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.

Objective: To gain insight into the natural history of FA patients in Israel and shed light on genotype-phenotype correlations in this population.

Methods: Patients with FA were registered by their treating physicians as part of the Israeli inherited bone marrow failure registry (I-IBMFR). Follow-up surveys were performed every year. For all patients for whom DNA was available, a genetic analysis was performed.

Results: One hundred and eleven (111) FA patients diagnosed between 1980 and 2016 were registered to the I-IBMFR and followed for a median of 9.7 years. Analysis showed a slight male predominance (53% males, 47% females) and a near-even split between those of Jewish descent (42%) and those of Muslim descent (38%) with a smaller representation of Bedouins (11%), Druze (6%) and Christians (2%). Over 60% of the patients were offspring of consanguineous parents. Overall, 83% of the patients had confirmed mutations in genes encoding DNA repair proteins, the majority detected in the FANCA gene (67%) with the rest in FANCC (13%), FANCG (14%), FANCJ (3%) and FANCD1 (2%). Only 2 patients who underwent genetic analysis remained undiagnosed.

Of the 111 patients, 90% had at least one congenital anomaly. No significant association was found between a specific congenital anomaly and the affected Fanconi gene or the type of mutation. Nearly one third of the patients developed myelodysplastic syndrome (MDS), leukemia or a solid tumor. The prevalence of MDS was higher in FANCC patients and lower in FANCG patients, reaching statistical significance (p=0.0078). There was a trend towards a higher prevalence of cancer in FANCD1 patients.

Over half of the FA patients in the registry underwent a hematopoietic stem cell transplant (HSCT), without any correlation to the genotype; 64% of the transplanted patients are alive, while the rest died of transplant-related complications or malignancy. Of the 10 patients who developed solid tumors; 4 were post-HSCT with a solid tumor diagnosed at a range of 2.5-18 years post-transplant. Fifty six percent (56%) of the patients who did not undergo a transplant are alive; mortality was mostly due to malignancy or sepsis. Currently, 68 FA patients from the registry (61%) are alive, with a median age of 17 years.

Conclusion: We hereby present a large cohort of FA patients in Israel, unique due to ethnic diversity combined with a high degree of consanguinity, the majority genetically diagnosed. Genotypic and clinical features of FA patients from the I-IBMFR correlate well with trends seen in larger previously published FA registries but also bring to light possible new links. Interestingly, MDS was more prevalent in FANCC patients and less in FANCG patients; a finding that will need further confirmation in future studies. Continuation of this registry may help to unravel further genotype-phenotype trends and enhance our understanding of the disease.