Putatively benign copy number variants in subjects with idiopathic autism spectrum disorder and/or intellectual disability

The intersection of autism spectrum disorder and intellectual disability

Editorial: Introduction to Special Section on Evidence-Based Practices for Persons With Intellectual and Developmental Disabilities

BackgroundRASopathies are genetic syndromes that result from pathogenic variants in the RAS-MAPK cellular signaling pathway. These syndromes, which include neurofibromatosis type 1, Noonan syndrome, cardiofaciocutaneous syndrome, and Costello syndrome, are associated with a complex array of medical and behavioral health complications. Despite a heightened risk for social challenges and autism spectrum disorder (ASD), few studies have compared different aspects of social behavior across these conditions. It is also unknown whether the underlying neuropsychological characteristics that contribute to social competence and socially empathetic (“prosocial”) behaviors differ in children with RASopathies as compared to children with nonsyndromic (i.e., idiopathic) ASD.MethodsIn this cross-sectional, survey-based investigation, caregivers of preschool and school-aged children with RASopathies (n = 202) or with idiopathic ASD (n = 109) provided demographic, medical, and developmental information about their child, including psychiatric comorbidities. For children who were able to communicate verbally, caregivers also completed standardized rating scales to assess social competence and empathetic behavior as well as symptoms of hyperactivity/inattention and emotional problems.ResultsAs compared to children with idiopathic ASD, children with RASopathies were rated as demonstrating more resilience in the domain of empathy relative to their overall social competence. Similarities and differences emerged in the psychological factors that predicted social behavior in these two groups. Stronger communication skills and fewer hyperactive-impulsive behaviors were associated with increased empathy and social competence for both groups. Greater emotional challenges were associated with lower social competence for children with RASopathies and stronger empathy for children with idiopathic ASD. Among children with RASopathy and a co-occurring ASD diagnosis, socially empathetic behaviors were observed more often as compared to children with idiopathic ASD.ConclusionsFindings suggest that the development of social behavior among children with RASopathies involves a distinct pattern of strengths and weaknesses as compared to a behaviorally defined disorder (idiopathic ASD). Identification of areas of resilience as well as behavioral and social challenges will support more targeted intervention.

BackgroundA crucial step to understanding the mechanistic underpinnings of autism spectrum disorder (ASD), is to examine if the biological underpinnings of ASD in genetic high-risk conditions, like 22q11.2 deletion syndrome (22q11.2DS), are similar to those in idiopathic illness. This study aimed to examine if ASD symptomatology in 22q11.2DS is underpinned by the same—or distinct—neural systems that mediate these symptoms in non-deletion carriers.MethodsWe examined vertex-wise estimates of cortical volume (CV), surface area (SA), and cortical thickness across 131 individuals between 6 and 25 years of age including (1) 50 individuals with 22q11.2DS, out of which n = 25 had a diagnosis of ASD, (2) 40 non-carriers of the microdeletion with a diagnosis of ASD (i.e., idiopathic ASD), and (3) 41 typically developing (TD) controls. We employed a 2-by-2 factorial design to identify neuroanatomical variability associated with the main effects of 22q11.2DS and ASD, as well as their interaction. Further, using canonical correlation analysis (CCA), we compared neuroanatomical variability associated with the complex (i.e., multivariate) clinical phenotype of ASD between 22q11.2 deletion carriers and non-carriers.ResultsThe set of brain regions associated with the main effect of 22q11.2DS was distinct from the neuroanatomical underpinnings of the main effect of ASD. Moreover, significant 22q11.2DS-by-ASD interactions were observed for CV and SA in the dorsolateral prefrontal cortex, precentral gyrus, and posterior cingulate cortex, suggesting that the neuroanatomy of ASD is significantly modulated by 22q11.2DS (p < 0.01). We further established that the multivariate patterns of neuroanatomical variability associated with differences in symptom profiles significantly differed between 22q11.2 deletion carriers and non-carriers.LimitationsWe employed a multicenter design to overcome single-site recruitment limitations; however, FreeSurfer-derived measures of surface anatomy have been shown to be highly reliable across scanner platforms and field strengths. Further, we controlled for gender to address the differing distribution between idiopathic ASD individuals and the other groups. Nonetheless, the gender distribution in our sample reflects that of the respective populations, adding to the generalizability of our results. Last, we included individuals with a relatively wide age range (i.e., 6–25 years).ConclusionsOur findings indicate that neuroanatomical correlates of ASD symptomatology in carriers of the 22q11.2 microdeletion diverge from those in idiopathic ASD.

To assess to what extent child neurologists (CNs) and developmental-behavioral pediatricians (DBPs) order diagnostic tests that are not recommended/indicated and/or fail to order tests that are recommended/indicated when evaluating children with an autism spectrum disorder (ASD). CNs and DBPs in the United States were asked which laboratory tests they would "routinely order" for a preschool child with ASD and IQ = 58 (ASD + Intellectual Disability (ID)), and a preschool child with ASD and IQ = 85 (ASD-ID). Chi-square tests were performed to identify differences (CNs vs DBPs) in laboratory testing. The sample consisted of 267 respondents (127 CN's; 140 DBPs). When evaluating ASD + ID or ASD - ID, inappropriate tests (≥1) were ordered by 76.8% and 76.4% of MDs, respectively. There was no significant difference between specialties in compliance with evaluation guidelines for ASD + ID (CN = 20.5% vs DBP = 16.4%; χ = 0.73). No significant differences were noted (DBP vs CN) regarding the percent ordering inappropriate tests for either clinical case or within each specialty when comparing testing for ASD + ID versus ASD - ID. Relative to DBPs, CNs were more likely to order EEGs and MRIs when evaluating children with ASD + ID or ASD - ID. 10% and 40% of respondents did not order any recommended genetic tests when evaluating ASD + ID and ASD - ID, respectively. When evaluating children with ASD, many CNs and DBPs fail to order tests that should be routinely performed and often order tests that are not routinely indicated yet are neither benign nor inexpensive. Recommended molecular genetic tests are often not ordered. Clinical guidelines must be updated and better promulgated.

Autism spectrum disorder (ASD) is a behaviorally defined disorder that is now thought to affect approximately 1 in 69 children in the United States. In most cases, the etiology is unknown, but several studies point to the interaction of genetic predisposition with environmental factors. The immune system is thought to have a causative role in ASD, and specific studies have implicated T lymphocytes, monocytes, natural killer (NK) cells, and certain cytokines. The human leukocyte antigen (HLA) system is involved in the underlying process for shaping an individual’s immune system, and specific HLA alleles are associated with specific diseases as risk factors. In this study, we determine whether a specific HLA allele was associated with ASD in a large cohort of patients with ASD. Identifying such an association could help in the identification of immune system components which may have a causative role in specific cohorts of patients with ASD who share similar specific clinical features. Specimens from 143 patients with ASD were analyzed with respect to race and ethnicity. Overall, HLA-Cw7 was present in a much greater frequency than expected in individuals with ASD as compared to the general population. Further, the cohort of patients who express HLA-Cw7 shares specific immune system/inflammatory clinical features including being more likely to have allergies, food intolerances, and chronic sinusitis as compared to those with ASD who did not express HLA-Cw7. HLA-Cw7 has a role in stimulating NK cells. Thus, this finding may indicate that chronic over-activation of NK cells may have a role in the manifestation of ASD in a cohort of patients with increased immune system/inflammatory features.

Reports of unrelated individuals with autism spectrum disorder (ASD) and similar clinical features having overlapping de novo interstitial deletions at 2p15-p16.1 suggest that this region harbors a gene(s) important to the development of autism. We molecularly characterized two such deletions, selecting two genes in this region, exportin 1 (XPO1) and orthodenticle homolog 1 (OTX1) for association studies in three North American cohorts (Autism Spectrum Disorder - Canadian American Research Consortium (ASD-CARC), New York, and Autism Genetic Resource Exchange (AGRE)) and one Italian cohort (Società Italiana per la Ricerca e la Formazione sull'Autismo (SIRFA)) of families with ASD. In XPO1, rs6735330 was associated with autism in all four cohorts (P<0.05), being significant in ASD-CARC cohorts (P-value following false discovery rate correction for multiple testing (P(FDR))=1.29 × 10(-5)), the AGRE cohort (P(FDR)=0.0011) and the combined families (P(FDR)=2.34 × 10(-9)). Similarly, in OTX1, rs2018650 and rs13000344 were associated with autism in ASD-CARC cohorts (P(FDR)=8.65 × 10(-7) and 6.07 × 10(5), respectively), AGRE cohort (P(FDR)=0.0034 and 0.015, respectively) and the combined families (P(FDR)=2.34 × 10(-9) and 0.00017, respectively); associations were marginal or insignificant in the New York and SIRFA cohorts. A significant association (P(FDR)=2.63 × 10(-11)) was found for the rs2018650G-rs13000344C haplotype. The above three SNPs were associated with severity of social interaction and verbal communication deficits and repetitive behaviors (P-values <0.01). No additional deletions were identified following screening of 798 ASD individuals. Our results indicate that deletion 2p15-p16.1 is not commonly associated with idiopathic ASD, but represents a novel contiguous gene syndrome associated with a constellation of phenotypic features (autism, intellectual disability, craniofacial/CNS dysmorphology), and that XPO1 and OXT1 may contribute to ASD in 2p15-p16.1 deletion cases and non-deletion cases of ASD mapping to this chromosome region.

Meta-analyses suggest an association between autism spectrum disorder (ASD) and obesity, but the factors underlying this association remain unclear. This study investigated the association between ASD and obesity stratified on intellectual disability (ID). In addition, in order to gain insight into possible shared etiological factors, the potential role of shared familial liability was examined. We studied a cohort of 3,141,696 individuals by linking several Swedish nationwide registers. We identified 35,461 individuals with ASD and 61,784 individuals with obesity. Logistic regression models were used to estimate the association between ASD and obesity separately by ID and sex and by adjusting for parental education, psychiatric comorbidity, and psychotropic medication. Potential shared familial etiologic factors were examined by comparing the risk of obesity in full siblings, maternal and paternal half-siblings, and full- and half-cousins of individuals with ASD to the risk of obesity in relatives of individuals without ASD. Individuals with ASD + ID (OR = 3.76 [95% CI, 3.38-4.19]) and ASD-ID (OR = 3.40 [95% CI, 3.23-3.58]) had an increased risk for obesity compared with individuals without ASD. The associations remained statistically significant when adjusting for parental education, psychiatric comorbidity, and medication. Sex-stratified analyses indicated a higher relative risk for males compared with females, with statistically significant interaction effects for ASD-ID, but not for ASD+ID in the fully adjusted model. First-degree relatives of individuals with ASD+ID and ASD-ID had an increased risk of obesity compared with first-degree relatives of individuals without ASD. The obesity risk was similar in second-degree relatives of individuals with ASD+ID but was lower for and ASD-ID. Full cousins of individuals with ASD+ID had a higher risk compared with half-cousins of individuals with ASD+ID). A similar difference in the obesity risk between full cousins and half-cousins was observed for ASD-ID. Individuals with ASD and their relatives are at increased risk for obesity. The risk might be somewhat higher for males than females. This warrants further studies examining potential common pleiotropic genetic factors and shared family-wide environmental factors for ASD and obesity. Such research might aid in identifying specific risks and underlying mechanisms in common between ASD and obesity.

Sensory processing disorders have been linked to stereotypical behaviours in children with intellectual disability (ID) and autism spectrum disorders (ASD) and to anxiety in children with ASD. In earlier phases of this study with the same participants, we found that those with both ASD and ID were more motivated than those with ID alone to engage in stereotypical behaviour to alleviate anxiety. In this phase, we confirmed that children with both ASD and ID and those with ID alone process sensation differently than typically developing children. We asked: Do the sensory processing difficulties of children with ASD and ID differ significantly from those of children with ID alone in a way that would help explain the increased anxiety of the former group? Parents of children with ASD and ID (n = 29; mean age 9.7 years) and with ID alone (n = 23; mean age 9.5 years) completed a Sensory Profile (SP) to provide information about their children's sensory processing abilities. SP quadrant scores for each group were compared with each other and with the published norms of typically developing children. Children with ASD and ID and with ID alone processed sensory information differently than typically developing children (P=0.0001;d= >2.00). Children with both ASD and ID were significantly more sensitive (P=0.007;d=0.70) and avoidant (P < 0.05;d=0.47) than the children with ID alone. We conclude that increased sensitivity and the tendency to avoid sensation may help explain anxiety in children with autism.

BackgroundSmall sample sizes have constrained the examination of dementia subtypes in Autism Spectrum Disorder (ASD) compared to other groups. Data from Medicaid and Medicare, which enroll tens of millions of Americans, can address this limitation and support identification of system‐level improvements to address needs of those with ASD and co‐occurring dementia. This study sought to examine dementia subtypes among autistic individuals compared to other groups.MethodIndividually‐linked national Medicare and Medicaid data from 2014–2016 included individuals age 30 and older with dementia from mutually exclusive groups with ASD (2,229 with no intellectual disability (ID), 4,263 with ID), 52,198 with ID, 1,199 with Down Syndrome (DS), and a random sample of 237,009 individuals without these diagnoses (RS). The validated Bynum algorithm was organized into the subtypes shown in Table 1. The last observed dementia diagnosis was used for dementia subtype. Following preliminary analyses showing similar data for those with ASD with and without ID, a single ASD category (ASD only and ASD+ID) was used.ResultUnspecified dementia represented the largest proportion of cases for all groups (50.0% for ASD, 56.3% for ID, 42.1% for DS, and 54.3% for RS). The ASD group had the lowest proportion of Alzheimer's disease cases (11.7%), compared to ID (14.2%), DS (32.2%), and RS (22%). Senile dementia represented a larger proportion of ASD dementia cases (11.5%) than the other categories combined (ID=1.5%, DS=0%, RS=0.1%). The relative proportion of other dementia subtypes did not differ substantially between ASD versus ID.The proportion of all dementia subtypes among autistic females was an average of 25% lower than females in RS. A lower proportion of all dementia cases in non‐white adults was observed for ASD compared to RS.ConclusionExamination of dementia subtypes suggests a lower proportion of Alzheimer's disease and a higher proportion of Senile dementia in ASD compared to other populations under examination, whereas the proportion of other dementia subtypes was generally aligned with that of participants with ID. Non‐white adults might be misdiagnosed or underdiagnosed in the ASD population, pointing to the possibility of ASD‐specific service implications amid the backdrop of rising dementia cases nationally.

ABSTRACTOver the past 10 years, research has suggested no negative effect on second language exposure in children with autism spectrum disorder (ASD), yet, parents and professionals may be concerned that using a second language with a child with ASD may negatively impact their communication and cognitive skills, especially if the child also has an intellectual disability. In this study, 396 children and adolesents (5–16 years) with and without ASD and with and without second language exposure participated in the study. Parents reported on language exposure and rated executive function (EF) and functional communication (FC) skills using a standardized questionnaire. IQ was directly measured using the WASI‐II and children were classified as having an intellectual disability if they had a full‐scale score of less than 70. The sample included 18 children with ASD and an intellectual disability (10 without second language exposure, 8 with second language exposure). Results showed that children with ASD and second language exposure had significantly better EF skills and were significantly less likely to have executive dysfunction in the clinical range than children with ASD with no second language exposure. Second language exposure also did not have a negative impact on EF skills in children with ASD even when an intellectual disability was present. For FC skills, we failed to find significant difference between children with ASD with and without second language exposure. For children with ASD and intellectual disability, there was no significant difference on FC skills between children with and without second language exposure. As our sample of children with ASD and intellectual disability was small, additional research with a larger sample is urgently needed.

The ComFor study has indicated that individuals with intellectual disability (ID) and autism spectrum disorder (ASD) show enhanced visual local processing compared with individuals with ID only. Items of the ComFor with meaningless materials provided the best discrimination between the two samples. These results can be explained by the weak central coherence account. The main focus of the present study is to examine whether enhanced visual perception is also present in low-functioning deaf individuals with and without ASD compared with individuals with ID, and to evaluate the underlying cognitive style in deaf and hearing individuals with ASD. Different sorting tasks (selected from the ComFor) were administered from four subsamples: (1) individuals with ID (n = 68); (2) individuals with ID and ASD (n = 72); (3) individuals with ID and deafness (n = 22); and (4) individuals with ID, ASD and deafness (n = 15). Differences in performance on sorting tasks with meaningful and meaningless materials between the four subgroups were analysed. Age and level of functioning were taken into account. Analyses of covariance revealed that results of deaf individuals with ID and ASD are in line with the results of hearing individuals with ID and ASD. Both groups showed enhanced visual perception, especially on meaningless sorting tasks, when compared with hearing individuals with ID, but not compared with deaf individuals with ID. In ASD either with or without deafness, enhanced visual perception for meaningless information can be understood within the framework of the central coherence theory, whereas in deafness, enhancement in visual perception might be due to a more generally enhanced visual perception as a result of auditory deprivation.

PurposeChildren and young people with comorbid intellectual disabilities (ID) and autism spectrum disorders (ASD) are more likely to exhibit comorbid mental health disorders (MHD) and other significant behaviours (SB) in addition to the core symptoms of ASD. The purpose of this paper is to identify the prevalence of comorbid MHD and behaviours in children and young people with ID and ASD in Egypt.Design/methodology/approachThe Reiss scale for children’s dual diagnosis was administered by parents and teachers of 222 Egyptian children and young people with mild/moderate ID and ASD to screen for MHD and SB. The mean age of children and young people was 12.3 years (SD = 3.64), with 75.6 per cent male.FindingsThe results revealed that 62.2 per cent of children and young people with ID and ASD had high rates of comorbid MHD and behaviour disorders were shown in 64.4 per cent of the participated children and young people. The results identified anger, anxiety and psychosis being the most frequently diagnosed disorders while crying spells and pica were the most SB. No differences were found between the male and female with ID and ASD in the current study.Research limitations/implicationsMental health assessment of children and young people with ID and ASD will help to highlight the needs of these vulnerable children and develop the appropriate services.Originality/valueThe findings highlight the prevalence of MHD in children and young people with ID and ASD in Egypt. This has implications on the assessment of comorbid disorders and services needed for children with ID and ASD in Egypt.

WPA Working Group on Defining and Managing Autism Spectrum Disorder: spreading knowledge for the next generations of psychiatrists.

Back to table of contents Previous article Next article Clinical and Research NewsFull AccessJournal DigestVabren WattsVabren WattsSearch for more papers by this authorPublished Online:26 Oct 2015https://doi.org/10.1176/appi.pn.2015.10b8Study Reveals Differences Between Girls, Boys with AutismJezper/ShutterstockThe brains of girls with autism spectrum disorder (ASD) appear to differ from boys with ASD, according to a study published in Molecular Autism. The study also revealed behavioral differences between the two groups. Researchers conducted two separate analyses, with data extrapolated from the National Database for Autism Research and Autism Brain Imaging Data Exchange. In the first analysis, the severity of ASD symptoms was examined in nearly 128 girls with ASD and 614 boys with the disorder. Compared with the boys, girls with ASD showed less severe repetitive/restricted behaviors and comparable deficits in social and communications domains on the Autism Diagnostic Interview, Revised (ADI-R). The researchers then examined symptom severity and structural imaging data obtained from 25 girls with ASD, 25 boys with ASD, and 19 girls and 19 boys without ASD. The researchers found that gray matter (GM) in the cortex, supplementary motor area (SMA), cerebellum, fusiform gyrus, and amygdala accurately discriminated girls and boys with ASD. They also found that the GM morphometry in the motor cortex, SMA, and cerebellum was correlated with scores on the repetitive/restricted behaviors domain of the ADI-R.“Our findings not only provide evidence for distinct behavioral phenotypes in girls with ASD, compared with boys, but also link behavioral differences to brain structure. Importantly, the severity of repetitive/restricted behaviors is lower in girls with ASD and is associated with sex differences in GM morphometry in cortical and cerebellar regions involved in motor control,” the researchers wrote. Supekar K and Menon V. Sex Differences in Structural Organization of Motor Systems and Their Dissociable Links With Repetitive/Restricted Behaviors in Children With Autism. Mol Autism. 2015 Sep 4;6:50.Smoke-Free Laws, Cigarette Taxes Deter Youth From SmokingPi-Lens/ShutterstockSmoke-free zone laws and higher taxes on cigarettes appear to deter young adults from smoking, according to a recent report in JAMA Pediatrics.Researchers from the University of California, San Francisco, tracked the smoking habits of youth aged 12 to 18 who participated in the 1997 Bureau of Labor Statistics National Longitudinal Survey of Youth for 11 years.The researchers found that youth living in places with laws for 100 percent smoke-free workplaces were 34 percent less likely to initiate smoking than youth living in places without such bans. Youth living in areas with 100 percent smoke-free bar laws were 20 percent less likely to be smokers and those who were smokers, spent fewer days smoking.The researchers also found that tax hikes on cigarettes deterred youth from smoking, with each 10-cent tax hike associated with a 3 percent drop in the odds of starting to smoke.The researchers noted that the current findings suggest that not only do smoking laws “protect bystanders from secondhand smoke, but also contribute to less smoking among adolescents and young adults.” Song A, Dutra L, Neilands T, et al. Association of Smoke-Free Laws With Lower Percentages of New and Current Smokers Among Adolescents and Young Adults: An 11-Year Longitudinal Study. JAMA Pediatr. 2015. 169(9):e152285.Multimorbidity May Be Associated With Greater Risk of MCI, DementiaRobert Kneschke/ShutterstockHaving multiple chronic conditions may be linked to an increased risk of mild cognitive impairment (MCI) or dementia, the Journal of the American Geriatrics Society reports. Researchers from the Mayo Clinic followed 2,176 seniors aged 70 to 89 without dementia for about 5 years to determine if an association existed between multiple chronic conditions and risk of mild cognitive impairment (MCI) and dementia.The results showed that participants with more than one chronic condition were 38 percent more likely to develop MCI or dementia than those with one or no chronic conditions. Participants with four or more chronic conditions had a 61 percent increased risk of MCI or dementia. Additionally, men with multiple chronic conditions were significantly more likely to develop MCI or dementia than women with equivalent numbers of chronic conditions.These findings are “consistent with the hypothesis that multiple etiologies may contribute to MCI and late-life dementia,” the researchers noted. Preventing chronic diseases may be beneficial in delaying or preventing MCI and dementia, they added.Vassilaki M, Aakre J, Cha R, et al. Multimorbidity and Risk of Mild Cognitive Impairment. J Am Geriatr Soc. 2015 Sep;63(9):1783-1790.Study Suggests That People With Intellectual Disabilities May Be Overprescribed Psychotropics r.classen/ShutterstockThe proportion of people with intellectual disabilities in the United Kingdom who have been treated with psychotropic drugs far exceeds the proportion with recorded severe mental illness, according to a recent study published in BMJ. To determine the rates of psychotropic prescriptions made to people with intellectual disabilities with or without comorbid psychiatric disorders, researchers from the University College London analyzed the electronic health records of 33,016 adults living in the United Kingdom with a diagnosed intellectual disability. The participants were followed over five years. Over the course of the trial, 9,135 participants were treated with antipsychotic drugs; 6,503 (71 percent of total prescribed antipsychotics) had no record of having been diagnosed with a severe mental illness. New prescriptions for antipsychotics were significantly more common in older people and those with a record of challenging behavior, autism, and dementia. “Psychotropic drugs are an important element in the management of specific psychiatric conditions,” the researchers noted. “However, we have shown that adults with intellectual disability are treated with psychotropic drugs at a rate far exceeding that of recorded mental illness and that certain subgroups (such as those with challenging behaviors) are significantly more likely to receive antipsychotic drugs.” ■Sheehan R, Hassiotis A, Walters K, et al. Mental Illness, Challenging Behaviour, and Psychotropic Drug Prescribing in People with Intellectual Disability: U.K. Population Based Cohort Study. BMJ. 2015 Sep 1;351:h4326. ISSUES NewArchived