Characterization and Genotype-Phenotype Correlation of Fanconi Anemia Patients in Israel

Background: Fanconi Anemia (FA) is an inherited bone marrow failure syndrome in which defects in the DNA repair pathway lead to chromosomal instability. The clinical phenotype includes multiple congenital anomalies, aplastic anemia, an increased tendency to develop malignancies, and extreme sensitivity to alkylating agents. To date, mutations in 21 different genes have been detected in FA patients. A clear genotype-phenotype correlation has not been established, with the exception of patients with FANCD1 (BRCA2) and FANCN mutations, in which early onset of malignancy is almost invariably present. One study found that patients with FANCG mutations have a higher risk for leukemia (Faivre et al., 2000), but this was not confirmed in the International Fanconi Anemia Registry (Kutler et al., 2003). Other evidence suggests that the type of mutation correlates better with the phenotype than the specific gene. For example, one report found that patients with FANCA null mutations present with a more severe phenotype than other types of FANCA mutations (Faivre at al., 2000). Conversely, in a separate report, no functional or clinical difference was found between null and missense mutations (Castella et al., 2011). It is possible that specific mutations best correlate with the phenotype (reviewed in Neveling et al., 2009). However, even for a specific mutation, there is a variable phenotypic severity in different ethnicities and among siblings, suggesting a role for gene modifiers and environmental factors.