Complementation Groups

Genetic heterogeneity was recognized as early as 1980 as a typical feature of FA when cell fusion studies by Sperling and colleagues provided the first evidence for the existence of at least two complementation groups (17). In 1992, Buchwald and coworkers in Toronto, using an expression cloning strategy, cloned the first FA gene (FANCC) and increased the number of complementation groups to four (18). In the following years, Joenje and associates in Amsterdam defined additional complementation groups by fusing genetically marked lymphoid cell lines from patients with FA and looking for reversal of mitomycin C (MMC) sensitivity, raising the total number of definitive FA genes to eight (19,20). One of these, complementation group H, was reassigned to group A in further studies (21). Since a number of primary cells and cell lines derived from patients with FA cannot currently be assigned to any of the known complementation groups, either by cell fusion or by transduction studies, it is very likely that additional complementation groups and genes will be found. The clinical course of the disease appears to be much more strongly determined by the type of mutation and ethnicity rather than by belonging to a given complementation group (22,23). For example, the IVS4+4A>T mutation in the complementation group C gene causes early onset of hematological symptoms and consistent short stature combined with radial ray defects, whereas the 322delG mutation in the same gene usually causes fewer somatic abnormalities and a much later onset of aplastic anemia (24). There are some indications that patients belonging to complementation group G and patients homozygous for null mutations in the complementation group A gene may have a more unfavorable clinical course (25), but definitive genotype-phenotype correlations require prospective studies.

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