CoChat
Sign Up
Cited by 424Autism Spectrum Disorder ResearchGenomic variations and chromosomal abnormalitiesGenetics and Neurodevelopmental Disorders

The DOI matches its Crossref record; 60 of the 60 references it cites were found in a registry or an index.

Genome-Wide Analyses of Exonic Copy Number Variants in a Family-Based Study Point to Novel Autism Susceptibility Genes

Open access
Bucan, Maja, Abrahams, Brett S., Wang, Kai, Glessner, Joseph T., Herman, Edward I., Sonnenblick, Lisa I., Alvarez Retuerto, Ana I., Imielinski, Marcin, Hadley, Dexter, Bradfield, Jonathan P., Kim, Cecilia, Gidaya, Nicole B., Lindquist, Ingrid, Hutman, Ted, Sigman, Marian, Kustanovich, Vlad, Lajonchere, Clara M., Singleton, Andrew, Kim, Junhyong, Wassink, Thomas H., McMahon, William M., Owley, Thomas, Sweeney, John A., Coon, Hilary, Nurnberger, John I., Li, Mingyao, Cantor, Rita M., Minshew, Nancy J., Sutcliffe, James S., Cook, Edwin H., Dawson, Geraldine, Buxbaum, Joseph D., Grant, Struan F. A., Schellenberg, Gerard D., Geschwind, Daniel H., Hakonarson, Hakon·2009·PLoS Genetics
DOI 10.1371/journal.pgen.1000536PMC PMC2695001
Open this paper in CoChat — free accountOpen PDF

Abstract

The genetics underlying the autism spectrum disorders (ASDs) is complex and remains poorly understood. Previous work has demonstrated an important role for structural variation in a subset of cases, but has lacked the resolution necessary to move beyond detection of large regions of potential interest to identification of individual genes. To pinpoint genes likely to contribute to ASD etiology, we performed high density genotyping in 912 multiplex families from the Autism Genetics Resource Exchange (AGRE) collection and contrasted results to those obtained for 1,488 healthy controls. Through prioritization of exonic deletions (eDels), exonic duplications (eDups), and whole gene duplication events (gDups), we identified more than 150 loci harboring rare variants in multiple unrelated probands, but no controls. Importantly, 27 of these were confirmed on examination of an independent replication cohort comprised of 859 cases and an additional 1,051 controls. Rare variants at known loci, including exonic deletions at NRXN1 and whole gene duplications encompassing UBE3A and several other genes in the 15q11-q13 region, were observed in the course of these analyses. Strong support was likewise observed for previously unreported genes such as BZRAP1, an adaptor molecule known to regulate synaptic transmission, with eDels or eDups observed in twelve unrelated cases but no controls (p = 2.3x10(-5)). Less is known about MDGA2, likewise observed to be case-specific (p = 1.3x10(-4)). But, it is notable that the encoded protein shows an unexpectedly high similarity to Contactin 4 (BLAST E-value = 3x10(-39)), which has also been linked to disease. That hundreds of distinct rare variants were each seen only once further highlights complexity in the ASDs and points to the continued need for larger cohorts.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1371/journal.pgen.1000536

Cites

60 of 60 references verified0 citation errors · 0 not checkable

Statistics

Figures

Figure 1 TaqMan experiments validate large de novo CNV calls. To validate results using an independent method we designed TaqMan assays to evaluate gene dosage. Results from representative experiments highlight results at loci at 1q21, 8q21, and 10q24. AGRE individual harboring deletions (red arrows) or gains (green arrows) are indicated.
Figure 1 TaqMan experiments validate large de novo CNV calls. To validate results using an independent method we designed TaqMan assays to evaluate gene dosage. Results from representative experiments highlight results at loci at 1q21, 8q21, and 10q24. AGRE individual harboring deletions (red arrows) or gains (green arrows) are indicated.CC0 · PubMed Central
Figure 2 Rare exonic deletions (eDels) in NRXN1 and novel candidate genes alter predicted protein structures. For each of BZRAP1 (a) NRXN1 (b) and MDGA2 (c) reference loci and encoded proteins (top) are contrasted against mutant loci and corresponding proteins (bottom; grey shading). Unique genomic deletions and corresponding protein truncations are highlighted in red and with black hatching, respectively. Schematized protein domains genes are as follows: BZRAP1—Src homology-3 (orange square), Fibronectin, type III (blue oval); NRXN1—Laminin G (orange hexagon), EGF-like (blue oval), 4.1 binding motif (green rectangle); MDGA2—IG-like domains (blue pentagon), MAM aka Meprin/A5-protein/PTPmu (blue oval).
Figure 2 Rare exonic deletions (eDels) in NRXN1 and novel candidate genes alter predicted protein structures. For each of BZRAP1 (a) NRXN1 (b) and MDGA2 (c) reference loci and encoded proteins (top) are contrasted against mutant loci and corresponding proteins (bottom; grey shading). Unique genomic deletions and corresponding protein truncations are highlighted in red and with black hatching, respectively. Schematized protein domains genes are as follows: BZRAP1—Src homology-3 (orange square), Fibronectin, type III (blue oval); NRXN1—Laminin G (orange hexagon), EGF-like (blue oval), 4.1 binding motif (green rectangle); MDGA2—IG-like domains (blue pentagon), MAM aka Meprin/A5-protein/PTPmu (blue oval).CC0 · PubMed Central
Figure 3 Observed replication unlikely to be attributable to chance alone. We performed 10,000 phenotype permutation trials on replication data and determined for each the number of loci harboring CNVs in cases but not controls. Thus, within each trial, the number of loci absent from controls in the replication cohort was determined. None of the permutation trials generated as many case-specific loci as observed in our actual dataset (n = 14; p<0.0001).
Figure 3 Observed replication unlikely to be attributable to chance alone. We performed 10,000 phenotype permutation trials on replication data and determined for each the number of loci harboring CNVs in cases but not controls. Thus, within each trial, the number of loci absent from controls in the replication cohort was determined. None of the permutation trials generated as many case-specific loci as observed in our actual dataset (n = 14; p<0.0001).CC0 · PubMed Central
Figure 4 Exonic deletions, although enriched in cases versus controls, show imperfect segregation with disease in multiplex families. Pedigrees for representative AGRE families harboring exonic deletions in BZRAP1 (A,B), kb), NRXN1 (C,D), and MDGA2 (E,F) are illustrated. Red filled circles correspond to exonic deletions. Black stars (upper right) highlight individuals for which CNV calls were not obtained (not genotyped or failing to meet criteria for quality control).
Figure 4 Exonic deletions, although enriched in cases versus controls, show imperfect segregation with disease in multiplex families. Pedigrees for representative AGRE families harboring exonic deletions in BZRAP1 (A,B), kb), NRXN1 (C,D), and MDGA2 (E,F) are illustrated. Red filled circles correspond to exonic deletions. Black stars (upper right) highlight individuals for which CNV calls were not obtained (not genotyped or failing to meet criteria for quality control).CC0 · PubMed Central

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 60 references

Cited by

Sorted by citations

Items 201–300 of 424

Related

See all

Metadata

Authors
Bucan, M., Abrahams, B. S., Wang, K., Glessner, J. T., Herman, E. I., Sonnenblick, L. I., Alvarez Retuerto, A. I., Imielinski, M., Hadley, D., Bradfield, J. P., Kim, C., Gidaya, N. B., Lindquist, I., Hutman, T., Sigman, M., Kustanovich, V., Lajonchere, C. M., Singleton, A., Kim, J., Wassink, T. H., McMahon, W. M., Owley, T., Sweeney, J. A., Coon, H., Nurnberger, J. I., Li, M., Cantor, R. M., Minshew, N. J., Sutcliffe, J. S., Cook, E. H., Dawson, G., Buxbaum, J. D., Grant, S. F. A., Schellenberg, G. D., Geschwind, D. H., & Hakonarson, H.
Affiliations
  • University of California, Los Angeles (US)
  • Children's Hospital of Philadelphia (US)
  • University of Pennsylvania (US)
  • Autism Speaks (US)
  • National Institutes of Health (US)
  • University of Iowa (US)
  • University of Utah (US)
  • University of Illinois Chicago (US)
  • University of Pittsburgh (US)
  • Vanderbilt University (US)
  • Icahn School of Medicine at Mount Sinai (US)
Corresponding author
Hakonarson, Hakon
ORCID
Venue
PLoS Genetics
Publisher
Public Library of Science (PLoS)
Published
2009-06-26
Volume
5
Issue
6
Pages
e1000536
ISSN
  • 1553-7390 (ISSN-L)
  • 1553-7404
DOI
10.1371/journal.pgen.1000536
PMC
PMC2695001
OpenAlex
W2125432692
Cited by
424
References
60
Citations by year
2026: 12 · 2025: 9 · 2024: 9 · 2023: 13 · 2022: 9 · 2021: 15 · 2020: 16 · 2019: 16 · 2018: 18 · 2017: 24 · 2016: 24 · 2015: 24 · 2014: 39 · 2013: 36 · 2012: 46
FWCI
25.74
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Genetics (publishedVersion, public-domain)
  • PubMed Central (publishedVersion, public-domain)
  • PubMed (publishedVersion)
  • D-Scholarship@Pitt (University of Pittsburgh) (acceptedVersion)
  • Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DukeSpace (Duke University) (submittedVersion, cc-by-nc-nd)
  • eScholarship (California Digital Library) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, public-domain)
  • Figshare (submittedVersion, cc-by)
  • UNC Libraries
Funders
  • U.S. Department of Health and Human Services
  • Autism Speaks
  • Massachusetts General Hospital
  • Yale University
  • Children's Hospital of Philadelphia (UL1-RR-024134)
  • University of Pennsylvania
  • Emory University
  • George Washington University
  • National Alliance for Research on Schizophrenia and Depression
  • Cotswold Foundation
  • National Institutes of Health (Z01-AG000949)
  • National Institute on Aging (K24AG000949, Z01AG000949)
  • National Institute of Mental Health (U24MH081810, MH081754, R01MH081754, R01MH604687)
  • National Institute of General Medical Sciences (P20GM069012, P20-GM69012)
  • National Center for Research Resources (UL1-RR024134-03, UL1RR024134)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (P50HD055784)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
autism spectrum disorder, copy number variation, exon deletion, autism susceptibility genes, structural variants, multiplex families, NRXN1, UBE3A, 15q11-q13, rare variants, gene prioritization
MeSH terms
Adolescent, Autistic Disorder, Calcium-Binding Proteins, Child, Child, Preschool, Exons, Female, Humans, Male, Nerve Tissue Proteins, Pedigree, Cohort Studies, Cell Adhesion Molecules, Neuronal, Case-Control Studies, Sequence Deletion, Gene Dosage, Neural Cell Adhesion Molecules, Genetic Predisposition to Disease, Gene Duplication, Ubiquitin-Protein Ligases, Genome-Wide Association Study, Young Adult

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review