ORPHA: 84; DO: 0111088;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11p14.3 | Fanconi anemia, complementation group F | 603467 | Autosomal recessive | 3 | FANCF | 613897 |
A number sign (#) is used with this entry because Fanconi anemia of complementation group F is caused by homozygous or compound heterozygous mutation in the FANCF gene (613897) on chromosome 11p14.
Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder that causes genomic instability. Characteristic clinical features include developmental abnormalities in major organ systems, early-onset bone marrow failure, and a high predisposition to cancer. The cellular hallmark of FA is hypersensitivity to DNA crosslinking agents and high frequency of chromosomal aberrations pointing to a defect in DNA repair (summary by Deakyne and Mazin, 2011).
Clinical features of FANCF include microcephaly, small or absent thumbs, short stature, microphthalmia, microtia, hearing loss, pigmentary anomalies (cafe-au-lait spots or hyperpigmentation), small or pelvic kidneys, and cardiac anomalies (Tryon et al., 2017; Zareifar et al., 2019).
For additional general information and a discussion of genetic heterogeneity of Fanconi anemia, see 227650.
Tryon et al. (2017) investigated 3 patients with Fanconi anemia complementation group F who demonstrated the clinical variability within this group. Patient 1 was a female born at 34 weeks' gestation following a pregnancy complicated by polyhydramnios and IUGR. Fanconi anemia was suspected on the basis of multiple congenital anomalies including single umbilical artery, microcephaly, microphthalmia, microtia, bilateral radial hypoplasia, absent thumbs, atrial septal defect, duodenal atresia, and left pelvic kidney. Chromosomal breakage testing with diepoxybutane (DEB) revealed 11.5 breaks/cell, confirming the diagnosis of Fanconi anemia. Complementation group analysis determined group F. Single lineage marrow failure (severe neutropenia) led to hematopoietic cell transplant (HCT) at 3 years 7 months and then death 144 days after HCT secondary to severe hemorrhagic cystitis and hemolytic anemia. Patient 2 was a male born full term and admitted at 4 months of age for a urinary tract infection, which led to the discovery of a right pelvic kidney. Because of other anomalies such as microcephaly, small thumbs, microphthalmia, and microphallus, Fanconi anemia was suspected. Chromosomal breakage assay demonstrated 13 breaks/cell exposed to DEB, and complementation group testing determined group F. Family history was significant for multiple family members with a history of cancer. He developed myelodysplastic syndrome (MDS) with monosomy 7 and underwent HCT at 4 years 8 months. He was alive at age 12 years. Patient 3 was a male born at 32 weeks' gestation following a placental abruption. At 9 years 8 months, a complete blood count revealed mild anemia and thrombocytopenia following an evaluation of abdominal pain and fatigue. DEB testing showed a mean of 6.0 breaks/cell in 90% of cells, indicating a possible low level of mosaicism. Complementation group testing identified group F. The family history was significant for multiple family members with a history of cancer. He received no treatment. At age 14 years he had an absolute neutrophil count of 500, and was found to have a partial 1q duplication in 25% of cells.
Zareifar et al. (2019) described a 3.5-year-old Iranian girl, born to first cousins, with short stature, microcephaly, skin hyperpigmentation, and pancytopenia. Bone marrow aspiration revealed moderate to severely hypocellular bone marrow. Chromosomal analysis with mitomycin C revealed an average of 7 to 8 breaks/cell compared to the control sample of 0.3 to 0.5 breaks/cell.
De Winter et al. (2000) identified mutations in the FANCF gene in 4 cell lines of Fanconi anemia complementation group F.
In 2 patients (patients 1 and 2) with a severe phenotype of Fanconi anemia complementation group F, including multiple congenital anomalies and early-onset bone marrow failure or MDS, Tryon et al. (2017) identified the previously reported c.484_485delCT mutation (613897.0004) in the FANCF gene in compound heterozygosity. Patient 1 additionally carried a 14-bp deletion (c.438_451del; 613897.0006), and patient 2 a 1-bp deletion (613897.0007).
In a 3.5-year-old girl with Fanconi anemia, Zareifar et al. (2019) identified a novel homozygous frameshift mutation (c.534delG; 613897.0008) in the FANCF gene. The mutation was identified using next-generation sequencing and confirmed by Sanger sequencing.
de Winter, J. P., Rooimans, M. A., van der Weel, L., van Berkel, C. G. M., Alon, N., Bosnoyan-Collins, L., de Groot, J., Zhi, Y., Waisfisz, Q., Pronk, J. C., Arwert, F., Mathew, C. G., Scheper, R. J., Hoatlin, M. E., Buchwald, M., Joenje, H. The Fanconi anaemia gene FANCF encodes a novel protein with homology to ROM. (Letter) Nature Genet. 24: 15-16, 2000. [PubMed: 10615118] [Full Text: https://doi.org/10.1038/71626]
Deakyne, J. S., Mazin, A. V. Fanconi anemia: at the crossroads of DNA repair. Biochemistry 76: 36-48, 2011. [PubMed: 21568838] [Full Text: https://doi.org/10.1134/s0006297911010068]
Tryon, R., Zierhut, H., MacMillan, M. L., Wagner, J. E. Phenotypic variability in patients with Fanconi anemia and biallelic FANCF mutations. Am. J. Med. Genet. 173A: 260-263, 2017. [PubMed: 27714961] [Full Text: https://doi.org/10.1002/ajmg.a.37998]
Zareifar, S., Dastsooz, H., Shahriari, M., Faghihi, M. A., Shekarkhar, G., Bordbar, M., Zekavat, O. R., Shakibazad, N. A novel frame-shift deletion in FANCF gene causing autosomal recessive Fanconi anemia: a case report. BMC Med. Genet. 20: 122, 2019. [PubMed: 31288759] [Full Text: https://doi.org/10.1186/s12881-019-0855-2]