title: Ready to clone: CNV detection and breakpoint fine-mapping in breast and ovarian cancer susceptibility genes by high-resolution array CGH.
abstract: OBJECTIVE
  Detection of predisposing copy number variants (CNV) in 330 families affected with hereditary breast and ovarian cancer (HBOC).
  
  
  METHODS
  In order to complement mutation detection with Illumina's TruSight Cancer panel, we designed a customized high-resolution 8 × 60k array for CGH (aCGH) that covers all 94 genes from the panel.
  
  
  RESULTS
  Copy number variants with immediate clinical relevance were detected in 12 families (3.6%). Besides 3 known CNVs in CHEK2, RAD51C, and BRCA1, we identified 3 novel pathogenic CNVs in BRCA1 (deletion of exons 4-13, deletion of exons 12-18) and ATM (deletion exons 57-63) plus an intragenic duplication of BRCA2 (exons 3-11) and an intronic BRCA1 variant with unknown pathogenicity. The precision of high-resolution aCGH enabled straight forward breakpoint amplification of a BRCA1 deletion which subsequently allowed for fast and economic CNV verification in family members of the index patient. Furthermore, we used our aCGH data to validate an algorithm that was able to detect all identified copy number changes from next-generation sequencing (NGS) data.
  
  
  CONCLUSIONS
  Copy number detection is a mandatory analysis in HBOC families at least if no predisposing mutations were found by sequencing. Currently, high-resolution array CGH is our first choice of method of analysis due to unmatched detection precision. Although it seems possible to detect CNV from sequencing data, there currently is no satisfying tool to do so in a routine diagnostic setting.
authors: Institut fuer Klinische Genetik, Medizinische Fakultaet Carl Gustav Carus, Technische Universitaet Dresden, Fetscherstr. 74, 01307, Dresden, Germany. karl.hackmann@uniklinikum-dresden.de.|German Cancer Consortium (DKTK), Dresden, Germany. karl.hackmann@uniklinikum-dresden.de.|German Cancer Research Center (DKFZ), Heidelberg, Germany. karl.hackmann@uniklinikum-dresden.de.|National Center for Tumor Diseases (NCT), Dresden, Germany. karl.hackmann@uniklinikum-dresden.de.
authors: Karl
authors: K
authors: Hackmann
authors: Institut fuer Klinische Genetik, Medizinische Fakultaet Carl Gustav Carus, Technische Universitaet Dresden, Fetscherstr. 74, 01307, Dresden, Germany.
authors: Franziska
authors: F
authors: Kuhlee
authors: Institut fuer Klinische Genetik, Medizinische Fakultaet Carl Gustav Carus, Technische Universitaet Dresden, Fetscherstr. 74, 01307, Dresden, Germany.
authors: Elitza
authors: E
authors: Betcheva-Krajcir
authors: Institut fuer Klinische Genetik, Medizinische Fakultaet Carl Gustav Carus, Technische Universitaet Dresden, Fetscherstr. 74, 01307, Dresden, Germany.
authors: Anne-Karin
authors: AK
authors: Kahlert
authors: Institut fuer Klinische Genetik, Medizinische Fakultaet Carl Gustav Carus, Technische Universitaet Dresden, Fetscherstr. 74, 01307, Dresden, Germany.
authors: Luisa
authors: L
authors: Mackenroth
authors: Institut fuer Klinische Genetik, Medizinische Fakultaet Carl Gustav Carus, Technische Universitaet Dresden, Fetscherstr. 74, 01307, Dresden, Germany.|German Cancer Consortium (DKTK), Dresden, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|National Center for Tumor Diseases (NCT), Dresden, Germany.
authors: Barbara
authors: B
authors: Klink
authors: Institut fuer Klinische Genetik, Medizinische Fakultaet Carl Gustav Carus, Technische Universitaet Dresden, Fetscherstr. 74, 01307, Dresden, Germany.
authors: Nataliya
authors: N
authors: Di Donato
authors: Institut fuer Klinische Genetik, Medizinische Fakultaet Carl Gustav Carus, Technische Universitaet Dresden, Fetscherstr. 74, 01307, Dresden, Germany.
authors: Andreas
authors: A
authors: Tzschach
authors: German Cancer Consortium (DKTK), Dresden, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|National Center for Tumor Diseases (NCT), Dresden, Germany.|Klinik und Poliklinik fuer Gynäkologie und Geburtshilfe, Universitaetsklinikum Carl Gustav Carus, Technische Universitaet Dresden, Fetscherstr. 74, 01307, Dresden, Germany.
authors: Karin
authors: K
authors: Kast
authors: German Cancer Consortium (DKTK), Dresden, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|National Center for Tumor Diseases (NCT), Dresden, Germany.|Klinik und Poliklinik fuer Gynäkologie und Geburtshilfe, Universitaetsklinikum Carl Gustav Carus, Technische Universitaet Dresden, Fetscherstr. 74, 01307, Dresden, Germany.
authors: Pauline
authors: P
authors: Wimberger
authors: Institut fuer Klinische Genetik, Medizinische Fakultaet Carl Gustav Carus, Technische Universitaet Dresden, Fetscherstr. 74, 01307, Dresden, Germany.|German Cancer Consortium (DKTK), Dresden, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|National Center for Tumor Diseases (NCT), Dresden, Germany.
authors: Evelin
authors: E
authors: Schrock
authors: Institut fuer Klinische Genetik, Medizinische Fakultaet Carl Gustav Carus, Technische Universitaet Dresden, Fetscherstr. 74, 01307, Dresden, Germany.|German Cancer Consortium (DKTK), Dresden, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|National Center for Tumor Diseases (NCT), Dresden, Germany.
authors: Andreas
authors: A
authors: Rump
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D056905:Chromosome Breakpoints; D002874:Chromosome Mapping; D055028:Comparative Genomic Hybridization / Q000379:methods*; D056915:DNA Copy Number Variations; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D010051:Ovarian Neoplasms / Q000235:genetics*; D017422:Sequence Analysis, DNA
keywords: Array CGH; Breast cancer; Copy number; Ovarian cancer