Association of complementation group and mutation type with clinical outcome in Fanconi anemia

Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder. Clinical care is complicated by variable age at onset and severity of hema tologic symptoms. Recent advances in the molecular biology of FA have allow ed us to investigate the relationship between FA genotype and the nature an d severity of the clinical phenotype. Two hundred forty-five patients from all 7 known complementation groups (FA-A to FA-G) were studied. Mutations w ere detected in one of the cloned FANC genes in 169 patients; in the remain der the complementation group was assigned by cell fusion or Western blotti ng. A range of qualitative and quantitative clinical parameters was compare d for each complementation group and for different classes of mutation. Sig nificant phenotypic differences were found. FA-G patients had more severe c ytopenia and a higher incidence of leukemia. Somatic abnormalities were les s prevalent in FA-C, but more common in the rare groups FA-D, FA-E, and FA- F. In FA-A, patients homozygous for null mutations had an earlier onset of anemia and a higher incidence of leukemia than those with mutations produci ng an altered protein. In FA-C, there was a later age of onset of aplastic anemia and fewer somatic abnormalities in patients with the 322delG mutatio n, but there were more somatic abnormalities in patients with IVS4 + 4A --> T. This study indicates that FA patients with mutations in the FANCG gene and patients homozygous for null mutations in FANCA are high-risk groups wi th a poor hematologic outcome and should be considered as candidates both f or frequent monitoring and early therapeutic intervention. (C) 2000 by The American Society of Hematology.