Genome-wide Transcriptome Profiling Reveals the Functional Impact of Rare De Novo and Recurrent CNVs in Autism Spectrum Disorders

Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, 90095, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 06/2012; 91(1):38-55. DOI: 10.1016/j.ajhg.2012.05.011
Source: PubMed


Copy-number variants (CNVs) are a major contributor to the pathophysiology of autism spectrum disorders (ASDs), but the functional impact of CNVs remains largely unexplored. Because brain tissue is not available from most samples, we interrogated gene expression in lymphoblasts from 244 families with discordant siblings in the Simons Simplex Collection in order to identify potentially pathogenic variation. Our results reveal that the overall frequency of significantly misexpressed genes (which we refer to here as outliers) identified in probands and unaffected siblings does not differ. However, in probands, but not their unaffected siblings, the group of outlier genes is significantly enriched in neural-related pathways, including neuropeptide signaling, synaptogenesis, and cell adhesion. We demonstrate that outlier genes cluster within the most pathogenic CNVs (rare de novo CNVs) and can be used for the prioritization of rare CNVs of potentially unknown significance. Several nonrecurrent CNVs with significant gene-expression alterations are identified (these include deletions in chromosomal regions 3q27, 3p13, and 3p26 and duplications at 2p15), suggesting that these are potential candidate ASD loci. In addition, we identify distinct expression changes in 16p11.2 microdeletions, 16p11.2 microduplications, and 7q11.23 duplications, and we show that specific genes within the 16p CNV interval correlate with differences in head circumference, an ASD-relevant phenotype. This study provides evidence that pathogenic structural variants have a functional impact via transcriptome alterations in ASDs at a genome-wide level and demonstrates the utility of integrating gene expression with mutation data for the prioritization of genes disrupted by potentially pathogenic mutations.

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    • "CNV carriers identified expression dysregulation of many genes located outside of the 16p11.2 locus, in addition to the changes of genes' dosage within the locus (Luo et al., 2012). Despite the progress in linking 16p11.2 "
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    ABSTRACT: The psychiatric disorders autism and schizophrenia have a strong genetic component, and copy number variants (CNVs) are firmly implicated. Recurrent deletions and duplications of chromosome 16p11.2 confer a high risk for both diseases, but the pathways disrupted by this CNV are poorly defined. Here we investigate the dynamics of the 16p11.2 network by integrating physical interactions of 16p11.2 proteins with spatiotemporal gene expression from the developing human brain. We observe profound changes in protein interaction networks throughout different stages of brain development and/or in different brain regions. We identify the late mid-fetal period of cortical development as most critical for establishing the connectivity of 16p11.2 proteins with their co-expressed partners. Furthermore, our results suggest that the regulation of the KCTD13-Cul3-RhoA pathway in layer 4 of the inner cortical plate is crucial for controlling brain size and connectivity and that its dysregulation by de novo mutations may be a potential determinant of 16p11.2 CNV deletion and duplication phenotypes. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neuron 02/2015; 85(4):742-54. DOI:10.1016/j.neuron.2015.01.010 · 15.05 Impact Factor
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    • "Our clustering analysis allowed us to group subjects in two clusters based on frequencies of abnormalities (median 28 or 13 per subject) and it will be interest to explore the mutation types and frequencies in these two groups of patients in the future. Establishing the functional consequences of gene copy number or sequence changes is also important for the assessment of their impact on the phenotype and studies addressing closer functional and phenomic linkages are becoming more common [29-33]. Efforts to use a more standardized and detailed phenotyping system in combination with array-CGH, sequencing and gene functional analysis is needed to improve our understanding of phenotype/genotype correlations and optimize their translation into accurate genetic counselling. "
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    ABSTRACT: Background DNA copy number variants (CNVs) are found in 15% of subjects with ID but their association with phenotypic abnormalities has been predominantly studied in smaller cohorts of subjects with detailed yet non-systematically categorized phenotypes, or larger cohorts (thousands of cases) with smaller number of generalized phenotypes. Methods We evaluated the association of de novo, familial and common CNVs detected in 78 ID subjects with phenotypic abnormalities classified using the Winter-Baraitser Dysmorphology Database (WBDD) (formerly the London Dysmorphology Database). Terminology for 34 primary (coarse) and 169 secondary (fine) phenotype features were used to categorize the abnormal phenotypes and determine the prevalence of each phenotype in patients grouped by the type of CNV they had. Results In our cohort more than 50% of cases had abnormalities in primary categories related to head (cranium, forehead, ears, eye globes, eye associated structures, nose) as well as hands and feet. The median number of primary and secondary abnormalities was 12 and 18 per subject, respectively, indicating that the cohort consisted of subjects with a high number of phenotypic abnormalities (median De Vries score for the cohort was 5). The prevalence of each phenotypic abnormality was comparable in patients with de novo or familial CNVs in comparison to those with only common CNVs, although a trend for increased frequency of cranial and forehead abnormalities was noted in subjects with rare de novo and familial CNVs. Two clusters of subjects were identified based on the prevalence of each fine phenotypic feature, with an average of 28.3 and 13.5 abnormal phenotypes/subject in the two clusters respectively (P < 0.05). Conclusions Our study is a rare example of using standardized, deep morphologic phenotype clustering with phenotype/CNV correlation in a cohort of subjects with ID. The composition of the cohort inevitably influences the phenotype/genotype association, and our studies show that the influence of the de novo CNVs on the phenotype is less obvious in cohorts consisting of subjects with a high number of phenotypic abnormalities. The outcome of phenotype/genotype analysis also depends on the choice of phenotypes assessed and standardized phenotyping is required to minimize variability.
    BMC Medical Genetics 07/2014; 15(1):82. DOI:10.1186/1471-2350-15-82 · 2.08 Impact Factor
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    • "With this lack of interest for a novel individual, the Ms2Yah mice develop a specific autistic phenotype. Several Autistic Spectrum Disorders (ASD) are linked with copy number variants (MORENO‐DE‐LUCA et al. 2010; SANDERS et al. 2011; LUO et al. 2012). In the Autism database (BASU et al. 2009), we found a few duplications and one deletion in patients that included segments from the Abcg1‐U2af1 region (JACQUEMONT et al. 2006; MARSHALL et al. 2008; PINTO et al. 2010; LEVY et al. 2011; SANDERS et al. 2011). "
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    ABSTRACT: Down syndrome (DS) is due to increased copy number of human chromosome 21. The contribution of different genetic regions has been tested using mouse models. As shown previously, the Abcg1-U2af1 genetic region contributes to cognitive defects in working and short-term recognition memory in Down syndrome mouse models. Here we analyzed the impact of monosomy of the same genetic interval using a new mouse model, named Ms2Yah. We used several cognitive paradigms, and did not detect defects in the object recognition nor the Morris water maze tests. However, surprisingly, Ms2Yah mice displayed increased associative memory in a pure contextual fear conditioning test, and decreased social novelty interaction along with a larger long term potentiation recorded in the CA1 area following stimulation of Schaffer collaterals. Whole genome expression studies carried out on hippocampus showed that only the transcription of a small number of genes is affected, mainly from the genetic interval (Cbs, Rsph1, Wdr4), with a few additional ones, including the postsynaptic Gabrr2, Gabbr1, Grid2p, Park2 and Dlg1 and the components of the Ubiquitin mediated proteolysis (Anapc1, Rnf7, Huwe1, Park2). The Abcg1-U2af1 region is undeniably encompassing dosage sensitive genes or elements whose change in copy number directly impact learning and memory, synaptic function and autistic related behavior.
    Genetics 04/2014; 197(3). DOI:10.1534/genetics.114.165241 · 5.96 Impact Factor
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