title: INDELseek: detection of complex insertions and deletions from next-generation sequencing data.
abstract: Complex insertions and deletions (indels) from next-generation sequencing (NGS) data were prone to escape detection by currently available variant callers as shown by large-scale human genomics studies. Somatic and germline complex indels in key disease driver genes could be missed in NGS-based genomics studies.
  
  
  
  INDELseek is an open-source complex indel caller designed for NGS data of random fragments and PCR amplicons. The key differentiating factor of INDELseek is that each NGS read alignment was examined as a whole instead of "pileup" of each reference position across multiple alignments. In benchmarking against the reference material NA12878 genome (n = 160 derived from high-confidence variant calls), GATK, SAMtools and INDELseek showed complex indel detection sensitivities of 0%, 0% and 100%, respectively. INDELseek also detected all known germline (BRCA1 and BRCA2) and somatic (CALR and JAK2) complex indels in human clinical samples (n = 8). Further experiments validated all 10 detected KIT complex indels in a discovery cohort of clinical samples. In silico semi-simulation showed sensitivities of 93.7-96.2% based on 8671 unique complex indels in >5000 genes from dbSNP and COSMIC. We also demonstrated the importance of complex indel detection in accurately annotating BRCA1, BRCA2 and TP53 mutations with gained or rescued protein-truncating effects.
  
  
  
  INDELseek is an accurate and versatile tool for complex indel detection in NGS data. It complements other variant callers in NGS-based genomics studies targeting a wide spectrum of genetic variations.
authors.affiliation: Division of Molecular Pathology, Department of Pathology, Hong Kong Sanatorium & Hospital, Happy Valley, Hong Kong SAR.
authors.forename: Chun Hang
authors.initials: CH
authors.lastname: Au
authors.affiliation: Department of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong SAR.
authors.forename: Anskar Y H
authors.initials: AY
authors.lastname: Leung
authors.affiliation: Department of Surgery, The University of Hong Kong, Pok Fu Lam, Hong Kong SAR.|Department of Surgery and Cancer Genetics Center, Hong Kong Sanatorium & Hospital, Happy Valley, Hong Kong SAR.|Hong Kong Hereditary Breast Cancer Family Registry, Shau Kei Wan, Hong Kong SAR.
authors.forename: Ava
authors.initials: A
authors.lastname: Kwong
authors.affiliation: Division of Molecular Pathology, Department of Pathology, Hong Kong Sanatorium & Hospital, Happy Valley, Hong Kong SAR.
authors.forename: Tsun Leung
authors.initials: TL
authors.lastname: Chan
authors.affiliation: Division of Molecular Pathology, Department of Pathology, Hong Kong Sanatorium & Hospital, Happy Valley, Hong Kong SAR. eskma@hksh.com.
authors.forename: Edmond S K
authors.initials: ES
authors.lastname: Ma
mesh_terms: D000465:Algorithms; D019295:Computational Biology / Q000379:methods*; D023281:Genomics / Q000379:methods; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D054643:INDEL Mutation; D009369:Neoplasms / Q000235:genetics; D015203:Reproducibility of Results; D017422:Sequence Analysis, DNA; D012984:Software
keywords: Bioinformatics; Complex indel; Next-generation sequencing; Variant calling