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Fanconi anemia in Israel
tions and six patients had a combination of mutation types.
In our cohort, the most common mutations in FANCA were c.2172-2173 insG (p.S725Vfs*69), most frequent in the Sephardic Jewish population, c.4261-2A>C (IVS43- 2a>c) in Arab Muslims and Christians and c.3788- 3790delTCT, detected in both Arab Druze and Sephardic Jews. The most common mutation in FANCC was c. 456+4a>t (IVS4+4 a>t) in the Ashkenazi Jewish popula- tion. The mutation most commonly found in FANCG was the novel mutation c.1742C<G (p.Ser581Ter) in the Arab Muslim population.
Genotype-phenotype correlations
Genotype-phenotype correlations were first analyzed by the specific affected gene. In addition, patients were grouped by function of altered genes into those encoding proteins of the core complex (FANCA, FANCC, FANCG) versus those downstream (FANCD1, FANCJ). Finally, analysis was done according to the type of mutation (dele- tion, frame shift, missense, nonsense, splice site).
No association was found between the affected gene and survival (Figure 4). Survival was not significantly dif- ferent between patients with core complex mutations and those with mutations in downstream genes. Neither the
specific FA gene nor function were associated with the development of BMF. Of note, neither of the patients with FANCD1 mutations developed BMF. One underwent HSCT for AML before the age of six months, while the other had no complications by the age of 17 years.
Looking at congenital anomalies, no association was found between the CAB score and the affected FA gene. Rib abnormalities were observed only in patients with FANCC mutations. Cleft lip was more common in patients with FANCD1 mutations, compared with other FA genes (P<0.001). Patients with mutations in the down- stream genes FANCD1 and FANCJ were significantly shorter compared with the others (P=0.003). Patients with downstream mutations were found to have significantly more skull anomalies (P<0.001), central nervous system (CNS) abnormalities (P=0.005) and genitourinary anom- alies (P=0.03), compared with patients with core complex mutations.
All the solid tumors in our cohort were reported in patients with FANCA mutations or in undiagnosed patients, except for one case of medulloblastoma in a patient with FANCD1 mutation (Table 3). Due to the rela- tively small numbers of reported cancers in patients with non-FANCA mutations (Table 3), we compared the age of the first cancer (including MDS) between patients with
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.
haematologica | 2020; 105(7)
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