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NDAR provides a single access to de-identified autism research data. For permission to download data, you will need an NDAR account with approved access to NDAR or a connected repository (AGRE, IAN, or the ATP). For NDAR access, you need to be a research investigator sponsored by an NIH recognized institution with federal wide assurance. See Request Access for more information.

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Evan Eichler eee@gs.washington.edu Shared

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General

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Collection Summary Collection Charts
Collection Title Collection Investigators Collection Description
Genomic Identification of Autism Loci
Evan E Eichler  (Owner: Eichler, Evan)
The goal of this grant is to use a targeted approach to identify the genes responsible for autism. Three different approaches were put forward to focus on genomic regions associated with autism, each was a dedicated specific aim.

No Data Shared

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NIH None

http://www.nature.com/ng/journal/v43/n6/full/ng.835.html Software Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations Qualified Researchers
http://www.nature.com/ng/journal/v43/n6/full/ng.835.html Publication Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations Qualified Researchers
sequencing_files_readme_col_1878.pdf Background Readme for sequencing files Qualified Researchers

R01HD65285 Genomic Identification of Autism Loci 09/30/2009 08/31/2011 UNIVERSITY OF WASHINGTON

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Experiments

Omics, eye tracking, fMRI and EEG experiments can be defined here by selecting Add New. Once an experiment is created, then raw files for these types of experiments should be provided, associating the experiment – through Experiment_ID – with the metadata defined in the experiments interface.

ID Name Creation Date Status Type
45 Exome Sequencing of 20 Sporadic Cases of Autism Spectrum Disorder Jul 15, 2011 Approved Omics
64 Refinement and discovery of new hotspots of copy number variation associated with autism spectrum disorder Jul 24, 2012 Approved Omics
83 Molecular Inversion Probe Resequencing ASD1 Probe Set May 23, 2013 Approved Omics
84 Molecular Inversion Probe Resequencing ASD2 Probe Set May 23, 2013 Approved Omics
85 Molecular Inversion Probe Resequencing ASD1/2 Combined Probe Set May 23, 2013 Approved Omics
92 Whole Exome Sequencing of SSC samples Jul 26, 2013 Approved Omics

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Genomics Sample Genomics 6842
Genomics Subject Genomics 6305

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Publications

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R01HD65285 Genomic Identification of Autism Loci 09/30/2009 08/31/2011 UNIVERSITY OF WASHINGTON
  "Bioinformatics (Oxford, England)"  Targeted interrogation of copy number variation using SCIMMkit.  (E)PubDate: 10/21/2009
  "Nature genetics"  A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay.  (E)PubDate: 02/14/2010
  "Journal of neurodevelopmental disorders"  Speech delays and behavioral problems are the predominant features in individuals with developmental delays and 16p11.2 microdeletions and microduplications.  (E)PubDate: 03/19/2010

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Associated Studies

Studies that have been defined using data from a Collection are important criteria to determine the value of data shared. The number of subjects column displays the counts from this Collection that are included in a Study, out of the total number of subjects in that study. The Data Use column represents whether or not the study is a primary analysis of the data or a secondary analysis. State indicates whether the study is private or shared with the research community.

Study Name Description Number of Subjects
Collection / Total
Data Use State
Detection of structural variants and indels within exome data. We report an algorithm to detect structural variation and indels from 1 base pair (bp) to 1 Mbp within exome sequence data sets. Splitread uses one end-anchored placements to cluster the mappings of subsequences of unanchored ends to identify the size, content and location of variants with high specificity and sensitivity. The algorithm discovers indels, structural variants, de novo events and copy number-polymorphic processed pseudogenes missed by other methods. 60 / 60 Primary Analysis Shared
The contribution of de novo coding mutations to autism spectrum disorder Whole exome sequencing has proven to be a powerful tool for understanding the genetic architecture of human disease. Here we apply it to more than 2,500 simplex families, each having a child with an autistic spectrum disorder. By comparing affected to unaffected siblings, we show that 13% of de novo missense mutations and 43% of de novo likely gene-disrupting (LGD) mutations contribute to 12% and 9% of diagnoses, respectively. Including copy number variants, coding de novo mutations contribute to about 30% of all simplex and 45% of female diagnoses. Almost all LGD mutations occur opposite wild-type alleles. LGD targets in affected females significantly overlap the targets in males of lower intelligence quotient (IQ), but neither overlaps significantly with targets in males of higher IQ. We estimate that LGD mutation in about 400 genes can contribute to the joint class of affected females and males of lower IQ, with an overlapping and similar number of genes vulnerable to contributory missense mutation. LGD targets in the joint class overlap with published targets for intellectual disability and schizophrenia, and are enriched for chromatin modifiers, FMRP-associated genes and embryonically expressed genes. Most of the significance for the latter comes from affected females. 2426 / 9458 Primary Analysis Shared
Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations Evidence for the etiology of autism spectrum disorders (ASDs) has consistently pointed to a strong genetic component complicated by substantial locus heterogeneity. We sequenced the exomes of 20 individuals with sporadic ASD (cases) and their parents, reasoning that these families would be enriched for de novo mutations of major effect. We identified 21 de novo mutations, 11 of which were protein altering. Protein-altering mutations were significantly enriched for changes at highly conserved residues. We identified potentially causative de novo events in 4 out of 20 probands, particularly among more severely affected individuals, in FOXP1, GRIN2B, SCN1A and LAMC3. In the FOXP1 mutation carrier, we also observed a rare inherited CNTNAP2 missense variant, and we provide functional support for a multi-hit model for disease risk. Our results show that trio-based exome sequencing is a powerful approach for identifying new candidate genes for ASDs and suggest that de novo mutations may contribute substantially to the genetic etiology of ASDs. 60 / 60 Primary Analysis Shared
Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. In addition to cohorts of Parents (N=418), Siblings (N=50), and Probands (N=209), the publication publication describes a subset of male (N=47) and female (N=26) autistic subjects, with significant impairment and intellectual disability, and with cognitive impairment, respectively. These subsets have been defined based on hi/low IQ value in Supplementary Table 1 from the publication. Publication Abstract: It is well established that autism spectrum disorders (ASD) have a strong genetic component; however, for at least 70% of cases, the underlying genetic cause is unknown. Under the hypothesis that de novo mutations underlie a substantial fraction of the risk for developing ASD in families with no previous history of ASD or related phenotypes--so-called sporadic or simplex families--we sequenced all coding regions of the genome (the exome) for parent-child trios exhibiting sporadic ASD, including 189 new trios and 20 that were previously reported. Additionally, we also sequenced the exomes of 50 unaffected siblings corresponding to these new (n = 31) and previously reported trios (n = 19), for a total of 677 individual exomes from 209 families. Here we show that de novo point mutations are overwhelmingly paternal in origin (4:1 bias) and positively correlated with paternal age, consistent with the modest increased risk for children of older fathers to develop ASD. Moreover, 39% (49 of 126) of the most severe or disruptive de novo mutations map to a highly interconnected ¿-catenin/chromatin remodelling protein network ranked significantly for autism candidate genes. In proband exomes, recurrent protein-altering mutations were observed in two genes: CHD8 and NTNG1. Mutation screening of six candidate genes in 1,703 ASD probands identified additional de novo, protein-altering mutations in GRIN2B, LAMC3 and SCN1A. Combined with copy number variant (CNV) data, these results indicate extreme locus heterogeneity but also provide a target for future discovery, diagnostics and therapeutics. 677 / 677 Primary Analysis Shared
Multiplex Targeted Sequencing Identifies Recurrently Mutated Genes in Autism Spectrum Disorders Abstract: Exome sequencing studies of autism spectrum disorders (ASDs) have identified many de novo mutations but few recurrently disrupted genes. We therefore developed a modified molecular inversion probe method enabling ultra-low-cost candidate gene resequencing in very large cohorts. To demonstrate the power of this approach, we captured and sequenced 44 candidate genes in 2446 ASD probands. We discovered 27 de novo events in 16 genes, 59% of which are predicted to truncate proteins or disrupt splicing. We estimate that recurrent disruptive mutations in six genes-CHD8, DYRK1A, GRIN2B, TBR1, PTEN, and TBL1XR1¿may contribute to 1% of sporadic ASDs. Our data support associations between specific genes and reciprocal subphenotypes (CHD8-macrocephaly and DYRK1A-microcephaly) and replicate the importance of a B-catenin-chromatin-remodeling network to ASD etiology. 3262 / 3262 Primary Analysis Shared
Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder. Rare copy-number variants (CNVs) have been implicated in autism and intellectual disability. These variants are large and affect many genes but lack clear specificity toward autism as opposed to developmental-delay phenotypes. We exploited the repeat architecture of the genome to target segmental duplication-mediated rearrangement hotspots (n = 120, median size 1.78 Mbp, range 240 kbp to 13 Mbp) and smaller hotspots flanked by repetitive sequence (n = 1,247, median size 79 kbp, range 3-96 kbp) in 2,588 autistic individuals from simplex and multiplex families and in 580 controls. Our analysis identified several recurrent large hotspot events, including association with 1q21 duplications, which are more likely to be identified in individuals with autism than in those with developmental delay (p = 0.01; OR = 2.7). Within larger hotspots, we also identified smaller atypical CNVs that implicated CHD1L and ACACA for the 1q21 and 17q12 deletions, respectively. Our analysis, however, suggested no overall increase in the burden of smaller hotspots in autistic individuals as compared to controls. By focusing on gene-disruptive events, we identified recurrent CNVs, including DPP10, PLCB1, TRPM1, NRXN1, FHIT, and HYDIN, that are enriched in autism. We found that as the size of deletions increases, nonverbal IQ significantly decreases, but there is no impact on autism severity; and as the size of duplications increases, autism severity significantly increases but nonverbal IQ is not affected. The absence of an increased burden of smaller CNVs in individuals with autism and the failure of most large hotspots to refine to single genes is consistent with a model where imbalance of multiple genes contributes to a disease state. 3285 / 3285 Primary Analysis Shared
Transmission disequilibrium of small CNVs in simplex autism. Cohorts: 411 ASD Quads from Simons Simplex Collection 177 Quads from Sanders et al. (PubMed ID: 22495306) 166 Quads from I. Iossifov et al. (PubMed ID: 22542183) 71 Quads from O'Roak et al. (PubMed ID: 22495309) Publication Abstract: We searched for disruptive, genic rare copy-number variants (CNVs) among 411 families affected by sporadic autism spectrum disorder (ASD) from the Simons Simplex Collection by using available exome sequence data and CoNIFER (Copy Number Inference from Exome Reads). Compared to high-density SNP microarrays, our approach yielded ¿2× more smaller genic rare CNVs. We found that affected probands inherited more CNVs than did their siblings (453 versus 394, p = 0.004; odds ratio [OR] = 1.19) and that the probands' CNVs affected more genes (921 versus 726, p = 0.02; OR = 1.30). These smaller CNVs (median size 18 kb) were transmitted preferentially from the mother (136 maternal versus 100 paternal, p = 0.02), although this bias occurred irrespective of affected status. The excess burden of inherited CNVs among probands was driven primarily by sibling pairs with discordant social-behavior phenotypes (p < 0.0002, measured by Social Responsiveness Scale [SRS] score), which contrasts with families where the phenotypes were more closely matched or less extreme (p > 0.5). Finally, we found enrichment of brain-expressed genes unique to probands, especially in the SRS-discordant group (p = 0.0035). In a combined model, our inherited CNVs, de novo CNVs, and de novo single-nucleotide variants all independently contributed to the risk of autism (p < 0.05). Taken together, these results suggest that small transmitted rare CNVs play a role in the etiology of simplex autism. Importantly, the small size of these variants aids in the identification of specific genes as additional risk factors associated with ASD. 1643 / 1643 Primary Analysis Shared
* Data not on individual level
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