title: Navigating highly homologous genes in a molecular diagnostic setting: a resource for clinical next-generation sequencing.
abstract: Next-generation sequencing (NGS) is now routinely used to interrogate large sets of genes in a diagnostic setting. Regions of high sequence homology continue to be a major challenge for short-read technologies and can lead to false-positive and false-negative diagnostic errors. At the scale of whole-exome sequencing (WES), laboratories may be limited in their knowledge of genes and regions that pose technical hurdles due to high homology. We have created an exome-wide resource that catalogs highly homologous regions that is tailored toward diagnostic applications.
  
  
  
  This resource was developed using a mappability-based approach tailored to current Sanger and NGS protocols.
  
  
  
  Gene-level and exon-level lists delineate regions that are difficult or impossible to analyze via standard NGS. These regions are ranked by degree of affectedness, annotated for medical relevance, and classified by the type of homology (within-gene, different functional gene, known pseudogene, uncharacterized noncoding region). Additionally, we provide a list of exons that cannot be analyzed by short-amplicon Sanger sequencing.
  
  
  
  This resource can help guide clinical test design, supplemental assay implementation, and results interpretation in the context of high homology.Genet Med 18 12, 1282-1289.
authors.affiliation: Department of Pathology, Harvard Medical School/Brigham and Women's Hospital, Boston, Massachusetts, USA.|Current affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York City, New York, USA (D.M.); Medical Genetics, Invitae Corporation, San Francisco, California, USA (K.M.G.).
authors.forename: Diana
authors.identifier: 0000-0003-4154-0567
authors.initials: D
authors.lastname: Mandelker
authors.affiliation: Department of Pathology, Harvard Medical School/Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Ryan J
authors.identifier: 0000-0001-8789-9917
authors.initials: RJ
authors.lastname: Schmidt
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Arunkanth
authors.initials: A
authors.lastname: Ankala
authors.affiliation: Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.|Current affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York City, New York, USA (D.M.); Medical Genetics, Invitae Corporation, San Francisco, California, USA (K.M.G.).
authors.forename: Kristin
authors.identifier: 0000-0002-3297-2002
authors.initials: K
authors.lastname: McDonald Gibson
authors.affiliation: Partners HealthCare Personalized Medicine, Laboratory for Molecular Medicine, Cambridge, Massachusetts, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Bowser
authors.affiliation: Partners HealthCare Personalized Medicine, Laboratory for Molecular Medicine, Cambridge, Massachusetts, USA.
authors.forename: Himanshu
authors.identifier: 0000-0001-7133-6327
authors.initials: H
authors.lastname: Sharma
authors.affiliation: Partners HealthCare Personalized Medicine, Laboratory for Molecular Medicine, Cambridge, Massachusetts, USA.
authors.forename: Elizabeth
authors.identifier: 0000-0002-3817-2145
authors.initials: E
authors.lastname: Duffy
authors.affiliation: Emory Genetics Lab, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Madhuri
authors.initials: M
authors.lastname: Hegde
authors.affiliation: Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: Avni
authors.identifier: 0000-0003-2871-4307
authors.initials: A
authors.lastname: Santani
authors.affiliation: Department of Pathology, Harvard Medical School/Brigham and Women's Hospital, Boston, Massachusetts, USA.|Partners HealthCare Personalized Medicine, Laboratory for Molecular Medicine, Cambridge, Massachusetts, USA.
authors.forename: Matthew
authors.identifier: 0000-0002-9733-5207
authors.initials: M
authors.lastname: Lebo
authors.affiliation: Partners HealthCare Personalized Medicine, Laboratory for Molecular Medicine, Cambridge, Massachusetts, USA.|Department of Pathology, Harvard Medical School/Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Birgit
authors.initials: B
authors.lastname: Funke
mesh_terms: D019295:Computational Biology; D059472:Exome / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D009154:Mutation; D057089:Pathology, Molecular / Q000379:methods*; D017422:Sequence Analysis, DNA