TY - JOUR
T1 - Robust identification of deletions in exome and genome sequence data based on clustering of Mendelian errors
AU - Manheimer, Kathryn B.
AU - Patel, Nihir
AU - Richter, Felix
AU - Gorham, Joshua
AU - Tai, Angela C.
AU - Homsy, Jason
AU - Boskovski, Marko T.
AU - Parfenov, Michael
AU - Goldmuntz, Elizabeth
AU - Chung, Wendy K.
AU - Brueckner, Martina
AU - Tristani-Firouzi, Martin
AU - Srivastava, Deepak
AU - Seidman, Jonathan G.
AU - Seidman, Christine E.
AU - Gelb, Bruce D.
AU - Sharp, Andrew J.
N1 - Publisher Copyright:
© 2018 Wiley Periodicals, Inc.
PY - 2018/6
Y1 - 2018/6
N2 - Multiple tools have been developed to identify copy number variants (CNVs) from whole exome (WES) and whole genome sequencing (WGS) data. Current tools such as XHMM for WES and CNVnator for WGS identify CNVs based on changes in read depth. For WGS, other methods to identify CNVs include utilizing discordant read pairs and split reads and genome-wide local assembly with tools such as Lumpy and SvABA, respectively. Here, we introduce a new method to identify deletion CNVs from WES and WGS trio data based on the clustering of Mendelian errors (MEs). Using our Mendelian Error Method (MEM), we identified 127 deletions (inherited and de novo) in 2,601 WES trios from the Pediatric Cardiac Genomics Consortium, with a validation rate of 88% by digital droplet PCR. MEM identified additional de novo deletions compared with XHMM, and a significant enrichment of 15q11.2 deletions compared with controls. In addition, MEM identified eight cases of uniparental disomy, sample switches, and DNA contamination. We applied MEM to WGS data from the Genome In A Bottle Ashkenazi trio and identified deletions with 97% specificity. MEM provides a robust, computationally inexpensive method for identifying deletions, and an orthogonal approach for verifying deletions called by other tools.
AB - Multiple tools have been developed to identify copy number variants (CNVs) from whole exome (WES) and whole genome sequencing (WGS) data. Current tools such as XHMM for WES and CNVnator for WGS identify CNVs based on changes in read depth. For WGS, other methods to identify CNVs include utilizing discordant read pairs and split reads and genome-wide local assembly with tools such as Lumpy and SvABA, respectively. Here, we introduce a new method to identify deletion CNVs from WES and WGS trio data based on the clustering of Mendelian errors (MEs). Using our Mendelian Error Method (MEM), we identified 127 deletions (inherited and de novo) in 2,601 WES trios from the Pediatric Cardiac Genomics Consortium, with a validation rate of 88% by digital droplet PCR. MEM identified additional de novo deletions compared with XHMM, and a significant enrichment of 15q11.2 deletions compared with controls. In addition, MEM identified eight cases of uniparental disomy, sample switches, and DNA contamination. We applied MEM to WGS data from the Genome In A Bottle Ashkenazi trio and identified deletions with 97% specificity. MEM provides a robust, computationally inexpensive method for identifying deletions, and an orthogonal approach for verifying deletions called by other tools.
KW - UPD
KW - copy number variant identification
KW - whole exome sequencing
KW - whole genome sequencing
UR - http://www.scopus.com/inward/record.url?scp=85044196371&partnerID=8YFLogxK
U2 - 10.1002/humu.23419
DO - 10.1002/humu.23419
M3 - Article
C2 - 29527824
AN - SCOPUS:85044196371
SN - 1059-7794
VL - 39
SP - 870
EP - 881
JO - Human Mutation
JF - Human Mutation
IS - 6
ER -