Evald Saemundsen

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 Childrens 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 Childrens 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 Childrens 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.

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.

Prevalence of Autism in Iceland

This clinic-based study estimated the prevalence of autism in Iceland in two consecutive birth cohorts, subjects born in 1974-1983 and in 1984-1993. In the older cohort classification was based on the ICD-9 in 72% of cases while in the younger cohort 89% of cases were classified according to the ICD-10. Estimated prevalence rates for Infantile autism/Childhood autism were 3.8 per 10,000 in the older cohort and 8.6 per 10,000 in the younger cohort. The characteristics of the autistic groups are presented in terms of level of intelligence, male:female ratio, and age at diagnosis. For the younger cohort scores on the Autism Diagnostic Interview-Revised and the Childhood Autism Rating Scale are reported as well. Results are compared with a previous Icelandic study and recent population-based studies in other countries based on the ICD-10 classification system. Methodological issues are discussed as well as implications for future research and service delivery.

Autism Diagnostic Interview-Revised and the Childhood Autism Rating Scale: convergence and discrepancy in diagnosing autism.

The agreement between the Autism Diagnostic Interview–Revised (ADI-R) and the Childhood Autism Rating Scale (CARS) was investigated in the diagnostic assessment of 54 children aged 22–114 months referred for possible autism. The observed agreement between the two systems was 66.7% (Cohens kappa = .40) when the ADI-R definition for autism was applied (i.e., scores reaching cutoff in three domains on the ADI-R), but increased considerably with less stringent criteria; that is, scores reaching cutoffs in two domains and in one domain on the ADI-R. As predicted, the CARS identified more cases of autism than the ADI-R. Children classified as autistic according to both instruments had significantly lower IQ/DQ and more severe autistic symptomatology than those classified with the CARS only.

Autism Spectrum Disorders in Children with Seizures in the First Year of Life—A Population-based Study

Summary:  Purpose: To describe autistic spectrum disorders (ASDs) in a cohort of children with history of unprovoked seizures other than infantile spasms in the first year of life.

Maternally derived microduplications at 15q11-q13: implication of imprinted genes in psychotic illness

OBJECTIVE Rare copy number variants have been implicated in different neurodevelopmental disorders, with the same copy number variants often increasing risk of more than one of these phenotypes. In a discovery sample of 22 schizophrenia patients with an early onset of illness (10-15 years of age), the authors observed in one patient a maternally derived 15q11-q13 duplication overlapping the Prader-Willi/Angelman syndrome critical region. This prompted investigation of the role of 15q11-q13 duplications in psychotic illness. METHOD The authors scanned 7,582 patients with schizophrenia or schizoaffective disorder and 41,370 comparison subjects without known psychiatric illness for copy number variants at 15q11-q13 and determined the parental origin of duplications using methylation-sensitive Southern hybridization analysis. RESULTS Duplications were found in four case patients and five comparison subjects. All four case patients had maternally derived duplications (0.05%), while only three of the five comparison duplications were maternally derived (0.007%), resulting in a significant excess of maternally derived duplications in case patients (odds ratio=7.3). This excess is compatible with earlier observations that risk for psychosis in people with Prader-Willi syndrome caused by maternal uniparental disomy is much higher than in those caused by deletion of the paternal chromosome. CONCLUSIONS These findings suggest that the presence of two maternal copies of a fragment of chromosome 15q11.2-q13.1 that overlaps with the Prader-Willi/Angelman syndrome critical region may be a rare risk factor for schizophrenia and other psychoses. Given that maternal duplications of this region are among the most consistent cytogenetic observations in autism, the findings provide further support for a shared genetic etiology between autism and psychosis.

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.

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.

Prevalence of autism spectrum disorders in an Icelandic birth cohort

Objectives A steady increase in the prevalence of autism spectrum disorders (ASD) has been reported in studies based on different methods, requiring adjustment for participation and missing data. Recent studies with high ASD prevalence rates rarely report on co-occurring medical conditions. The aim of the study was to describe the prevalence of clinically confirmed cases of ASD in Iceland and concomitant medical conditions. Design The cohort is based on a nationwide database on ASD among children born during 1994–1998. Participants A total of 267 children were diagnosed with ASD, 197 boys and 70 girls. Only clinically confirmed cases were included. All received physical and neurological examination, standardised diagnostic workup for ASD, as well as cognitive testing. ASD diagnosis was established by interdisciplinary teams. Information on medical conditions and chromosomal testing was obtained by record linkage with hospital registers. Setting Two tertiary institutions in Iceland. The population registry recorded 22 229 children in the birth cohort. Results Prevalence of all ASD was 120.1/10 000 (95% CI 106.6 to 135.3), for boys 172.4/10 000 (95% CI 150.1 to 198.0) and for girls 64.8/10 000 (95% CI 51.3 to 81.8). Prevalence of all medical conditions was 17.2% (95% CI 13.2 to 22.2), including epilepsy of 7.1% (95% CI 4.6 to 10.8). The proportion of ASD cases with cognitive impairment (intellectual quotient <70) was 45.3%, but only 34.1% were diagnosed with intellectual disability (ID). Children diagnosed earlier or later did not differ on mean total score on a standardised interview for autism. Conclusions The number of clinically verified cases is larger than in previous studies, yielding a prevalence of ASD on a similar level as found in recent non-clinical studies. The prevalence of co-occurring medical conditions was high, considering the low proportion of ASD cases that also had ID. Earlier detection is clearly desirable in order to provide counselling and treatment.

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.