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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 du... Full description

Journal Title: American journal of human genetics 2013, Vol.92 (2), p.221-237
Main Author: Girirajan, Santhosh
Other Authors: Dennis, Megan Y , Baker, Carl , Malig, Maika , Coe, Bradley P , Campbell, Catarina D , Mark, Kenneth , Vu, Tiffany H , Alkan, Can , Cheng, Ze , Biesecker, Leslie G , Bernier, Raphael , Eichler, Evan E
Format: Electronic Article Electronic Article
Language: English
Subjects:
Quelle: Alma/SFX Local Collection
Publisher: United States: Elsevier Inc
ID: ISSN: 0002-9297
Link: https://www.ncbi.nlm.nih.gov/pubmed/23375656
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recordid: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3567267
title: Refinement and Discovery of New Hotspots of Copy-Number Variation Associated with Autism Spectrum Disorder
format: Article
creator:
  • Girirajan, Santhosh
  • Dennis, Megan Y
  • Baker, Carl
  • Malig, Maika
  • Coe, Bradley P
  • Campbell, Catarina D
  • Mark, Kenneth
  • Vu, Tiffany H
  • Alkan, Can
  • Cheng, Ze
  • Biesecker, Leslie G
  • Bernier, Raphael
  • Eichler, Evan E
subjects:
  • Analysis
  • Article
  • Autism
  • Biological variation
  • Case-Control Studies
  • Causes of
  • Child
  • Child Development Disorders, Pervasive - genetics
  • Chromosome Deletion
  • Chromosome Duplication - genetics
  • Diagnosis
  • DNA Copy Number Variations - genetics
  • DNA sequencing
  • Exons - genetics
  • Gene amplification
  • Gene Rearrangement - genetics
  • Genes
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Genetic research
  • Genetic variation
  • Genetics
  • Genetics(clinical)
  • Genome, Human - genetics
  • Genomics
  • Genotype & phenotype
  • Humans
  • mental disorders
  • Nucleotide sequencing
  • Phenotype
  • Segmental Duplications, Genomic - genetics
ispartof: American journal of human genetics, 2013, Vol.92 (2), p.221-237
description: 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.
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0002-9297
fulltext: fulltext
issn:
  • 0002-9297
  • 1537-6605
url: Link


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titleRefinement and Discovery of New Hotspots of Copy-Number Variation Associated with Autism Spectrum Disorder
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creatorGirirajan, Santhosh ; Dennis, Megan Y ; Baker, Carl ; Malig, Maika ; Coe, Bradley P ; Campbell, Catarina D ; Mark, Kenneth ; Vu, Tiffany H ; Alkan, Can ; Cheng, Ze ; Biesecker, Leslie G ; Bernier, Raphael ; Eichler, Evan E
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descriptionRare 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.
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subjectAnalysis ; Article ; Autism ; Biological variation ; Case-Control Studies ; Causes of ; Child ; Child Development Disorders, Pervasive - genetics ; Chromosome Deletion ; Chromosome Duplication - genetics ; Diagnosis ; DNA Copy Number Variations - genetics ; DNA sequencing ; Exons - genetics ; Gene amplification ; Gene Rearrangement - genetics ; Genes ; Genetic Association Studies ; Genetic Predisposition to Disease ; Genetic research ; Genetic variation ; Genetics ; Genetics(clinical) ; Genome, Human - genetics ; Genomics ; Genotype & phenotype ; Humans ; mental disorders ; Nucleotide sequencing ; Phenotype ; Segmental Duplications, Genomic - genetics
ispartofAmerican journal of human genetics, 2013, Vol.92 (2), p.221-237
rights
02013 The American Society of Human Genetics
1Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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42013 The American Society of Human Genetics. Published by Elsevier Ltd. All right reserved. 2013 The American Society of Human Genetics
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10Biesecker, Leslie G
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descriptionRare 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.
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titleRefinement and Discovery of New Hotspots of Copy-Number Variation Associated with Autism Spectrum Disorder
authorGirirajan, Santhosh ; Dennis, Megan Y ; Baker, Carl ; Malig, Maika ; Coe, Bradley P ; Campbell, Catarina D ; Mark, Kenneth ; Vu, Tiffany H ; Alkan, Can ; Cheng, Ze ; Biesecker, Leslie G ; Bernier, Raphael ; Eichler, Evan E
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abstractRare 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.
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