PHENOTYPIC CONSEQUENCES OF MUTATIONS IN THE FANCONI-ANEMIA FAC GENE -AN INTERNATIONAL-FANCONI-ANEMIA-REGISTRY STUDY

Fanconi anemia (FA) is a genetically and phenotypically heterogeneous disorder defined by cellular hypersensitivity to DNA cross-linking age nts; mutations in the gene defective in FA complementation group C, FA C, are responsible for the syndrome in a subset of patients. We have p erformed an analysis of the clinical effects of specific mutations in the FAC gene. Using the amplification refractory mutation system assay s that we developed to rapidly detect FAC-mutations, at least one muta ted copy of the FAC gene was identified in 59 FA patients from the Int ernational Fanconi Anemia Registry (IFAR), This represents 15% of the 397 FA patients tested. FA-C patients were divided into three subgroup s based on results of a genotype-phenotype analysis using the Cox prop ortional 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 Q1 3X) and no known exon 14 mutation (n = 17). Kaplan-Meier analysis show s that IVS4 or exon 14 mutations define poor risk subgroups, as they a re associated with significantly earlier onset of hematologic abnormal ities and poorer survival compared to exon 1 patients and to the non-F A-C IFAR population. There was no direct correlation between the degre e of cellular hypersensitivity to the clastogenic effect of diepoxybut ane and severity of clinical phenotype. Sixteen of the 59 FA-C patient s (27%) have developed acute myelogenous leukemia. Thirteen of these p atients have died; AML was the cause of death in 46% of the expired FA -C patients. This study enables us to define this clinically heterogen eous disorder genotypically to better predict clinical outcome and aid decision-making regarding major therapeutic modalities for a subset o f FA patients. (C) 1997 by The American Society of Hematology.