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Detection of Clinically Relevant Genetic Variants in Autism Spectrum Disorder by Whole-Genome Sequencing

Autism Spectrum Disorder (ASD) demonstrates high heritability and familial clustering, yet the genetic causes remain only partially understood as a result of extensive clinical and genomic heterogeneity. Whole-genome sequencing (WGS) shows promise as a tool for identifying ASD risk genes as well as... Full description

Journal Title: American journal of human genetics 2013-08-08, Vol.93 (2), p.249-263
Main Author: Jiang, Yong-hui
Other Authors: Yuen, Ryan K.C , Jin, Xin , Wang, Mingbang , Chen, Nong , Wu, Xueli , Ju, Jia , Mei, Junpu , Shi, Yujian , He, Mingze , Wang, Guangbiao , Liang, Jieqin , Wang, Zhe , Cao, Dandan , Carter, Melissa T , Chrysler, Christina , Drmic, Irene E , Howe, Jennifer L , Lau, Lynette , Marshall, Christian R , Merico, Daniele , Nalpathamkalam, Thomas , Thiruvahindrapuram, Bhooma , Thompson, Ann , Uddin, Mohammed , Walker, Susan , Luo, Jun , Anagnostou, Evdokia , Zwaigenbaum, Lonnie , Ring, Robert H , Wang, Jian , Lajonchere, Clara , Wang, Jun , Shih, Andy , Szatmari, Peter , Yang, Huanming , Dawson, Geraldine , Li, Yingrui , Scherer, Stephen W
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/23849776
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title: Detection of Clinically Relevant Genetic Variants in Autism Spectrum Disorder by Whole-Genome Sequencing
format: Article
creator:
  • Jiang, Yong-hui
  • Yuen, Ryan K.C
  • Jin, Xin
  • Wang, Mingbang
  • Chen, Nong
  • Wu, Xueli
  • Ju, Jia
  • Mei, Junpu
  • Shi, Yujian
  • He, Mingze
  • Wang, Guangbiao
  • Liang, Jieqin
  • Wang, Zhe
  • Cao, Dandan
  • Carter, Melissa T
  • Chrysler, Christina
  • Drmic, Irene E
  • Howe, Jennifer L
  • Lau, Lynette
  • Marshall, Christian R
  • Merico, Daniele
  • Nalpathamkalam, Thomas
  • Thiruvahindrapuram, Bhooma
  • Thompson, Ann
  • Uddin, Mohammed
  • Walker, Susan
  • Luo, Jun
  • Anagnostou, Evdokia
  • Zwaigenbaum, Lonnie
  • Ring, Robert H
  • Wang, Jian
  • Lajonchere, Clara
  • Wang, Jun
  • Shih, Andy
  • Szatmari, Peter
  • Yang, Huanming
  • Dawson, Geraldine
  • Li, Yingrui
  • Scherer, Stephen W
subjects:
  • Adult
  • Article
  • Autism
  • Bioinformatics
  • Child
  • Child Development Disorders, Pervasive - genetics
  • DNA sequencing
  • Female
  • Genetic aspects
  • Genetic Heterogeneity
  • Genetic Predisposition to Disease
  • Genetic research
  • Genetic variation
  • Genetics
  • Genetics(clinical)
  • Genome
  • Genomes
  • Genomics
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Male
  • mental disorders
  • Mutation
  • Neurogenetics
  • Nucleotide sequencing
  • Pedigree
  • Physiological aspects
ispartof: American journal of human genetics, 2013-08-08, Vol.93 (2), p.249-263
description: Autism Spectrum Disorder (ASD) demonstrates high heritability and familial clustering, yet the genetic causes remain only partially understood as a result of extensive clinical and genomic heterogeneity. Whole-genome sequencing (WGS) shows promise as a tool for identifying ASD risk genes as well as unreported mutations in known loci, but an assessment of its full utility in an ASD group has not been performed. We used WGS to examine 32 families with ASD to detect de novo or rare inherited genetic variants predicted to be deleterious (loss-of-function and damaging missense mutations). Among ASD probands, we identified deleterious de novo mutations in six of 32 (19%) families and X-linked or autosomal inherited alterations in ten of 32 (31%) families (some had combinations of mutations). The proportion of families identified with such putative mutations was larger than has been previously reported; this yield was in part due to the comprehensive and uniform coverage afforded by WGS. Deleterious variants were found in four unrecognized, nine known, and eight candidate ASD risk genes. Examples include CAPRIN1 and AFF2 (both linked to FMR1, which is involved in fragile X syndrome), VIP (involved in social-cognitive deficits), and other genes such as SCN2A and KCNQ2 (linked to epilepsy), NRXN1, and CHD7, which causes ASD-associated CHARGE syndrome. Taken together, these results suggest that WGS and thorough bioinformatic analyses for de novo and rare inherited mutations will improve the detection of genetic variants likely to be associated with ASD or its accompanying clinical symptoms.
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0002-9297
fulltext: fulltext
issn:
  • 0002-9297
  • 1537-6605
url: Link


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titleDetection of Clinically Relevant Genetic Variants in Autism Spectrum Disorder by Whole-Genome Sequencing
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creatorJiang, Yong-hui ; Yuen, Ryan K.C ; Jin, Xin ; Wang, Mingbang ; Chen, Nong ; Wu, Xueli ; Ju, Jia ; Mei, Junpu ; Shi, Yujian ; He, Mingze ; Wang, Guangbiao ; Liang, Jieqin ; Wang, Zhe ; Cao, Dandan ; Carter, Melissa T ; Chrysler, Christina ; Drmic, Irene E ; Howe, Jennifer L ; Lau, Lynette ; Marshall, Christian R ; Merico, Daniele ; Nalpathamkalam, Thomas ; Thiruvahindrapuram, Bhooma ; Thompson, Ann ; Uddin, Mohammed ; Walker, Susan ; Luo, Jun ; Anagnostou, Evdokia ; Zwaigenbaum, Lonnie ; Ring, Robert H ; Wang, Jian ; Lajonchere, Clara ; Wang, Jun ; Shih, Andy ; Szatmari, Peter ; Yang, Huanming ; Dawson, Geraldine ; Li, Yingrui ; Scherer, Stephen W
creatorcontribJiang, Yong-hui ; Yuen, Ryan K.C ; Jin, Xin ; Wang, Mingbang ; Chen, Nong ; Wu, Xueli ; Ju, Jia ; Mei, Junpu ; Shi, Yujian ; He, Mingze ; Wang, Guangbiao ; Liang, Jieqin ; Wang, Zhe ; Cao, Dandan ; Carter, Melissa T ; Chrysler, Christina ; Drmic, Irene E ; Howe, Jennifer L ; Lau, Lynette ; Marshall, Christian R ; Merico, Daniele ; Nalpathamkalam, Thomas ; Thiruvahindrapuram, Bhooma ; Thompson, Ann ; Uddin, Mohammed ; Walker, Susan ; Luo, Jun ; Anagnostou, Evdokia ; Zwaigenbaum, Lonnie ; Ring, Robert H ; Wang, Jian ; Lajonchere, Clara ; Wang, Jun ; Shih, Andy ; Szatmari, Peter ; Yang, Huanming ; Dawson, Geraldine ; Li, Yingrui ; Scherer, Stephen W
descriptionAutism Spectrum Disorder (ASD) demonstrates high heritability and familial clustering, yet the genetic causes remain only partially understood as a result of extensive clinical and genomic heterogeneity. Whole-genome sequencing (WGS) shows promise as a tool for identifying ASD risk genes as well as unreported mutations in known loci, but an assessment of its full utility in an ASD group has not been performed. We used WGS to examine 32 families with ASD to detect de novo or rare inherited genetic variants predicted to be deleterious (loss-of-function and damaging missense mutations). Among ASD probands, we identified deleterious de novo mutations in six of 32 (19%) families and X-linked or autosomal inherited alterations in ten of 32 (31%) families (some had combinations of mutations). The proportion of families identified with such putative mutations was larger than has been previously reported; this yield was in part due to the comprehensive and uniform coverage afforded by WGS. Deleterious variants were found in four unrecognized, nine known, and eight candidate ASD risk genes. Examples include CAPRIN1 and AFF2 (both linked to FMR1, which is involved in fragile X syndrome), VIP (involved in social-cognitive deficits), and other genes such as SCN2A and KCNQ2 (linked to epilepsy), NRXN1, and CHD7, which causes ASD-associated CHARGE syndrome. Taken together, these results suggest that WGS and thorough bioinformatic analyses for de novo and rare inherited mutations will improve the detection of genetic variants likely to be associated with ASD or its accompanying clinical symptoms.
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subjectAdult ; Article ; Autism ; Bioinformatics ; Child ; Child Development Disorders, Pervasive - genetics ; DNA sequencing ; Female ; Genetic aspects ; Genetic Heterogeneity ; Genetic Predisposition to Disease ; Genetic research ; Genetic variation ; Genetics ; Genetics(clinical) ; Genome ; Genomes ; Genomics ; High-Throughput Nucleotide Sequencing ; Humans ; Male ; mental disorders ; Mutation ; Neurogenetics ; Nucleotide sequencing ; Pedigree ; Physiological aspects
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17Howe, Jennifer L
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19Marshall, Christian R
20Merico, Daniele
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24Uddin, Mohammed
25Walker, Susan
26Luo, Jun
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28Zwaigenbaum, Lonnie
29Ring, Robert H
30Wang, Jian
31Lajonchere, Clara
32Wang, Jun
33Shih, Andy
34Szatmari, Peter
35Yang, Huanming
36Dawson, Geraldine
37Li, Yingrui
38Scherer, Stephen W
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0Detection of Clinically Relevant Genetic Variants in Autism Spectrum Disorder by Whole-Genome Sequencing
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descriptionAutism Spectrum Disorder (ASD) demonstrates high heritability and familial clustering, yet the genetic causes remain only partially understood as a result of extensive clinical and genomic heterogeneity. Whole-genome sequencing (WGS) shows promise as a tool for identifying ASD risk genes as well as unreported mutations in known loci, but an assessment of its full utility in an ASD group has not been performed. We used WGS to examine 32 families with ASD to detect de novo or rare inherited genetic variants predicted to be deleterious (loss-of-function and damaging missense mutations). Among ASD probands, we identified deleterious de novo mutations in six of 32 (19%) families and X-linked or autosomal inherited alterations in ten of 32 (31%) families (some had combinations of mutations). The proportion of families identified with such putative mutations was larger than has been previously reported; this yield was in part due to the comprehensive and uniform coverage afforded by WGS. Deleterious variants were found in four unrecognized, nine known, and eight candidate ASD risk genes. Examples include CAPRIN1 and AFF2 (both linked to FMR1, which is involved in fragile X syndrome), VIP (involved in social-cognitive deficits), and other genes such as SCN2A and KCNQ2 (linked to epilepsy), NRXN1, and CHD7, which causes ASD-associated CHARGE syndrome. Taken together, these results suggest that WGS and thorough bioinformatic analyses for de novo and rare inherited mutations will improve the detection of genetic variants likely to be associated with ASD or its accompanying clinical symptoms.
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titleDetection of Clinically Relevant Genetic Variants in Autism Spectrum Disorder by Whole-Genome Sequencing
authorJiang, Yong-hui ; Yuen, Ryan K.C ; Jin, Xin ; Wang, Mingbang ; Chen, Nong ; Wu, Xueli ; Ju, Jia ; Mei, Junpu ; Shi, Yujian ; He, Mingze ; Wang, Guangbiao ; Liang, Jieqin ; Wang, Zhe ; Cao, Dandan ; Carter, Melissa T ; Chrysler, Christina ; Drmic, Irene E ; Howe, Jennifer L ; Lau, Lynette ; Marshall, Christian R ; Merico, Daniele ; Nalpathamkalam, Thomas ; Thiruvahindrapuram, Bhooma ; Thompson, Ann ; Uddin, Mohammed ; Walker, Susan ; Luo, Jun ; Anagnostou, Evdokia ; Zwaigenbaum, Lonnie ; Ring, Robert H ; Wang, Jian ; Lajonchere, Clara ; Wang, Jun ; Shih, Andy ; Szatmari, Peter ; Yang, Huanming ; Dawson, Geraldine ; Li, Yingrui ; Scherer, Stephen W
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19Marshall, Christian R
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21Nalpathamkalam, Thomas
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8Shi, Yujian
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24Uddin, Mohammed
25Walker, Susan
26Luo, Jun
27Anagnostou, Evdokia
28Zwaigenbaum, Lonnie
29Ring, Robert H
30Wang, Jian
31Lajonchere, Clara
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33Shih, Andy
34Szatmari, Peter
35Yang, Huanming
36Dawson, Geraldine
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abstractAutism Spectrum Disorder (ASD) demonstrates high heritability and familial clustering, yet the genetic causes remain only partially understood as a result of extensive clinical and genomic heterogeneity. Whole-genome sequencing (WGS) shows promise as a tool for identifying ASD risk genes as well as unreported mutations in known loci, but an assessment of its full utility in an ASD group has not been performed. We used WGS to examine 32 families with ASD to detect de novo or rare inherited genetic variants predicted to be deleterious (loss-of-function and damaging missense mutations). Among ASD probands, we identified deleterious de novo mutations in six of 32 (19%) families and X-linked or autosomal inherited alterations in ten of 32 (31%) families (some had combinations of mutations). The proportion of families identified with such putative mutations was larger than has been previously reported; this yield was in part due to the comprehensive and uniform coverage afforded by WGS. Deleterious variants were found in four unrecognized, nine known, and eight candidate ASD risk genes. Examples include CAPRIN1 and AFF2 (both linked to FMR1, which is involved in fragile X syndrome), VIP (involved in social-cognitive deficits), and other genes such as SCN2A and KCNQ2 (linked to epilepsy), NRXN1, and CHD7, which causes ASD-associated CHARGE syndrome. Taken together, these results suggest that WGS and thorough bioinformatic analyses for de novo and rare inherited mutations will improve the detection of genetic variants likely to be associated with ASD or its accompanying clinical symptoms.
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pmid23849776
doi10.1016/j.ajhg.2013.06.012
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