ORPHA: 84; DO: 0111096;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17q22 | Fanconi anemia, complementation group O | 613390 | Autosomal recessive | 3 | RAD51C | 602774 |
A number sign (#) is used with this entry because Fanconi anemia of complementation group O (FANCO) is caused by homozygous mutation in the RAD51C gene (602774) on chromosome 17q22.
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).
For additional general information and a discussion of genetic heterogeneity of Fanconi anemia, see 227650.
Vaz et al. (2010) reported a consanguineous Pakistani family in which 3 sibs had multiple severe congenital abnormalities characteristic of Fanconi anemia. One girl died at 2 months of age with 1 absent and 1 vestigial thumb, a congenital heart defect, imperforate anus, and hydronephrosis. Her lymphocytes showed elevated chromosome breakage after treatment with the DNA interstrand cross-linking agent mitomycin C, indicating a diagnosis of Fanconi anemia. A son died 2 days after birth with congenital abnormalities similar to those of his sister, and another pregnancy miscarried at 11 weeks. The youngest affected child was age 10 years at the time of the report. He had multiple congenital abnormalities, including short stature, bilateral radial hypoplasia, anal atresia, bilateral cryptorchidism, small genitalia, bilateral cystic dysplasia of the kidneys, and chronic renal failure. Primary cultured fibroblasts showed increased chromosomal breakage after exposure to interstrand cross-linking agents, with pronounced arrest of the cell cycle at G2 associated with impaired RAD51 (179617) focus formation. Since this child had not developed hematologic abnormalities or cancer, Vaz et al. (2010) referred to the phenotype as 'Fanconi anemia-like,' but noted that these features may develop with time.
By genomewide autozygosity mapping followed by candidate gene sequencing in a Pakistani family with Fanconi anemia, Vaz et al. (2010) identified a homozygous mutation in the RAD51C gene (R258H; 602774.0001). In vitro functional studies showed that the mutation resulted in loss of RAD51 focus formation in response to DNA damage, and that the defect could be rescued by expression of wildtype RAD51C. The authors provisionally designated the locus FANCO.
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]
Vaz, F., Hanenberg, H., Schuster, B., Barker, K., Wiek, C., Erven, V., Neveling, K., Endt, D., Kesterton, I., Autore, F., Fraternali, F., Freund, M., Hartmann, L., Grimwade, D., Roberts, R. G., Schaal, H., Mohammed, S., Rahman, N., Schindler, D., Mathew, C. G. Mutation of the RAD51C gene in a Fanconi anemia-like disorder. Nature Genet. 42: 406-409, 2010. [PubMed: 20400963] [Full Text: https://doi.org/10.1038/ng.570]