Genotype-phenotype correlations in Fanconi anemia

Abstract Although still incomplete, we now have a remarkably detailed and nuanced picture of both phenotypic and genotypic components of the FA spectrum. Initially described as a combination of pancytopenia with a limited number of physical anomalies, it was later recognized that additional features were compatible with the FA phenotype, including a form without detectable malformations (Estren–Dameshek variant). The discovery of somatic mosaicism extended the boundaries of the FA phenotype to cases even without any overt hematological manifestations. This clinical heterogeneity was augmented by new conceptualizations. There was the realization of a constant risk for the development of myelodysplasia and certain malignancies, including acute myelogenous leukemia and squamous cell carcinoma, and there was the emergence of a distinctive cellular phenotype. A striking degree of genetic heterogeneity became apparent with the delineation of at least 12 complementation groups and the identification of their underlying genes. Although functional genetic insights have fostered the interpretation of many phenotypic features, surprisingly few stringent genotype–phenotype connections have emerged. In addition to myriad genetic alterations, less predictable influences are likely to modulate the FA phenotype, including modifier genes, environmental factors and chance effects. In reviewing the current status of genotype–phenotype correlations, we arrive at a unifying hypothesis to explain the remarkably wide range of FA phenotypes. Given the large body of evidence that genomic instability is a major underlying mechanism of accelerated ageing phenotypes, we propose that the numerous FA variants can be viewed as differential modulations and compression in time of intrinsic biological ageing.