Global increases in both common and rare copy number load associated with autism

Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195.
Human Molecular Genetics (Impact Factor: 6.39). 03/2013; 22(14). DOI: 10.1093/hmg/ddt136
Source: PubMed


Children with autism have an elevated frequency of large, rare copy number variants (CNVs). However, the global load of deletions or duplications, per se, and their size, location and relationship to clinical manifestations of autism have not been documented. We examined CNV data from 516 individuals with autism or typical development from the population-based Childhood Autism Risks from Genetics and Environment (CHARGE) study. We interrogated 120 regions flanked by segmental duplications (genomic hotspots) for events >50 kbp and the entire genomic backbone for variants >300 kbp using a custom targeted DNA microarray. This analysis was complemented by a separate study of five highly dynamic, hotspots associated with autism or developmental delay syndromes using a finely-tiled array platform (>1 kbp) in 142 children matched for gender and ethnicity. In both studies, a significant increase in the number of base pairs of duplication, but not deletion, was associated with autism. Significantly elevated levels of CNV load remained after removal of rare and likely pathogenic events. Further, the entire CNV load detected with the finely-tiled array was contributed by common variants. The impact of this variation was assessed by examining the correlation of clinical outcomes with CNV load. The level of personal and social skills, measured by Vineland Adaptive Behavior Scales, negatively correlated (Spearman's r=-0.13, p=0.034) with the duplication CNV load for the affected children; the strongest association was found for communication (p=0.048) and socialization (p=0.022) scores. We propose that CNV load, predominantly increased genomic base pairs of duplication, predisposes to autism.

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Available from: Isaac Pessah, Jan 24, 2014
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    • "To our knowledge this is the first study that shows rare CNVs in carriers of the FMR1 premutation. A significant increase in the number of CNVs, specifically duplications, even after removal of rare and perhaps pathogenic events, has been found to be associated with autism [53]. The frequency of CNVs observed in the premutation with ASD is comparable to the rates seen in autism alone. "
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    ABSTRACT: Background The FMR1 premutation is defined as having 55 to 200 CGG repeats in the 5′ untranslated region of the fragile X mental retardation 1 gene (FMR1). The clinical involvement has been well characterized for fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI). The behavior/psychiatric and other neurological manifestations remain to be specified as well as the molecular mechanisms that will explain the phenotypic variability observed in individuals with the FMR1 premutation. Methods Here we describe a small pilot study of copy number variants (CNVs) in 56 participants with a premutation ranging from 55 to 192 repeats. The participants were divided into four different clinical groups for the analysis: those with behavioral problems but no autism spectrum disorder (ASD); those with ASD but without neurological problems; those with ASD and neurological problems including seizures; and those with neurological problems without ASD. Results We found 12 rare CNVs (eight duplications and four deletions) in 11 cases (19.6%) that were not found in approximately 8,000 controls. Three of them were at 10q26 and two at Xp22.3, with small areas of overlap. The CNVs were more commonly identified in individuals with neurological involvement and ASD. Conclusions The frequencies were not statistically significant across the groups. There were no significant differences in the psychometric and behavior scores among all groups. Further studies are necessary to determine the frequency of second genetic hits in individuals with the FMR1 premutation; however, these preliminary results suggest that genomic studies can be useful in understanding the molecular etiology of clinical involvement in premutation carriers with ASD and neurological involvement.
    Journal of Neurodevelopmental Disorders 07/2014; 6(1):27. DOI:10.1186/1866-1955-6-27 · 3.27 Impact Factor
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    • "Although the costs are progressively decreasing, a-CGH is still an expensive and labour- intensive technique, and as such, cost-, clinical impact- and genotype/phenotype-analysis have tried to define the convenience and the correct indications to perform the analysis in selected categories of patients [7]. For example, the presence of pathogenic CNVs has been correlated with a severe clinical presentation or with a pleiotropic expression of the disease [5,8,9]; other studies have demonstrated that the presence of at least two clinical features increases the likelihood that the phenotype is associated with CNVs [10], although many exceptions exist, which underlie the extreme phenotypic heterogeneity of genomic disorders. "
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    ABSTRACT: Array comparative genomic hybridization (a-CGH) has become the first-tier investigation in patients with unexplained developmental delay/intellectual disability (DD/ID). Although the costs are progressively decreasing, a-CGH is still an expensive and labour-intensive technique: for this reason a definition of the categories of patients that can benefit the most of the analysis is needed. Aim of the study was to retrospectively analyze the clinical features of children with DD/ID attending the outpatient clinic of the Mother & Child Department of the University Hospital of Modena subjected to a-CGH, to verify by uni- and multivariate analysis the independent predictors of pathogenic CNVs. 116 patients were included in the study. Data relative to the CNVs and to the patients' clinical features were analyzed for genotype/phenotype correlations.Results and conclusions: 27 patients (23.3%) presented pathogenic CNVs (21 deletions, 3 duplications and 3 cases with both duplications and deletions). Univariate analysis showed a significant association of the pathogenic CNVs with the early onset of symptoms (before 1 yr of age) and the presence of malformations and dysmorphisms. Logistic regression analysis showed a significant independent predictive value for diagnosing a pathogenic CNV for malformations (P = 0.002) and dysmorphisms (P = 0.023), suggesting that those features should address a-CGH analysis as a high-priority test for diagnosis.
    Italian Journal of Pediatrics 04/2014; 40(1):39. DOI:10.1186/1824-7288-40-39 · 1.52 Impact Factor
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    • "Copy-number variants (CNVs) are a growing area of genetic variant exploration for neurodevelopmental disorders. Recently, a comparison was made of two microarray technologies used in the detection of CNVs. Figure 7 shows the CNV region overlap between results of an Illumina microarray and a custom microarray that was targeted for genomic hotspots of deletions and duplications [7,8]. Another example, using this approach for single SNPs instead of CNVs (not shown here), would be to use PhenoGram with two different colors highlighting the density and location of a series of low frequency variants vs. the density and location of a series of more common variants. "
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    ABSTRACT: With the abundance of information and analysis results being collected for genetic loci, user-friendly and flexible data visualization approaches can inform and improve the analysis and dissemination of these data. A chromosomal ideogram is an idealized graphic representation of chromosomes. Ideograms can be combined with overlaid points, lines, and/or shapes, to provide summary information from studies of various kinds, such as genome-wide association studies or phenome-wide association studies, coupled with genomic location information. To facilitate visualizing varied data in multiple ways using ideograms, we have developed a flexible software tool called PhenoGram which exists as a web-based tool and also a command-line program. With PhenoGram researchers can create chomosomal ideograms annotated with lines in color at specific base-pair locations, or colored base-pair to base-pair regions, with or without other annotation. PhenoGram allows for annotation of chromosomal locations and/or regions with shapes in different colors, gene identifiers, or other text. PhenoGram also allows for creation of plots showing expanded chromosomal locations, providing a way to show results for specific chromosomal regions in greater detail. We have now used PhenoGram to produce a variety of different plots, and provide these as examples herein. These plots include visualization of the genomic coverage of SNPs from a genotyping array, highlighting the chromosomal coverage of imputed SNPs, copy-number variation region coverage, as well as plots similar to the NHGRI GWA Catalog of genome-wide association results. PhenoGram is a versatile, user-friendly software tool fostering the exploration and sharing of genomic information. Through visualization of data, researchers can both explore and share complex results, facilitating a greater understanding of these data.
    BioData Mining 10/2013; 6(1):18. DOI:10.1186/1756-0381-6-18 · 2.02 Impact Factor
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