Whole-exome sequencing in consanguineous familial breast cancer families

Background: Germ-line mutations of BRCA1 and BRCA2 genes are responsible for approximately 25-30% of dominantly inherited familial breast cancers; still a large part of genetic component is unknown. The aim of this study was to investigate genetic causes of familial breast cancer in pedigrees with a recessive pattern of inheritance. Material and methods:We applied whole exome sequencing to analyze coding DNA in 30 individuals from 5 families with breast cancer-affected children as result of consanguineous marriage. Candidate variants were validated by Sanger sequencing and were screened in DNA samples of 100 healthy female individuals to assess their frequencies. Results:We identified three novel BRCA2 mutations (c.262_263delCT, c.C2918G and c.C266T) in two families. Moreover, several novel rare heterozygous susceptibility variants were identified in non-BRCA (BRCAX) families including p.R903W in ZNF217, p.K123E in HIST3H3, and p.R294S in RAPGEF3.Conclusion: To our knowledge this study is the first report on investigating possible recessive patterns of inheritance in familial breast cancer in consanguineous families. By applying stringent criteria for family selection, we identified family-specific novel rare heterozygous mutations in genes already involved in carcinogenesis which may be regarded as moderate to low penetrance susceptibility alleles for breast cancer.