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. 2020 Jul;105(7):1825-1834.
doi: 10.3324/haematol.2019.222877. Epub 2019 Sep 26.

Characterization and genotype-phenotype correlation of patients with Fanconi anemia in a multi-ethnic population

Orna Steinberg-Shemer  1   2   3 , Tracie A Goldberg  4 , Joanne Yacobovich  4   2 , Carina Levin  5   6 , Ariel Koren  5   6 , Shoshana Revel-Vilk  7 , Tal Ben-Ami  8 , Amir A Kuperman  9   10 , Vered Shkalim Zemer  4   2 , Amos Toren  2   11 , Joseph Kapelushnik  12 , Ayelet Ben-Barak  13 , Hagit Miskin  7 , Tanya Krasnov  3 , Sharon Noy-Lotan  3 , Orly Dgany  3 , Hannah Tamary  1   2   3
Affiliations
Free PMC article

Characterization and genotype-phenotype correlation of patients with Fanconi anemia in a multi-ethnic population

Orna Steinberg-Shemer et al. Haematologica. 2020 Jul.
Free PMC article

Abstract

Fanconi anemia (FA), an inherited bone marrow failure (BMF) syndrome, caused by mutations in DNA repair genes, is characterized by congenital anomalies, aplastic anemia, high risk of malignancies and extreme sensitivity to alkylating agents. We aimed to study the clinical presentation, molecular diagnosis and genotype-phenotype correlation among patients with FA from the Israeli inherited BMF registry. Overall, 111 patients of Arab (57%) and Jewish (43%) descent were followed for a median of 15 years (range: 0.1-49); 63% were offspring of consanguineous parents. One-hundred patients (90%) had at least one congenital anomaly; over 80% of the patients developed bone marrow failure; 53% underwent hematopoietic stem-cell transplantation; 33% of the patients developed cancer; no significant association was found between hematopoietic stem-cell transplant and solid tumor development. Nearly 95% of the patients tested had confirmed mutations in the Fanconi genes FANCA (67%), FANCC (13%), FANCG (14%), FANCJ (3%) and FANCD1 (2%), including twenty novel mutations. Patients with FANCA mutations developed cancer at a significantly older age compared to patients with mutations in other Fanconi genes (mean 18.5 and 5.2 years, respectively, P=0.001); however, the overall survival did not depend on the causative gene. We hereby describe a large national cohort of patients with FA, the vast majority genetically diagnosed. Our results suggest an older age for cancer development in patients with FANCA mutations and no increased incidence of solid tumors following hematopoietic stem-cell transplant. Further studies are needed to guide individual treatment and follow-up programs.

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Figures

Figure 1
Figure 1
Survival curves for patients with Fanconi anemia (FA) in Israel, calculating the proportion of live patients by age using the Kaplan-Meier methods. (A) Survival for the whole cohort. (B) Survival divided by cab score 0 (blue), 1 (red) or greater than 1 (green). No significant difference was found between the groups.
Figure 2
Figure 2
Cumulative incidence (CI) by age for adverse events in patient with Fanconi anemia (FA). (A) CI by age of first cancer. Myelodysplastic syndrome (MDS) – blue; leukemia – red; solid tumors – green. MDS and leukemia events both appeared significantly earlier than solid tumors (P=0.001 and P<0.001, respectively). No significant difference was found between the age of first event of MDS versus leukemia; (B) CI of HSCT. (C) CI of solid tumors for patient who underwent hematopoietic stem cell transplantation (HSCT) (blue) or did not have a transplant (red). No significant difference was found between the groups.
Figure 3
Figure 3
The distribution of the Fanconi anemia (FA) genes in Israel: (A) including siblings and (B) excluding siblings.
Figure 4
Figure 4
Survival according to the Fanconi anemia (FA) gene. Survival curves for patients with FA in Israel, calculating the proportion of live patients by age using the Kaplan-Meier methods according to the mutated gene: FANCA (blue), FANCC (red), FANCD1 (green), FANCG (purple) and FANCJ (orange). No significant difference was found between the groups.
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References

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