CNVs conferring risk of autism or schizophrenia affect cognition in controls.

In a small fraction of patients with schizophrenia or autism, alleles of copy-number variants (CNVs) in their genomes are probably the strongest factors contributing to the pathogenesis of the disease. These CNVs may provide an entry point for investigations into the mechanisms of brain function and dysfunction alike. They are not fully penetrant and offer an opportunity to study their effects separate from that of manifest disease. Here we show in an Icelandic sample that a few of the CNVs clearly alter fecundity (measured as the number of children by age 45). Furthermore, we use various tests of cognitive function to demonstrate that control subjects carrying the CNVs perform at a level that is between that of schizophrenia patients and population controls. The CNVs do not all affect the same cognitive domains, hence the cognitive deficits that drive or accompany the pathogenesis vary from one CNV to another. Controls carrying the chromosome 15q11.2 deletion between breakpoints 1 and 2 (15q11.2(BP1-BP2) deletion) have a history of dyslexia and dyscalculia, even after adjusting for IQ in the analysis, and the CNV only confers modest effects on other cognitive traits. The 15q11.2(BP1-BP2) deletion affects brain structure in a pattern consistent with both that observed during first-episode psychosis in schizophrenia and that of structural correlates in dyslexia.

Parental Origin of Interstitial Duplications at 15q11.2-q13.3 in Schizophrenia and Neurodevelopmental Disorders.

Duplications at 15q11.2-q13.3 overlapping the Prader-Willi/Angelman syndrome (PWS/AS) region have been associated with developmental delay (DD), autism spectrum disorder (ASD) and schizophrenia (SZ). Due to presence of imprinted genes within the region, the parental origin of these duplications may be key to the pathogenicity. Duplications of maternal origin are associated with disease, whereas the pathogenicity of paternal ones is unclear. To clarify the role of maternal and paternal duplications, we conducted the largest and most detailed study to date of parental origin of 15q11.2-q13.3 interstitial duplications in DD, ASD and SZ cohorts. We show, for the first time, that paternal duplications lead to an increased risk of developing DD/ASD/multiple congenital anomalies (MCA), but do not appear to increase risk for SZ. The importance of the epigenetic status of 15q11.2-q13.3 duplications was further underlined by analysis of a number of families, in which the duplication was paternally derived in the mother, who was unaffected, whereas her offspring, who inherited a maternally derived duplication, suffered from psychotic illness. Interestingly, the most consistent clinical characteristics of SZ patients with 15q11.2-q13.3 duplications were learning or developmental problems, found in 76% of carriers. Despite their lower pathogenicity, paternal duplications are less frequent in the general population with a general population prevalence of 0.0033% compared to 0.0069% for maternal duplications. This may be due to lower fecundity of male carriers and differential survival of embryos, something echoed in the findings that both types of duplications are de novo in just over 50% of cases. Isodicentric chromosome 15 (idic15) or interstitial triplications were not observed in SZ patients or in controls. Overall, this study refines the distinct roles of maternal and paternal interstitial duplications at 15q11.2-q13.3, underlining the critical importance of maternally expressed imprinted genes in the contribution of Copy Number Variants (CNVs) at this interval to the incidence of psychotic illness. This work will have tangible benefits for patients with 15q11.2-q13.3 duplications by aiding genetic counseling.

European studies on prevalence and risk of autism spectrum disorders according to immigrant status-a review.

BACKGROUND: Autism spectrum disorders (ASDs), once considered to be rare, are now reaching prevalence estimates of 1% and higher. Studies conducted in North America indicate large racial/ethnic disparities in the diagnosis of ASDs. Others show, that immigrant children have similar prevalence rates of ASDs as native children, although they are diagnosed later compared with native children. In relation to a EU funded network action, Enhancing the Scientific Study of Early Autism, it was considered important to review the literature on this subject. METHOD: A comprehensive literature search was undertaken for original articles reporting on prevalence and risk for ASD in Europe among immigrants and ethnic minorities and data across studies were compared. RESULTS: Seventeen studies conducted in Europe concerning immigrants and ethnic minorities were found. Fifteen studies suggest a higher prevalence rate of ASDs among children of immigrants in comparison to native children (RR = 1.02-1.74; OR = 0.6-10.5). One study revealed higher prevalence of autism (OR = 2.2; 95% CI 1.6-3.1) and lower prevalence of Asperger syndrome in immigrants (OR = 0.6; 95% CI 0.3-0.97). One study showed a lower prevalence of Asperger syndrome in immigrants (aOR = 0.1, 95% CI 0.01-0.5). The majority of those analyses involved immigrants from outside Europe, e.g. from Africa and South America. CONCLUSION: After analysing the results of studies conducted in Europe, it is unclear if higher prevalence estimates of ASDs among immigrants in this region reflect true differences, especially considering many potential confounding factors, e.g. genetic, biological, environmental and cultural. Considering the number of people migrating within Europe there is a substantial need to study further the prevalence of ASDs in immigrant groups.

Evaluating screening for autism spectrum disorder using cluster randomization.

We evaluated the rate of autism spectrum disorder (ASD) in a group invited to a screening program compared to the rates in two groups who received usual care. The population eligible for screening was all children in Iceland registered for their 30-month well-child visits at primary healthcare centers (PHCs) from March 1, 2016, to October 31, 2017 (N = 7173). The PHCs in the capital area of Reykjavik were the units of cluster randomization. Nine PHCs were selected for intervention (invited group), while eight PHCs received usual care (control group 1). PHCs outside the capital area were without randomization (control group 2). An interdisciplinary team, including a pediatrician contributing with physical and neurological examination, a psychologist evaluating autism symptoms using a diagnostic instrument, and a social worker interviewing the parents, reached a consensus on the clinical diagnosis of ASD according to the ICD-10 diagnostic system. Children in the population were followed up for at least two years and 119 cases were identified. The overall cumulative incidence of ASD was 1.66 (95% confidence interval (CI): 1.37, 1.99). In the invited group the incidence rate was 2.13 (95% CI: 1.60, 2.78); in control group 1, the rate was 1.83 (95% CI: 1.31, 2.50); and in control group 2, the rate was 1.02 (95% CI: 0.66, 1.50). Although the rate of ASD was higher in the invited group than in the control groups, the wide confidence intervals prevented us from concluding definitively that the screening detected ASD more readily than usual care.

Psychiatric disorders in an urban sample of preschool children.

BACKGROUND: To increase limited epidemiological knowledge of early childhood psychopathology, a study of prevalence estimates and demographic correlates of psychiatric disorders was conducted in a sample of preschool children. METHODS: In a two-stage study, parents of 339 children aged 4-6 years who came for a medical check-up at three primary care centres in Reykjavik were invited to participate. First, the participants were screened with Brigance Screens and the Strengths and Difficulties Questionnaire (SDQ) for parents and teachers. Subsequently, the children were tested with a short version of Wechsler Preschool and Primary Scales of Intelligence - Revised and their parents were interviewed with the Schedule for Affective Disorders and Schizophrenia for School Aged Children Present and Lifetime Version. Weighted prevalence estimates were calculated and logistic regression was used to analyse the association between risk factors and psychiatric disorders. RESULTS: Of those invited to participate, 317 (93.5%) were included in the screening and of those, 131 received a full diagnostic assessment. The final study sample included 151 girls (47.6%) and 166 boys (52.4%) who represented 11.6% of the total birth cohort in Reykjavik. Weighted prevalence of DSM-IV psychiatric disorders was 10.1% (95% CI 6.7-13.5%) and 57/317 or 18.0% (95% CI 13.8-22.2%), including elimination disorders. Anxiety disorders (5.7%) and attention deficit hyperactivity disorder (3.8%) were the most common disorders in this preschool sample. Poor physical health of parents and higher education was associated with DSM-IV psychiatric disorders of the children. SDQ Total Difficulties score was associated with male gender and poor physical health of parents. CONCLUSIONS: This study indicates that psychiatric disorders in preschool children are common and may be correlated with parental health factors.

Validation of the Modified Checklist for Autism in Toddlers, Revised with Follow-up in a Population Sample of 30-Month-Old Children in Iceland: A Prospective Approach.

The Modified Checklist for Autism in Toddlers, Revised with Follow-up was validated on a population sample in Reykjavik, Iceland. The participants (N = 1585) were screened in well-child care at age 30 months and followed up for at least 2 years to identify autism cases. The sensitivity, specificity, positive and negative predictive values were 0.62, 0.99, 0.72, and 0.99, respectively. True-positive children were diagnosed 10 months earlier than false-negative children. Autism symptom severity and the proportions of children with verbal and performance IQs/DQs < 70 were similar between groups. Although the sensitivity was suboptimal, the screening contributed to lowering the age at diagnosis for many children. Adding autism-specific screening to the well-child care program should be considered.

Autistic Adult Services Availability, Preferences, and User Experiences: Results From the Autism Spectrum Disorder in the European Union Survey.

There is very little knowledge regarding autistic adult services, practices, and delivery. The study objective was to improve understanding of current services and practices for autistic adults and opportunities for improvement as part of the Autism Spectrum Disorder in the European Union (ASDEU) project. Separate survey versions were created for autistic adults, carers of autistic adults, and professionals in adult services. 2,009 persons responded to the survey and 1,085 (54%) of them completed at least one of the services sections: 469 autistic adults (65% female; 55% <35 years old), 441 carers of autistic adults (27% female; 6% <35 years old), 175 professionals in adult services (76% female; 67% in non-medical services). Top choices by autistic adults, carers or professionals for services best suiting their current needs were: residential services: "help in own home" (adults, carers of high independent adults, professionals), "fulltime residential facility" (carers of low independent adults); employment services: "job mentors" (adults, carers of high independent adults, professionals), "Sheltered employment" (carers of low independent adults); education services: "support in regular education setting" (all groups); financial services: financial support in lieu of employment ("Supplementary income for persons unable to have full employment" for adults, "full pension" for carers of low independent adults) or to supplement employment earnings for carers of high independent adults and professionals; social services: "behavior training" (adults) and "life skills training" (carers and professionals). Waiting times for specific services were generally < 1 month or 1-3 months, except for residential services which could be up to 6 months; most professionals were uninformed of waiting times (>50% responded "don't know"). Five of seven residential services features recommended for autistic adults were experienced by <50% of adults. The knowledge of good local services models that work well for autistic adults was generally low across all services areas. The variation in services experiences and perceptions reported by autistic adults, carers, or professionals underscore the need to query all groups for a complete picture of community services availability and needs. The results showed areas for potential improvement in autistic adult services delivery in the EU to achieve recommended standards.

Intervention Services for Autistic Adults: An ASDEU Study of Autistic Adults, Carers, and Professionals' Experiences.

The Autism Spectrum Disorders in the European Union (ASDEU) survey investigated local services' use experiences of autistic adults, carers and professionals with interventions for autistic adults. The majority of the 697 participants experienced recommended considerations prior to deciding on intervention and during the intervention plan and implementation. Psychosocial interventions were the most commonly experienced interventions, while pharmacological interventions NOT recommended for core autistic symptoms were reported by fairly large proportions of participants. Family interventions were experienced slightly more commonly by carers than adults or professionals. Less than the 26% of autistic adult responders who had experienced challenging behaviors reported receiving an intervention to change them. These results provide insights for improving gaps in service provision of interventions among autistic adults.

Determinants of satisfaction with the detection process of autism in Europe: Results from the ASDEU study.

LAY ABSTRACT: Professional guidance and support in response to first concerns appears to be an important predictor of the level of satisfaction with the detection process of autism in young children. In this study, we analyzed the views of 1342 family members, including 1278 parents, who completed an online survey form collecting information about their experience and satisfaction with the early detection of autism in their child. Specifically, we were interested in how specific experiences with the detection process relate to the satisfaction with it and whether we could identify important predictors of satisfaction. The detection process is an emotionally charged period for parents, often described as painful, chaotic, and lengthy. A better understanding of their experiences is important to take appropriate action to improve the detection process. In our sample, the level of satisfaction with the detection process varied greatly from one respondent to another. Among the different experiences we considered, whether or not respondents received professional guidance and support in response to first concerns explained most of this variation. We also found that difficulty finding information about detection services, lack of professional guidance and support in response to first concerns, having to find a diagnostic service on one's own, and longer delays between confirmation of concerns and first appointment with a specialist were experiences associated with a greater likelihood of being unsatisfied. The findings of this study highlight the importance of the parent-professional relationship in the detection process and have important practical implications for health administrations to improve the detection process.

Association between microdeletion and microduplication at 16p11.2 and autism.

BACKGROUND: Autism spectrum disorder is a heritable developmental disorder in which chromosomal abnormalities are thought to play a role. METHODS: As a first component of a genomewide association study of families from the Autism Genetic Resource Exchange (AGRE), we used two novel algorithms to search for recurrent copy-number variations in genotype data from 751 multiplex families with autism. Specific recurrent de novo events were further evaluated in clinical-testing data from Children's Hospital Boston and in a large population study in Iceland. RESULTS: Among the AGRE families, we observed five instances of a de novo deletion of 593 kb on chromosome 16p11.2. Using comparative genomic hybridization, we observed the identical deletion in 5 of 512 children referred to Children's Hospital Boston for developmental delay, mental retardation, or suspected autism spectrum disorder, as well as in 3 of 299 persons with autism in an Icelandic population; the deletion was also carried by 2 of 18,834 unscreened Icelandic control subjects. The reciprocal duplication of this region occurred in 7 affected persons in AGRE families and 4 of the 512 children from Children's Hospital Boston. The duplication also appeared to be a high-penetrance risk factor. CONCLUSIONS: We have identified a novel, recurrent microdeletion and a reciprocal microduplication that carry substantial susceptibility to autism and appear to account for approximately 1% of cases. We did not identify other regions with similar aggregations of large de novo mutations.

No association between a common single nucleotide polymorphism, rs4141463, in the MACROD2 gene and autism spectrum disorder.

The Autism Genome Project (AGP) Consortium recently reported genome-wide significant association between autism and an intronic single nucleotide polymorphism marker, rs4141463, within the MACROD2 gene. In the present study we attempted to replicate this finding using an independent case-control design of 1,170 cases with autism spectrum disorder (ASD) (874 of which fulfilled narrow criteria for Autism (A)) from five centers within Europe (UK, Germany, the Netherlands, Italy, and Iceland), and 35,307 controls. The combined sample size gave us a non-centrality parameter (NCP) of 11.9, with 93% power to detect allelic association of rs4141463 at an alpha of 0.05 with odds ratio of 0.84 (the best odds ratio estimate of the AGP Consortium data), and for the narrow diagnosis of autism, an NCP of 8.9 and power of 85%. Our case-control data were analyzed for association, stratified by each center, and the summary statistics were combined using the meta-analysis program, GWAMA. This resulted in an odds ratio (OR) of 1.03 (95% CI 0.944-1.133), with a P-value of 0.5 for ASD and OR of 0.99 (95% CI 0.88-1.11) with P-value = 0.85 for the Autism (A) sub-group. Therefore, this study does not provide support for the reported association between rs4141463 and autism.

Real-World Experiences in Autistic Adult Diagnostic Services and Post-diagnostic Support and Alignment with Services Guidelines: Results from the ASDEU Study.

Research providing an evidence-base for autistic adult services is sparse. The Autism Spectrum Disorders in the European Union (ASDEU) network implemented an on-line survey to determine gaps in autistic adult diagnostic evaluation and post-diagnostic support services. More than 55% in all groups experienced most of the recommended features for diagnostic evaluation for autistic adults. In contrast, < 2% of adults or carers, and < 21% of professionals experienced each of the recommended features for post-diagnostic support. In contrast to 61% of professionals, only about 30% of autistic adults and carers had knowledge of good local services models for autism diagnosis in adulthood. There are major differences between good practice guidelines for diagnostic and post-diagnostic care for autistic adults, and what is actually experienced by services users and professionals.

Autistic Adult Health and Professional Perceptions of It: Evidence From the ASDEU Project.

The Autism Spectrum Disorders in the European Union (ASDEU) survey investigated the knowledge and health service experiences of users and providers to generate new hypotheses and scientific investigations that would contribute to improvement in health care for autistic adults. An online survey designed for autistic adults, carers of autistic adults, and professionals in adult services was translated into 11 languages and distributed electronically by organizations and in-country adult service facilities in 2017; 522 autistic adults, 442 carers, and 113 professionals provided answers to the health questions. Professionals, the majority in non-medical services, appeared to be poorly informed about whether certain co-occurring conditions were more frequent in autistic adults than typical adults-especially some medical conditions, suicide attempts, accidents, and pain. A minority of autistic adults reported preventive health behaviors such as routine health check-ups. The majority of users and providers expressed the desire to make health care services more user-friendly for autistic adults. Among the three groups, <20% of responders knew an organization or clinician which has developed a way to monitor health, and prevent poor health, that works well for adults on the autism spectrum. The results point to means for better management of co-occurring conditions associated with autism in adulthood in order to reduce hospital admissions and potential areas of improvement in health and social services for autistic adults. Specifically, efforts should be focused on (1) professionals' education on risks for co-occurring conditions in autistic adults; (2) promoting preventive health behaviors; (3) making services user-friendly for autistic adults and their families; and (4) encouraging knowledge of good local services.

Early Detection, Diagnosis and Intervention Services for Young Children with Autism Spectrum Disorder in the European Union (ASDEU): Family and Professional Perspectives.

Early services for ASD need to canvas the opinions of both parents and professionals. These opinions are seldom compared in the same research study. This study aims to ascertain the views of families and professionals on early detection, diagnosis and intervention services for young children with ASD. An online survey compiled and analysed data from 2032 respondents across 14 European countries (60.9% were parents; 39.1% professionals). Using an ordinal scale from 1 to 7, parents' opinions were more negative (mean = 4.6; SD 2.2) compared to those of professionals (mean = 4.9; SD 1.5) when reporting satisfaction with services. The results suggest services should take into account child's age, delays in accessing services, and active stakeholders' participation when looking to improve services.

Correction to: Early Detection, Diagnosis and Intervention Services for Young Children with Autism Spectrum Disorder in the European Union (ASDEU): Family and Professional Perspectives.

The original version of this article unfortunately contained a mistake in one of the co-author's family name. The correct name should be María Victoria Martín-Cilleros instead of María Victoria Cilleros-Martín.

Risk of autism spectrum disorders after infantile spasms: a population-based study nested in a cohort with seizures in the first year of life.

PURPOSE: No population-based study has investigated the risk of autism spectrum disorders (ASDs) in children after unprovoked seizures with onset in the first year of life. Our objective was to determine whether infantile spasms were related to risk of ASD as compared to unprovoked seizures with onset in the first year of life after adjusting for symptomatic origin of seizures. METHODS: This is a population-based case-control study nested in a cohort of children with unprovoked seizures in the first year of life. The cohort comprised 95 children, 34 boys and 61 girls. Cases were defined as children with ASD, controls were without ASD, and exposure was a history of infantile spasms. The Mantel-Haenszel test and logistic regression were used to calculate the odds ratio (OR) and 95% confidence intervals (CI). RESULTS: The crude OR for ASD associated with infantile spasms was 5.53 (95% CI 1.25-23.06). Stratification on age and gender did not change the OR. The OR for ASD associated with infantile spasms adjusted for symptomatic seizures was 1.55 (95% CI 0.33-7.37), while the OR for ASD associated with symptomatic seizures adjusted for infantile spasms was 8.73 (95% CI 1.88-40.54). Restriction to mental age 24 months or higher yielded higher ORs. DISCUSSION: Infantile spasms predicted high risk for ASD, but this was to a large extent explained by the association of ASD with symptomatic origin of seizures.

Long-term outcome of children with autism who received different forms of early intervention during their preschool years: a pilot study of 15 young adults.

BACKGROUND: Studies on early intervention have reported significant gains for many children with autism. Knowledge on how these children fare in adulthood is limited. OBJECTIVE: To examine long-term outcome of children with autism who received different forms of early intervention. METHOD: Participants were 15 young people who had all been diagnosed with ICD-10 childhood autism during the preschool years. Five received intervention based on the UCLA model for early intensive behavioral intervention, and 10 received eclectic treatment. Participants were followed from their first autism diagnosis during the preschool years (time 1) to the age of six years (time 2). The participants are now in their twenties (time 3), and at this point in time, information on autism symptoms, co-occurring disorders, quality of life, functioning, participation, adaptive behavior, and overall outcome was gathered from parents. Six of the participants answered questionnaires on quality of life, functioning, and participation. RESULTS: The groups were comparable on all measures at time 1. Reassessment at time 2 showed that the early intensive behavioral intervention group had made significant gains in IQ, and that autism symptoms had decreased significantly, whereas such changes were not found for the eclectic treatment group. At time 3, most participants had considerable autism symptoms. Approximately half of them had received diagnosis of a co-occurring condition. Their quality of life and adaptive behavior was less favorable than that of the general population, but only a third had "poor" overall outcome. However, at time 3, hardly any differences were found between the groups. CONCLUSIONS: To maintain gains made during the preschool years, appropriate intervention and services may need to be extended into adulthood. These services should take into account the perceived needs of the individual, as expressed by himself/herself and his/her family.

MAP1B mutations cause intellectual disability and extensive white matter deficit.

Discovery of coding variants in genes that confer risk of neurodevelopmental disorders is an important step towards understanding the pathophysiology of these disorders. Whole-genome sequencing of 31,463 Icelanders uncovers a frameshift variant (E712KfsTer10) in microtubule-associated protein 1B (MAP1B) that associates with ID/low IQ in a large pedigree (genome-wide corrected P = 0.022). Additional stop-gain variants in MAP1B (E1032Ter and R1664Ter) validate the association with ID and IQ. Carriers have 24% less white matter (WM) volume (ß = -2.1SD, P = 5.1 × 10-8), 47% less corpus callosum (CC) volume (ß = -2.4SD, P = 5.5 × 10-10) and lower brain-wide fractional anisotropy (P = 6.7 × 10-4). In summary, we show that loss of MAP1B function affects general cognitive ability through a profound, brain-wide WM deficit with likely disordered or compromised axons.

Follow-up of children diagnosed with pervasive developmental disorders: stability and change during the preschool years.

Forty-one children with pervasive developmental disorders (PDDs) receiving eclectic services were assessed twice during their preschool years. Measures were compared over time for the whole group and for diagnostic subgroups: Childhood autism (CA group) and Other PDDs group. The mean intelligence quotient/developmental quotient (IQ/DQ) of the whole group was stable (P = 0.209) and scores on the Childhood Autism Rating Scale (CARS) decreased (P = 0.001). At time 2, the CA group was more impaired than the other PDDs group: autistic symptoms were more severe (P = 0.01), adaptive behavior scores were lower (P = 0.014), and a trend for lower IQ/DQs (P = 0.06). Children in this study seemed to fare better than reported in previous follow-up studies on children with autism.

Autism spectrum disorders in children with a history of infantile spasms: a population-based study.

The objective of this article is to describe autistic spectrum disorders in children diagnosed with infantile spasms in the first year of life. The source of data was the records of all 3 pediatric departments in Iceland. Twenty children born between 1981 and 1998 who had infantile spasms were invited to participate. When appropriate, the parents of these children were asked to complete the Social Communication Questionnaire. Children scoring 10 points or higher on the questionnaire were selected for further examination using the Autism Diagnostic Interview- Revised and either the Autism Diagnostic Observation Schedule or the Childhood Autism Rating Scale. All participants were given appropriate cognitive tests or measures of adaptive behavior. The parents of 17 children (10 boys, 7 girls) agreed to participate in the study. Age at assessment ranged from 5 to 19 years with a mean age of 11 years and 6 months. Fourteen children had at least one neurodevelopmental disorder. Six (6/17), or 35.3%, were diagnosed with autism spectrum disorder (3 boys, 3 girls), five of these had a history of symptomatic infantile spasms, and four were profoundly mentally retarded (IQ/DQ<20). If the diagnosis of autism spectrum disorder was restricted to children with a developmental age of 24 months or more (3 cases), the prevalence was 17.6%. The estimates found in this study exceed the estimated prevalence of autism spectrum disorder in the general population.