantly lower than in the Modified Algorithm, which had both good sensitivity and specificity. Relaxing the domain A rules improved sensitivity of the Youden J Algorithm, but it remained less sensitive than the Modified Algorithm. Moreover, this was the only algorithm with variable sensitivity across age. All versions of the algorithm performed well across ability level. CONCLUSIONS: This study demonstrates that good levels of both sensitivity and specificity can be achieved for a diagnostic algorithm adhering to the DSM-5 criteria that is suitable across age and ability level.

Impact of the COVID-19 Pandemic on Daily Life: Diverse Experiences for Autistic Adults.

Using a mixed methods design, this study aimed to examine the impact of the COVID-19 pandemic on autistic and non-autistic adults. We conducted an online survey with 196 autistic and 228 non-autistic adults from Belgium, the Netherlands and the United Kingdom focusing on their experiences during the first period of the pandemic. Our results indicate rather diverse experiences within the group of autistic participants across all domains of life. In comparison with non-autistic adults, autistic adults reported less negative impact on their social life and more negative impact on health and support services. In the autism group, stress was mainly related to changing and unclear measures. A wide range of coping strategies were described as helpful in reducing stress during the pandemic.

Mental health of autistic adults during the COVID-19 pandemic: The impact of perceived stress, intolerance of uncertainty, and coping style.

LAY ABSTRACT: More and more research shows us that autistic individuals are at risk of experiencing mental health problems in response to the COVID-19 pandemic. However, little is known about why this is the case. At two timepoints during the pandemic, we asked 149 autistic and 147 non-autistic adults about feelings of anxiety, depression, and stress, and about characteristics that may explain why some (autistic) people have a larger chance of developing anxiety and depression during this pandemic. In our study, autistic adults experienced more anxiety and depression than non-autistic adults. Across autistic and non-autistic individuals, the people who experienced more stress at timepoint 1 experienced more anxiety and depression 4 months later. This was especially the case for those individuals who use maladaptive coping styles, such as denial or venting, and for those who have difficulties dealing with uncertain situations. Our findings show the burden of the COVID-19 pandemic on the mental health of autistic adults. Interventions to support autistic adults during and after the pandemic are needed, and they may want to focus on the negative impact of stress and teach autistic (and non-autistic) adults more adaptive ways to cope with stressful circumstances.

The complexity of early diagnostic decision making: A follow-up study of young children with language difficulties.

Background & aims: Due to the complexity of early diagnostic decision making, we examined the predictive value of an early diagnostic classification and early abilities on later best estimate diagnosis for 22 clinically referred children with language difficulties. Methods and procedures: Four years after initial evaluation (Time 1), the clinical files of these children were reviewed. A best-estimate (BE) diagnosis of language disorder (LD), intellectual disability (ID), or autism spectrum disorder (ASD) was established, with ASD being most common. Outcomes and results: Early clinical classifications were relatively unstable or difficult to establish at a young age. The magnitude of children's cognitive and receptive language delay was a significant predictor of a later BE diagnosis of ID and LD respectively. A BE diagnosis of ASD, by contrast, could not be predicted from children's early social communication problems nor the presence of restricted and repetitive behaviors and interests. Conclusions: Taken together, the results of this study suggest that language difficulties can be an early marker of a neurodevelopmental disorder which is often not identified at the age of first referral. Implications: Eligibility for treatment should, therefore, be based on biopsychosocial case formulation rather than DSM or ICD diagnostic classification. What this paper adds?: In this study a dimensional approach was used to characterize the abilities of young children referred with mild to profound receptive and/or expressive language difficulties. Later on, a categorical approach was adopted to establish best estimate diagnoses. Our clinical, broadly defined sample reflects the heterogeneous intake of young children referred for diagnostic assessment. Other studies on diagnostic stability often only focus on one diagnostic category (and are explicitly excluding children with specific other diagnoses), not taking into account the difficulties of early differential diagnostic decision making and stability across different categories over time. Investigations of differential diagnosis within a clinical group, instead of only differentiating children with a specific diagnosis from typically developing children, may be more informative for clinicians.

Do Parental Interviews for ASD Converge with Clinical Diagnoses? An Empirical Comparison of the 3di and the DISCO in Children with ASD, a Clinically-Referred Group, and Typically Developing Children.

Two semi-structured parental interviews are available with algorithms developed to measure DSM-5 criteria of ASD, namely the Developmental, Dimensional and Diagnostic Interview (3di) and the Diagnostic Interview for Social and Communication Disorders (DISCO-11). The main aim of this study was to examine the agreement between classification according to both interviews, and their convergence with the clinical diagnosis. Therefore, the 3di and DISCO-11 were administered from three groups of parents of a 4-18 year old. Results showed 75% agreement between both instruments, but in the ASD group only 16% of the children scored above threshold on both instruments. Exploratory analyses suggested that the 3di failed to detect rigid and repetitive behaviors, whereas the DISCO-11 was insufficiently sensitive in detecting socio-communicative problems.

Problem behavior in young children referred with language difficulties: Relations to language and intentional communication.

Background and aims: This exploratory study aims to examine the relative contribution of language and intentional communication to internalizing and externalizing problem behavior. Methods: Twenty-nine Dutch-speaking children (age range 24-46 months) referred with language difficulties participated in this study. For the majority of children, these early language difficulties appeared to be part of a broader neurodevelopmental disorder, mainly autism spectrum disorder. Parent ratings on the Achenbach Child Behavior Checklist 1½-5 were predicted from children's language level and intentional communicative abilities, the latter being assessed by both parent report and direct observation. In all series of hierarchical regression analyses, chronological age and nonverbal mental age were included as covariates. Results: Parents commonly reported withdrawal, emotionally reactive behavior, attention problems, and aggressive behavior. Parent-rated intentional communication was the most important predictor of internalizing problem behavior and played an important role in the prediction of aggressive behavior as well. However, chronological age and/or nonverbal mental age also predicted parent-rated levels of externalizing problem behavior, especially attention problems. Conclusions: The relation between language difficulties and problem behavior may be influenced by maturation and children's ability to communicate intentionally.Implications: Language proficiency should, therefore, be independently assessed from children's intentional communicative abilities which, in turn, may differ across contexts.

Describing the Profile of Diagnostic Features in Autistic Adults Using an Abbreviated Version of the Diagnostic Interview for Social and Communication Disorders (DISCO-Abbreviated).

The rate of diagnosis of autism in adults has increased over recent years; however, the profile of behaviours in these individuals is less understood than the profile seen in those diagnosed in childhood. Better understanding of this profile will be essential to identify and remove potential barriers to diagnosis. Using an abbreviated form of the Diagnostic Interview for Social and Communication Disorders, comparisons were drawn between the profile of a sample of able adults diagnosed in adulthood and the profile of a sample of able children. Results revealed both similarities and differences. A relative strength in non-verbal communication highlighted a potential barrier to diagnosis according to DSM-5 criteria for the adult sample, which may also have prevented them from being diagnosed as children.

ZNF462 and KLF12 are disrupted by a de novo translocation in a patient with syndromic intellectual disability and autism spectrum disorder.

We describe a patient with a de novo balanced translocation 46,XY,t(9; 13)(q31.2; q22.1) and autism spectrum disorder, intellectual disability, a metopic craniosynostosis, a corpus callosum dysgenesis and dysmorphic facial features, most notably ptosis. Breakpoint mapping was performed by means of targeted locus amplification (TLA) and sequencing, because conventional breakpoint mapping by means of fluorescent in situ hybridization and long-range PCR was hampered by a complex submicroscopic rearrangement. The translocation breakpoints directly affected the genes KLF12 (chromosome 13) and ZNF462 (chromosome 9). The latter gene was disrupted by multiple breakpoints, resulting in the loss of three fragments and a rearrangement of the remaining fragments. Therefore, haploinsufficiency of ZNF462 was assumed. Loss-of-function variants in ZNF462 have recently been published by Weiss et al. (2017) in a series of eight patients from six independent families delineating the ZNF462-associated phenotype. The latter closely matches with the clinical features of the current translocation patient. Besides, no direct evidence for an association of KLF12 to the phenotypic features was found. Therefore, we conclude that the phenotype of the current patient is mainly caused by the disruption of ZNF462. We present clinical data from birth to adulthood and data on the cognitive and behavioral profile of the current patient which may add to a more precise counseling and surveillance of development in young children with ZNF462 mutations. In addition, the current case illustrates that TLA is an efficient method for determining complex chromosomal breakpoints.

Parenting Behavior in Mothers of Preschool Children with ASD: Development of a Self-Report Questionnaire.

Parents of young children with autism spectrum disorder (ASD) encounter many daily challenges and often experience much stress. However, little research exists about parenting behavior among these parents. With this study, we aim to address this gap. We examined the structure and internal consistency of a questionnaire intended to measure parenting behavior among mothers of young children with ASD. Furthermore, we compared parenting behavior among mothers of young children with and without ASD between two and six years old. Factor analyses resulted in a factor solution with seven subscales of parenting behavior. Two additional subscales especially relevant for parenting preschoolers with ASD were also considered. Analyses of covariance, controlling for gender and age, showed significantly higher scores for Discipline and Stimulating the Development in the control group in comparison with the ASD group. These findings suggest that mothers of preschoolers with ASD are still trying to find strategies to guide and stimulate their child's behavior and development effectively.

Mothers' Parenting Behaviors in Families of School-Aged Children with Autism Spectrum Disorder: An Observational and Questionnaire Study.

Although parents of children with ASD face specific challenges in parenting, only a few studies have empirically investigated parenting behaviors among these parents. The current study examined differences in parenting behaviors between mothers of school-aged children with ASD (n = 30) and mothers of typically developing children (n = 39), using both an observational measure and a self-report questionnaire. Results indicated that mothers of children with ASD obtained significantly lower scores on Sensitivity and Provision of structure as measured during the observation. They reported significantly higher scores on Material rewarding and Adapting the environment on the questionnaire. When controlling for parenting stress, the group differences on Sensitivity and Material rewarding did not remain significant.

Maternal parenting behavior and child behavior problems in families of children and adolescents with autism spectrum disorder.

Parents of a child with autism spectrum disorder (ASD) face specific challenges in parenting, but concrete parenting behavior has never been properly investigated in these families. This exploratory questionnaire study compared parenting behaviors among mothers of children and adolescents with ASD (n = 552) and without ASD (n = 437) and examined associations between child behavior problems and parenting behavior. Results showed that mothers of children with ASD reported significantly lower scores on Rules and Discipline and higher scores on Positive Parenting, Stimulating the Development, and Adapting the Environment. Age was differently related to parenting behavior in the ASD versus control group. Furthermore, distinctive correlation patterns between parenting behavior and externalizing or internalizing behavior problems were found for both groups.

Young children with language difficulties: a dimensional approach to subgrouping.

A dimensional approach was used to create bottom-up constructed subgroups that captured the behavioral heterogeneity in 36 Dutch-speaking children with language difficulties. Four subgroups were delineated based upon differences in cognitive ability, symbol understanding, joint attention and autism spectrum disorder related characteristics. Children with a different developmental disorder were found within a single cluster. Therefore, the results of this study suggest that bottom-up constructed subgroups might capture the heterogeneous behavioral profiles of young children with developmental difficulties in a more meaningful way. Furthermore, joint attention and symbol understanding seem important skills to assess in young children presenting with language difficulties.

Language in low-functioning children with autistic disorder: differences between receptive and expressive skills and concurrent predictors of language.

Language profiles of children with autistic disorder and intellectual disability (n = 36) were significantly different from the comparison groups of children with intellectual disability (n = 26) and typically developing children (n = 34). The group low-functioning children with autistic disorder obtained a higher mean score on expressive than on receptive language, whereas both comparison groups showed the reverse pattern. Nonverbal mental age, joint attention, and symbolic understanding of pictures were analyzed in relation to concurrent receptive and expressive language abilities. In the group with autistic disorder and intellectual disability, symbol understanding and joint attention were most strongly related to language abilities. Nonverbal mental age was the most important predictor of language abilities in the comparison groups.

Evaluation of the criterion and convergent validity of the Diagnostic Interview for Social and Communication Disorders in young and low-functioning children.

The Diagnostic Interview for Social and Communication Disorders (DISCO; Wing, 2006) is a standardized, semi-structured and interviewer-based schedule for diagnosis of autism spectrum disorder (ASD). The objective of this study was to evaluate the criterion and convergent validity of the DISCO-11 ICD-10 algorithm in young and low-functioning children. The DISCO-11, Autism Diagnostic Observation Schedule (ADOS), and Social Communication Questionnaire (SCQ) were administered to a Dutch sample of 115 children comprising 52 children with ASD (both with and without intellectual disability), 26 children with intellectual disability (non-ASD), and 37 typically developing children. Results indicated high sensitivity and specificity for DISCO-11 classifications in differentiating ASD from non-ASD according to the clinical classification in children with mild intellectual disability or average intelligence. Among children with a moderate or severe intellectual disability the sensitivity was equally high, but the specificity was significantly lower. The agreement between DISCO-11 and ADOS classifications was substantial, between DISCO-11 and SCQ moderate. The correlations between raw scores of the DISCO and ADOS algorithm or SCQ were both high. In conclusion, the DISCO-11 differentiates accurately between autistic disorder and non-ASD in young children with an average intelligence or mild intellectual disability, but is over inclusive in the lower levels of intellectual disability.