Fanconi anemia (FA) is a genetically and phenotypically heterogeneous disorder 
defined by cellular hypersensitivity to DNA cross-linking agents; mutations in 
the gene defective in FA complementation group C, FAC, are responsible for the 
syndrome in a subset of patients. We have performed an analysis of the clinical 
effects of specific mutations in the FAC gene. Using the amplification 
refractory mutation system assays that we developed to rapidly detect FAC 
mutations, at least one mutated copy of the FAC gene was identified in 59 FA 
patients from the International Fanconi Anemia Registry (IFAR). This represents 
15% of the 397 FA patients tested. FA-C patients were divided into three 
subgroups based on results of a genotype-phenotype analysis using the Cox 
proportional hazards model: (1) patients with the IVS4 mutation (n = 26); (2) 
patients with at least one exon 14 mutation (R548X or L554P) (n = 16); and (3) 
patients with at least one exon 1 mutation (322delG or Q13X) and no known exon 
14 mutation (n = 17). Kaplan-Meier analysis shows that IVS4 or exon 14 mutations 
define poor risk subgroups, as they are associated with significantly earlier 
onset of hematologic abnormalities and poorer survival compared to exon 1 
patients and to the non-FA-C IFAR population. There was no direct correlation 
between the degree of cellular hypersensitivity to the clastogenic effect of 
diepoxybutane and severity of clinical phenotype. Sixteen of the 59 FA-C 
patients (27%) have developed acute myelogenous leukemia. Thirteen of these 
patients have died; AML was the cause of death in 46% of the expired FA-C 
patients. This study enables us to define this clinically heterogeneous disorder 
genotypically to better predict clinical outcome and aid decision-making 
regarding major therapeutic modalities for a subset of FA patients.