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HDR-del: A tool based on Hamming distance for prioritizing pathogenic chromosomal deletions in exome sequencing.

Authors
  • Imai-Okazaki, Atsuko1, 2, 3, 4
  • Kohda, Masakazu5
  • Kobayashi, Kaori1, 6
  • Hirata, Tomoko5
  • Sakata, Yasushi2
  • Murayama, Kei7
  • Ohtake, Akira8
  • Okazaki, Yasushi5, 9
  • Nakaya, Akihiro1
  • Ott, Jurg4
  • 1 Department of Genome Informatics, Osaka University Graduate School of Medicine, Osaka, Japan. , (Japan)
  • 2 Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan. , (Japan)
  • 3 Division of Genomic Medicine Research, Medical Genomics Center, National Center for Global Health and Medicine, Tokyo, Japan. , (Japan)
  • 4 Laboratory of Statistical Genetics, Rockefeller University, New York.
  • 5 Division of Translational Research, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan. , (Japan)
  • 6 Medical Solutions Division, NEC Corporation, Tokyo, Japan. , (Japan)
  • 7 Department of Metabolism, Chiba Children's Hospital, Chiba, Japan. , (Japan)
  • 8 Department of Pediatrics, Saitama Medical University, Saitama, Japan. , (Japan)
  • 9 Division of Functional Genomics & Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan. , (Japan)
Type
Published Article
Journal
Human Mutation
Publisher
Wiley (John Wiley & Sons)
Publication Date
Dec 01, 2017
Volume
38
Issue
12
Pages
1796–1800
Identifiers
DOI: 10.1002/humu.23298
PMID: 28722338
Source
Medline
Keywords
License
Unknown

Abstract

High-density oligonucleotide arrays have widely been used to detect pathogenic chromosomal deletions. In addition to high-density oligonucleotide arrays, programs using whole-exome sequencing have become available for estimating copy-number variations using depth of coverage. Here, we propose a new statistical method, HDR-del, to prioritize pathogenic chromosomal deletions based on Hamming distance in exome sequencing. In vcf (variant call format) files generated from exome sequencing, hemizygous chromosomal deletion regions lack heterozygous variants and lead to apparent long runs of homozygosity (ROH). In our Hamming distance ratio (HDR)-del approach, we calculate the "difference" in heterozygous status between an affected individual and control individuals using the HDR over all candidate chromosomal deletion regions defined as ROH longer than 1Mbp. Using a suitable test statistic, which is expected to be large for a true pathogenic deletion region, we prioritize candidate chromosomal deletion regions based on this statistic. In our approach, we were able to considerably narrow down true pathogenic chromosomal deletion regions, which were confirmed by high-density oligonucleotide arrays in four mitochondrial disease patients. Our HDR-del approach represents an easy method for detecting chromosomal deletions.

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