Fanconi anemia (FA) is characterized by congenital abnormalities, bone marrow 
failure, chromosome fragility, and cancer susceptibility. Eight FA-associated 
genes have been identified so far, the products of which function in the FA/BRCA 
pathway. A key event in the pathway is the monoubiquitination of the FANCD2 
protein, which depends on a multiprotein FA core complex. In a number of 
patients, spontaneous genetic reversion can correct FA mutations, leading to 
somatic mosaicism. We analyzed the FA/BRCA pathway in 53 FA patients by FANCD2 
immunoblots and chromosome breakage tests. Strikingly, FANCD2 monoubiquitination 
was detected in peripheral blood lymphocytes (PBLs) in 8 (15%) patients. FA 
reversion was further shown in these patients by comparison of primary 
fibro-blasts and PBLs. Reversion was associated with higher blood counts and 
clinical stability or improvement. Once constitutional FANCD2 patterns were 
determined, patients could be classified based on the level of FA/BRCA pathway 
disruption, as "FA core" (upstream inactivation; n = 47, 89%), FA-D2 (n = 4, 
8%), and an unidentified downstream group (n = 2, 4%). FA-D2 and unidentified 
group patients were therefore relatively common, and they had more severe 
congenital phenotypes. These results show that specific analysis of the FA/BRCA 
pathway, combined with clinical and chromosome breakage data, allows a 
comprehensive characterization of FA patients.