title: Family-specific, novel, deleterious germline variants provide a rich resource to identify genetic predispositions for BRCAx familial breast cancer.
abstract: BACKGROUND
  Genetic predisposition is the primary risk factor for familial breast cancer. For the majority of familial breast cancer, however, the genetic predispositions remain unknown. All newly identified predispositions occur rarely in disease population, and the unknown genetic predispositions are estimated to reach up to total thousands. Family unit is the basic structure of genetics. Because it is an autosomal dominant disease, individuals with a history of familial breast cancer must carry the same genetic predisposition across generations. Therefore, focusing on the cases in lineages of familial breast cancer, rather than pooled cases in disease population, is expected to provide high probability to identify the genetic predisposition for each family.
  
  
  METHODS
  In this study, we tested genetic predispositions by analyzing the family-specific variants in familial breast cancer. Using exome sequencing, we analyzed three families and 22 probands with BRCAx (BRCA-negative) familial breast cancer.
  
  
  RESULTS
  We observed the presence of family-specific, novel, deleterious germline variants in each family. Of the germline variants identified, many were shared between the disease-affected family members of the same family but not found in different families, which have their own specific variants. Certain variants are putative deleterious genetic predispositions damaging functionally important genes involved in DNA replication and damaging repair, tumor suppression, signal transduction, and phosphorylation.
  
  
  CONCLUSIONS
  Our study demonstrates that the predispositions for many BRCAx familial breast cancer families can lie in each disease family. The application of a family-focused approach has the potential to detect many new predispositions.
authors: Hongxiu
authors: H
authors: Wen
authors: Yeong C
authors: YC
authors: Kim
authors: Carrie
authors: C
authors: Snyder
authors: Fengxia
authors: F
authors: Xiao
authors: Elizabeth A
authors: EA
authors: Fleissner
authors: Dina
authors: D
authors: Becirovic
authors: Jiangtao
authors: J
authors: Luo
authors: Bradley
authors: B
authors: Downs
authors: Simon
authors: S
authors: Sherman
authors: Kenneth H
authors: KH
authors: Cowan
authors: Department of Genetics, Cell Biology and Anatomy, College of Medicine, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, NE 68198, USA. htlynch@creighton.edu.
authors: Henry T
authors: HT
authors: Lynch
authors: San Ming
authors: SM
authors: Wang
mesh_terms: D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics; D059472:Exome; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008954:Models, Biological; D010375:Pedigree