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Fanconi anemia in Israel
them either not previously published or reported only by our group (Table 4).
In this Israeli cohort of FA patients, two-thirds of genet- ically diagnosed patients had biallelic FANCA mutations. These numbers are similar to the International Fanconi Anemia Registry, in which 60% of the diagnosed patients had FANCA mutations,17 and the European cohort, in which 70% had FANCA mutations7 but in contrast to the Italian cohort, in which 90% of the patients diagnosed were found to have FANCA mutations.16 The other FA genes were represented in our cohort similar to previous publications.22,23 We did not find a significant correlation between survival and the affected gene. This is in contrast to the International Fanconi Anemia Registry, in which patients with FANCC mutations had a poorer survival.17
Some mutations were exclusively or more commonly found in specific ethnic populations in our cohort. For example, in the Ashkenazi Jewish population, the most common mutation was c. 456+4a>t (IVS4+4 a>t) in FANCC, as previously described.24 In contrast, in the Sephardic Jewish population, the most common muta- tions was in c.2172-2173 insG (p.S725Vfs*69) in FANCA. Both these mutations were exclusive to Ashkenazi Jewish and Sephardic Jewish patients with FA, respectively. Patients with FANCG and FANCJ mutations were all from Arab Muslim descent.
A number of correlations were found between the geno- type and development of cancer in our cohort. Patients with FANCA mutations developed cancer at a significantly older age, compared with patients with non-FANCA mutations. In addition, there was a trend towards a higher prevalence of MDS in patients with FANCC mutations and less MDS and cancer in patients with FANCG muta- tions in our cohort. In contrast, in a larger cohort recently published from the National Cancer Institute,20 there was no clear association between the genotype and malignan- cy. Patients with FANCG mutations were even reported previously to have a higher incidence of leukemia.7 These data may reflect the unique population in our cohort, as most of the patients with FANCG mutations were of Arab Muslim origin, and all 13 patients were homozygous for 1 of 3 mutations: c.1742C>G (p.Ser581Ter), c.212T>C (p.Leu71Pro) and c.510+3A>G (IVS4+3 A>G). Further studies will be needed to elucidate the specific character- istics of these mutations.
Regarding the type of mutation in our cohort, no asso- ciation was found between the mutation type and sur- vival, the risk of development of cancer or the CAB score. However, we found a few correlations between specific congenital anomalies and the type of mutation. A few pre- vious publications looked at correlations between specific mutation types of FANCA and phenotype. One study reported a higher incidence of leukemia in patients with null mutations of FANCA, compared to those with other types of mutations.7 In contrast, in the Spanish cohort, no association was found between the type of FANCA muta- tions and hematologic disease or somatic malformations.8 The discrepancies between these studies may reflect spe- cific population characteristics, making it difficult to rely on the Fanconi group or the type of mutation in defining the risk for disease complications.
This cohort includes patients treated in various medical centers in Israel. The biggest limitation of this report is that not all patients were seen by the same medical team. We overcame this by using a standardized and elaborate medical form for each patient included in the I-IBMFR, fol- lowed by an annual update. In addition, genetic analysis was uniformly performed in our centralized hematology molecular laboratory.
This study includes a relatively large cohort of patients with FA in a nation with a unique ethnic diversity and a high degree of consanguinity. Our high success rate of genetic diagnosis has enabled the detection of several novel mutations and unreported genotype-phenotype cor- relations. We found that patients with FANCA mutations developed cancer at a later age; however the causative gene was not found to affect the overall survival of patients. In our cohort, HSCT did not increase the risk of solid tumor development. Continuation of this registry and establishment of similar registries worldwide are paramount for further advancement of our understanding of this rare disease.
Acknowledgments
The authors are grateful to Dr. Blanche Alter, from the Division of Cancer Epidemiology and Genetics, National Cancer Institute, for her helpful suggestions with writing this manuscript. The authors would like to thank Ms. Pearl Lilos for her help with the statistical analyses. The I-IBMF registry was supported by the Hayim association for children with cancer in Israel.
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