Homozygous and hemizygous CNV detection from exome sequencing data in a Mendelian disease cohort
We developed an algorithm, HMZDelFinder, that uses whole exome sequencing (WES) data to identify rare and intragenic homozygous and hemizygous (HMZ) deletions that may represent complete loss-of-function of the indicated gene. HMZDelFinder was applied to 4866 samples in the Baylor-Hopkins Center for...
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Published in | Nucleic acids research Vol. 45; no. 4; pp. gkw1237 - 1648 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
England
Oxford University Press
28.02.2017
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Subjects | |
Online Access | Get full text |
ISSN | 0305-1048 1362-4962 1362-4962 |
DOI | 10.1093/nar/gkw1237 |
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Abstract | We developed an algorithm, HMZDelFinder, that uses whole exome sequencing (WES) data to identify rare and intragenic homozygous and hemizygous (HMZ) deletions that may represent complete loss-of-function of the indicated gene. HMZDelFinder was applied to 4866 samples in the Baylor-Hopkins Center for Mendelian Genomics (BHCMG) cohort and detected 773 HMZ deletion calls (567 homozygous or 206 hemizygous) with an estimated sensitivity of 86.5% (82% for single-exonic and 88% for multi-exonic calls) and precision of 78% (53% single-exonic and 96% for multi-exonic calls). Out of 773 HMZDelFinder-detected deletion calls, 82 were subjected to array comparative genomic hybridization (aCGH) and/or breakpoint PCR and 64 were confirmed. These include 18 single-exon deletions out of which 8 were exclusively detected by HMZDelFinder and not by any of seven other CNV detection tools examined. Further investigation of the 64 validated deletion calls revealed at least 15 pathogenic HMZ deletions. Of those, 7 accounted for 17-50% of pathogenic CNVs in different disease cohorts where 7.1-11% of the molecular diagnosis solved rate was attributed to CNVs. In summary, we present an algorithm to detect rare, intragenic, single-exon deletion CNVs using WES data; this tool can be useful for disease gene discovery efforts and clinical WES analyses. |
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AbstractList | We developed an algorithm, HMZDelFinder, that uses whole exome sequencing (WES) data to identify rare and intragenic homozygous and hemizygous (HMZ) deletions that may represent complete loss-of-function of the indicated gene. HMZDelFinder was applied to 4866 samples in the Baylor–Hopkins Center for Mendelian Genomics (BHCMG) cohort and detected 773 HMZ deletion calls (567 homozygous or 206 hemizygous) with an estimated sensitivity of 86.5% (82% for single-exonic and 88% for multi-exonic calls) and precision of 78% (53% single-exonic and 96% for multi-exonic calls). Out of 773 HMZDelFinder-detected deletion calls, 82 were subjected to array comparative genomic hybridization (aCGH) and/or breakpoint PCR and 64 were confirmed. These include 18 single-exon deletions out of which 8 were exclusively detected by HMZDelFinder and not by any of seven other CNV detection tools examined. Further investigation of the 64 validated deletion calls revealed at least 15 pathogenic HMZ deletions. Of those, 7 accounted for 17–50% of pathogenic CNVs in different disease cohorts where 7.1–11% of the molecular diagnosis solved rate was attributed to CNVs. In summary, we present an algorithm to detect rare, intragenic, single-exon deletion CNVs using WES data; this tool can be useful for disease gene discovery efforts and clinical WES analyses. We developed an algorithm, HMZDelFinder, that uses whole exome sequencing (WES) data to identify rare and intragenic homozygous and hemizygous (HMZ) deletions that may represent complete loss-of-function of the indicated gene. HMZDelFinder was applied to 4866 samples in the Baylor-Hopkins Center for Mendelian Genomics (BHCMG) cohort and detected 773 HMZ deletion calls (567 homozygous or 206 hemizygous) with an estimated sensitivity of 86.5% (82% for single-exonic and 88% for multi-exonic calls) and precision of 78% (53% single-exonic and 96% for multi-exonic calls). Out of 773 HMZDelFinder-detected deletion calls, 82 were subjected to array comparative genomic hybridization (aCGH) and/or breakpoint PCR and 64 were confirmed. These include 18 single-exon deletions out of which 8 were exclusively detected by HMZDelFinder and not by any of seven other CNV detection tools examined. Further investigation of the 64 validated deletion calls revealed at least 15 pathogenic HMZ deletions. Of those, 7 accounted for 17-50% of pathogenic CNVs in different disease cohorts where 7.1-11% of the molecular diagnosis solved rate was attributed to CNVs. In summary, we present an algorithm to detect rare, intragenic, single-exon deletion CNVs using WES data; this tool can be useful for disease gene discovery efforts and clinical WES analyses.We developed an algorithm, HMZDelFinder, that uses whole exome sequencing (WES) data to identify rare and intragenic homozygous and hemizygous (HMZ) deletions that may represent complete loss-of-function of the indicated gene. HMZDelFinder was applied to 4866 samples in the Baylor-Hopkins Center for Mendelian Genomics (BHCMG) cohort and detected 773 HMZ deletion calls (567 homozygous or 206 hemizygous) with an estimated sensitivity of 86.5% (82% for single-exonic and 88% for multi-exonic calls) and precision of 78% (53% single-exonic and 96% for multi-exonic calls). Out of 773 HMZDelFinder-detected deletion calls, 82 were subjected to array comparative genomic hybridization (aCGH) and/or breakpoint PCR and 64 were confirmed. These include 18 single-exon deletions out of which 8 were exclusively detected by HMZDelFinder and not by any of seven other CNV detection tools examined. Further investigation of the 64 validated deletion calls revealed at least 15 pathogenic HMZ deletions. Of those, 7 accounted for 17-50% of pathogenic CNVs in different disease cohorts where 7.1-11% of the molecular diagnosis solved rate was attributed to CNVs. In summary, we present an algorithm to detect rare, intragenic, single-exon deletion CNVs using WES data; this tool can be useful for disease gene discovery efforts and clinical WES analyses. |
Author | Yuan, Bo Eldomery, Mohammad K. Belmont, John W. Beaudet, Arthur L. Gibbs, Richard A. Chiang, Theodore Karaca, Ender Boone, Philip M. Bayram, Yavuz Akdemir, Zeynep C. Gu, Shen Shaw, Chad Bahrambeigi, Vahid Muzny, Donna Boerwinkle, Eric Jhangiani, Shalini Charng, Wu-Lin Lupski, James R. Gambin, Tomasz Carvalho, Claudia M.B. Stray-Pedersen, Asbjørg |
AuthorAffiliation | 5 Graduate Program in Diagnostic Genetics, School of Health Professions, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 6 Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX 77030, USA 8 Texas Children's Hospital, Houston, TX 77030, USA 2 Institute of Computer Science, Warsaw University of Technology, Warsaw, 00-665 Warsaw, Poland 3 Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA 7 Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA 1 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA 4 Norwegian National Unit for Newborn Screening, Division for Pediatric and Adolescent Medicine, Oslo University Hospital, N-0424 Oslo, Norway |
AuthorAffiliation_xml | – name: 2 Institute of Computer Science, Warsaw University of Technology, Warsaw, 00-665 Warsaw, Poland – name: 6 Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX 77030, USA – name: 7 Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA – name: 1 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA – name: 3 Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA – name: 5 Graduate Program in Diagnostic Genetics, School of Health Professions, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA – name: 8 Texas Children's Hospital, Houston, TX 77030, USA – name: 4 Norwegian National Unit for Newborn Screening, Division for Pediatric and Adolescent Medicine, Oslo University Hospital, N-0424 Oslo, Norway |
Author_xml | – sequence: 1 givenname: Tomasz surname: Gambin fullname: Gambin, Tomasz – sequence: 2 givenname: Zeynep C. surname: Akdemir fullname: Akdemir, Zeynep C. – sequence: 3 givenname: Bo surname: Yuan fullname: Yuan, Bo – sequence: 4 givenname: Shen surname: Gu fullname: Gu, Shen – sequence: 5 givenname: Theodore surname: Chiang fullname: Chiang, Theodore – sequence: 6 givenname: Claudia M.B. surname: Carvalho fullname: Carvalho, Claudia M.B. – sequence: 7 givenname: Chad surname: Shaw fullname: Shaw, Chad – sequence: 8 givenname: Shalini surname: Jhangiani fullname: Jhangiani, Shalini – sequence: 9 givenname: Philip M. surname: Boone fullname: Boone, Philip M. – sequence: 10 givenname: Mohammad K. surname: Eldomery fullname: Eldomery, Mohammad K. – sequence: 11 givenname: Ender surname: Karaca fullname: Karaca, Ender – sequence: 12 givenname: Yavuz surname: Bayram fullname: Bayram, Yavuz – sequence: 13 givenname: Asbjørg surname: Stray-Pedersen fullname: Stray-Pedersen, Asbjørg – sequence: 14 givenname: Donna surname: Muzny fullname: Muzny, Donna – sequence: 15 givenname: Wu-Lin surname: Charng fullname: Charng, Wu-Lin – sequence: 16 givenname: Vahid surname: Bahrambeigi fullname: Bahrambeigi, Vahid – sequence: 17 givenname: John W. surname: Belmont fullname: Belmont, John W. – sequence: 18 givenname: Eric surname: Boerwinkle fullname: Boerwinkle, Eric – sequence: 19 givenname: Arthur L. surname: Beaudet fullname: Beaudet, Arthur L. – sequence: 20 givenname: Richard A. surname: Gibbs fullname: Gibbs, Richard A. – sequence: 21 givenname: James R. orcidid: 0000-0001-9907-9246 surname: Lupski fullname: Lupski, James R. |
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Snippet | We developed an algorithm, HMZDelFinder, that uses whole exome sequencing (WES) data to identify rare and intragenic homozygous and hemizygous (HMZ) deletions... |
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StartPage | gkw1237 |
SubjectTerms | Algorithms Alternative Splicing Cohort Studies Computational Biology Computational Biology - methods Consanguinity Datasets as Topic DNA Copy Number Variations Exome Genetic Diseases, Inborn - diagnosis Genetic Diseases, Inborn - genetics Hemizygote High-Throughput Nucleotide Sequencing Homozygote Humans Inheritance Patterns Models, Genetic Pedigree Reproducibility of Results Sequence Deletion Workflow |
Title | Homozygous and hemizygous CNV detection from exome sequencing data in a Mendelian disease cohort |
URI | https://www.ncbi.nlm.nih.gov/pubmed/27980096 https://www.proquest.com/docview/1852687141 https://pubmed.ncbi.nlm.nih.gov/PMC5389578 |
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