Anxiety is common in children with ASD; however, the burden of specific anxiety disorders for adults with ASD is under-researched. Using the Stockholm Youth Cohort, we compared anxiety disorder ...diagnoses among autistic adults (n = 4049), with or without intellectual disability, and population controls (n = 217,645). We conducted additional sibling analyses. Anxiety disorders were diagnosed in 20.1% of adults with ASD compared with 8.7% of controls (RR = 2.62 95% CI 2.47–2.79), with greatest risk for autistic people without intellectual disability. Rates of almost all individual anxiety disorders were raised, notably obsessive–compulsive disorder and phobic anxiety disorders. Anxiety disorders were more common in full siblings and half-siblings of people with ASD. The implications of this are explored.
Children and young people with intellectual disability and/or Autism Spectrum Disorder (autism) experience higher rates of mental health problems, including depression, than their typically ...developing peers. Although international guidelines suggest psychological therapies as first-line intervention for children and young people, there is limited evidence for psychological therapy for depression in children and young people with intellectual disability and/or autism.
To evaluate the current evidence base for psychological interventions for depression in children and young people with intellectual disability and/or autism, and examine the experiences of children and young people with intellectual disability and/or autism, their families and therapists, in receiving and delivering psychological treatment for depression.
Databases were searched up to 30 April 2020 using pre-defined search terms and criteria. Articles were independently screened and assessed for risk of bias. Data were synthesised and reported in a narrative review format.
A total of 10 studies met the inclusion criteria. Four identified studies were clinical case reports and six were quasi-experimental or experimental studies. All studies were assessed as being of moderate or high risk of bias. Participants with intellectual disability were included in four studies. There was limited data on the experiences of young people, their families or therapists in receiving or delivering psychological treatment for depression.
Well-designed, randomised controlled trials are critical to develop an evidence base for psychological treatment for young people with intellectual disability and/or autism with depression. Future research should evaluate the treatment experiences of young people, their families and therapists.
Genome sequencing (GS) has been used in the diagnosis of global developmental delay (GDD)/intellectual disability (ID). However, the performance of GS in patients with inconclusive results from ...chromosomal microarray analysis (CMA) and exome sequencing (ES) is unknown. We recruited 100 pediatric GDD/ID patients from multiple sites in China from February 2018 to August 2020 for GS. Patients have received at least one genomic diagnostic test before enrollment. Reanalysis of their CMA/ES data was performed. The yield of GS was calculated and explanations for missed diagnoses by CMA/ES were investigated. Clinical utility was assessed by interviewing the parents by phone. The overall diagnostic yield of GS was 21%. Seven cases could have been solved with reanalysis of ES data. Thirteen families were missed by previous CMA/ES due to improper methodology. Two remained unsolved after ES reanalysis due to complex variants missed by ES, and a CNV in untranslated regions. Follow‐up of the diagnosed families revealed that nine families experienced changes in clinical management, including identification of targeted treatments, cessation of unnecessary treatment, and considerations for family planning. GS demonstrated high diagnostic yield and clinical utility in this undiagnosed GDD/ID cohort, detecting a wide range of variant types of different sizes in a single workflow.
GS demonstrates high diagnostic yield in children with undiagnosed GDD/ID
White‐Sutton syndrome (WHSUS) is a recently‐identified genetic disorder resulting from de novo heterozygous pathogenic variants in POGZ. Thus far, over 50 individuals have been reported worldwide, ...however phenotypic characterization and data regarding the natural history are still incomplete. Here we report the clinical features of 22 individuals with 21 unique loss of function POGZ variants. We observed a broad spectrum of intellectual disability and/or developmental delay with or without autism, and speech delay in all individuals. Other common problems included ocular abnormalities, hearing loss and gait abnormalities. A validated sleep disordered breathing questionnaire identified symptoms of obstructive sleep apnea in 4/12 (33%) individuals. A higher‐than‐expected proportion of cases also had gastrointestinal phenotypes, both functional and anatomical, as well as genitourinary anomalies. In line with previous publications, we observed an increased body mass index (BMI) z‐score compared to the general population (mean 0.59, median 0.9; p 0.0253). Common facial features included microcephaly, broad forehead, midface hypoplasia, triangular mouth, broad nasal root and flat nasal bridge. Analysis of the Baylor Genetics clinical laboratory database revealed that POGZ variants were implicated in approximately 0.14% of cases who underwent clinical exome sequencing for neurological indications with or without involvement of other body systems. This study describes a greater allelic series and expands the phenotypic spectrum of this new syndromic form of intellectual disability and autism.
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.
Lay Summary
DYRK1A syndrome has been identified as a genetic cause of autism spectrum disorder (ASD). We found that individuals with DYRK1A syndrome had high rates of ASD and intellectual disability (ID). Individuals with DYRK1A syndrome showed many similarities in ASD traits when compared to individuals with ASD and ID without a known genetic cause, but individuals with DYRK1A syndrome showed particular differences in social reciprocity, nonverbal communication, and sensory‐seeking behaviors.
ABSTRACT
De novo mutations in SYNGAP1, which codes for a RAS/RAP GTP‐activating protein, cause nonsyndromic intellectual disability (NSID). All disease‐causing point mutations identified until now in ...SYNGAP1 are truncating, raising the possibility of an association between this type of mutations and NSID. Here, we report the identification of the first pathogenic missense mutations (c.1084T>C p.W362R, c.1685C>T p.P562L) and three novel truncating mutations (c.283dupC p.H95PfsX5, c.2212_2213del p.S738X, and (c.2184del p.N729TfsX31) in SYNGAP1 in patients with NSID. A subset of these patients also showed ataxia, autism, and a specific form of generalized epilepsy that can be refractory to treatment. All of these mutations occurred de novo, except c.283dupC, which was inherited from a father who is a mosaic. Biolistic transfection of wild‐type SYNGAP1 in pyramidal cells from cortical organotypic cultures significantly reduced activity‐dependent phosphorylated extracellular signal‐regulated kinase (pERK) levels. In contrast, constructs expressing p.W362R, p.P562L, or the previously described p.R579X had no significant effect on pERK levels. These experiments suggest that the de novo missense mutations, p.R579X, and possibly all the other truncating mutations in SYNGAP1 result in a loss of its function. Moreover, our study confirms the involvement of SYNGAP1 in autism while providing novel insight into the epileptic manifestations associated with its disruption.
We identified the first pathogenic de novo missense mutations (p.W362R, p.P562L) and three novel truncating mutations in SYNGAP1 in patients with non‐syndromic intellectual disability (NSID) with or without autism or epilepsy. Both missense mutations and the previously described p.R579X impaired SYNGAP1 ability to reduce pERK levels in transfected cortical organotypic cultures, suggesting a possible loss of SYNGAP1 function. Moreover, our study confirms the involvement of SYNGAP1 in autism while providing novel insight into the epileptic manifestations associated with its disruption.
Intellectual disability (ID) and autism spectrum disorder (ASD) are two of the most common neurodevelopmental disorders. Both disorders are extremely heterogenous, and only ~ 40% of reported cases ...have so far been attributed to genetic mutations. Of the many cellular processes that are affected, the ubiquitin system (UbS) is of particular relevance in that it can rapidly regulate multiple signaling cascades simultaneously. The UbS is a post-translational modification process that revolves around the covalent attachment of a ubiquitin moiety to a substrate, thereby influencing different elements of protein biology, including trafficking, signal transduction, and degradation. Importantly, the UbS has been implicated in regulating multiple pathophysiological pathways related to ASD and ID. This review will discuss how the UbS acts as major signaling hub in the pathogenesis of ASD and ID, raising the prospect of treating broader patient cohorts by targeting the UbS as a common point of convergence of various mutations.
Identifying and characterizing novel causes of autosomal recessive intellectual disability based on systematic clinical and genetic evaluation, followed by functional experiments.
Clinical ...examinations, genome-wide positional mapping, and sequencing were followed by quantitative polymerase chain reaction and western blot of the protein SVBP and its interaction partners. We then knocked down the gene in rat primary hippocampal neurons and evaluated the consequences on synapses.
We identified a founder, homozygous stop-gain variant in SVBP (c.82C>T; p.Gln28*) in four affected individuals from two independent families with intellectual disability, microcephaly, ataxia, and muscular hypotonia. SVBP encodes a small chaperone protein that transports and stabilizes two angiogenesis regulators, VASH1 and VASH2. The altered protein is unstable and nonfunctional since transfected HeLa cells with mutant SVBP did not reveal evidence for immunoreactive SVBP protein fragments and cotransfection with VASH1 showed a severe reduction of VASH1 in medium and cell lysate. Knocking down Svbp in rat primary hippocampal neurons led to a significant decrease in the number of excitatory synapses.
SVBP is not only involved in angiogenesis, but also has vital functions in the central nervous system. Biallelic loss-of-function variants in SVBP lead to intellectual disability.
Duplications of the Xq28 region are a common cause of X‐linked intellectual disability (XLID). The RAB39B gene locates in Xq28 and has been implicated in disease pathogenesis. However, whether ...increased dosage of RAB39B leads to cognitive impairment and synaptic dysfunction remains elusive. Herein, we overexpressed RAB39B in mouse brain by injecting AAVs into bilateral ventricles of neonatal animals. We found that at 2 months of age, neuronal overexpression of RAB39B impaired the recognition memory and the short‐term working memory in mice and resulted in certain autism‐like behaviours, including social novelty defect and repetitive grooming behaviour in female mice. Moreover, overexpression of RAB39B decreased dendritic arborization of primary neurons in vitro and reduced synaptic transmission in female mice. Neuronal overexpression of RAB39B also altered autophagy without affecting levels and PSD distribution of synaptic proteins. Our results demonstrate that overexpression of RAB39B compromises normal neuronal development, thereby resulting in dysfunctional synaptic transmission and certain intellectual disability and behavioural abnormalities in mice. These findings identify a molecular mechanism underlying XLID with increased copy numbers of Xq28 and provide potential strategies for disease intervention.
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