Biallelic Mutations in BRCA1 Cause a New Fanconi Anemia Subtype

Deficiency in BRCA dependent DNA inter-strand crosslink (ICL) repair is intimately connected to breast cancer susceptibility and to the rare developmental syndrome, Fanconi Anemia (FA). Bona fide FA proteins, BRCA2 (FANCD1), PALB2 (FANCN), and BRIP1 (FANCJ) interact with BRCA1 during ICL repair. However, lack of detailed phenotypic and cellular characterization of a patient with biallelic BRCA1 mutations has precluded assignment of BRCA1 as a definitive FA susceptibility gene. Here we report the presence of biallelic BRCA1 mutations in a woman with multiple congenital anomalies consistent with a FA-like disorder and breast cancer at age 23. Patient cells exhibited deficiency in BRCA1 (FANCS) 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 subtype (FA-S).