Homozygous and hemizygous CNV detection from exome sequencing data in a Mendelian disease cohort

Tomasz Gambin , Zeynep C. Akdemir , Bo Yuan , Theodore Chiang , Claudia M.B. Carvalho , Chad Shaw , Shalini N. Jhangiani , Philip M. Boone , Mohammad K. Eldomery , Ender Karaca , Yavuz Bayram , Asbjørg Stray-Pedersen , Donna Muzny , Wu-Lin Charng , Vahid Bahrambeigi , John W. Belmont , Eric Boerwinkle , Arthur L. Beaudet , Richard A. Gibbs , James R. Lupski


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 Tomasz Gambin II
Tomasz Gambin,,
- The Institute of Computer Science
, Zeynep C. Akdemir
Zeynep C. Akdemir,,
, Bo Yuan - [Department of Molecular and Human Genetics (DMHG) [Baylor College of Medicine (BCM)]]
Bo Yuan,,
- Department of Molecular and Human Genetics
, Theodore Chiang
Theodore Chiang,,
, Claudia M.B. Carvalho
Claudia M.B. Carvalho,,
, Chad Shaw
Chad Shaw,,
, Shalini N. Jhangiani - Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas
Shalini N. Jhangiani,,
, Philip M. Boone
Philip M. Boone,,
, Mohammad K. Eldomery
Mohammad K. Eldomery,,
, Ender Karaca
Ender Karaca,,
et al.
Journal seriesNucleic Acids Research, ISSN 0305-1048
Issue year2016
Noonline 14 December 2016
Publication size in sheets0.75
URL https://academic.oup.com/nar/article/doi/10.1093/nar/gkw1237/2681735/Homozygous-and-hemizygous-CNV-detection-from-exome
Languageen angielski
Homozygous.pdf (file archived - login or check accessibility on faculty) Homozygous.pdf 4.14 MB
Score (nominal)40
ScoreMinisterial score = 40.0, 27-03-2017, ArticleFromJournal
Ministerial score (2013-2016) = 40.0, 27-03-2017, ArticleFromJournal
Publication indicators WoS Impact Factor: 2016 = 10.162 (2) - 2016=9.338 (5)
Citation count*2 (2017-05-14)
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* presented citation count is obtained through Internet information analysis and it is close to the number calculated by the Publish or Perish system.