title: Biallelic mutations in BRCA1 cause a new Fanconi anemia subtype.
abstract: Deficiency in BRCA-dependent DNA interstrand crosslink (ICL) repair is intimately connected to breast cancer susceptibility and to the rare developmental syndrome Fanconi anemia. Bona fide Fanconi anemia proteins, BRCA2 (FANCD1), PALB2 (FANCN), and BRIP1 (FANCJ), interact with BRCA1 during ICL repair. However, the lack of detailed phenotypic and cellular characterization of a patient with biallelic BRCA1 mutations has precluded assignment of BRCA1 as a definitive Fanconi anemia susceptibility gene. Here, we report the presence of biallelic BRCA1 mutations in a woman with multiple congenital anomalies consistent with a Fanconi anemia-like disorder and breast cancer at age 23. Patient cells exhibited deficiency in BRCA1 and RAD51 localization to DNA-damage sites, combined with radial chromosome formation and hypersensitivity to ICL-inducing agents. Restoration of these functions was achieved by ectopic introduction of a BRCA1 transgene. These observations provide evidence in support of BRCA1 as a new Fanconi anemia gene (FANCS).
  
  
  CONCLUSIONS
  We establish that biallelic BRCA1 mutations cause a distinct FA-S, which has implications for risk counselling in families where both parents harbor BRCA1 mutations. The genetic basis of hereditary cancer susceptibility syndromes provides diagnostic information, insights into treatment strategies, and more accurate recurrence risk counseling to families.
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Sawyer
authors.affiliation: Department of Cancer Biology, Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Department of Pathology, Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Lei
authors.initials: L
authors.lastname: Tian
authors.affiliation: Pirkanmaa Hospital District, Fimlab Laboratories, Laboratory of Clinical Genetics, Tampere, Finland.
authors.forename: Marketta
authors.initials: M
authors.lastname: Kähkönen
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambs, United Kingdom.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Schwartzentruber
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington.
authors.forename: Martin
authors.initials: M
authors.lastname: Kircher
authors.affiliation: Department of Human Genetics, McGill University, Montréal, Quebec, Canada. McGill University and Genome Quebec Innovation Centre, Montréal, Quebec, Canada.
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: David A
authors.initials: DA
authors.lastname: Dyment
authors.affiliation: Department of Medical Genetics and Alberta Children's Hospital Research Institute for Child and Maternal Health, University of Calgary, Calgary, Alberta, Canada.
authors.forename: A Micheil
authors.initials: AM
authors.lastname: Innes
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Kym M
authors.initials: KM
authors.lastname: Boycott
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Department of Pediatrics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Moreau
authors.affiliation: Department of Clinical Genetics and Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.
authors.forename: Jukka S
authors.initials: JS
authors.lastname: Moilanen
authors.affiliation: Department of Cancer Biology, Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Department of Pathology, Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. rogergr@mail.med.upenn.edu.
authors.forename: Roger A
authors.initials: RA
authors.lastname: Greenberg
mesh_terms: D000328:Adult; D000483:Alleles; D019313:BRCA1 Protein / Q000235:genetics; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics*; D005199:Fanconi Anemia / Q000235:genetics*; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics; D005260:Female; D019398:Genes, BRCA1; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation; D055815:Young Adult
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D051856:Fanconi Anemia Complementation Group Proteins