ORPHA: 84; DO: 0111082;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2p16.1 | Fanconi anemia, complementation group L | 614083 | Autosomal recessive | 3 | PHF9 | 608111 |
A number sign (#) is used with this entry because Fanconi anemia of complementation group L (FANCL) is caused by homozygous or compound heterozygous mutation in the PHF9 (FANCL; 608111) gene on chromosome 2p16.
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.
Meetei et al. (2003) detected little or no PHF9 protein in a cell line (EURA868) from an individual with Fanconi anemia of unassigned complementation group (subsequently designated FANCL). The phenotype of the cells from EURA868 resembled that of other Fanconi anemia cells, including the absence of monoubiquitinated FANCD2 (613984) and hypersensitivity to mitomycin C. These Fanconi anemia defects were corrected by ectopic expression of PHF9.
Ali et al. (2009) reported a male patient with FANCL who had developmental delay, a cafe-au-lait spot, mild hypocellularity, and a family history of leukemia.
Vetro et al. (2015) reported 2 unrelated infants with a severe form of FANCL presenting as multiple congenital anomalies reminiscent of VACTERL (192350) or VACTERL-H (276950). The first patient (case 1b), born of consanguineous Moroccan parents, was noted to have radial hypoplasia and intrauterine growth retardation on prenatal ultrasound at 14 weeks' gestation. Later investigations showed tetralogy of Fallot, left kidney agenesis, right kidney hydronephrosis, and esophageal atresia. After birth, the patient showed hypertelorism, broad nasal root and puffy cheeks, and bilateral absence of the thumbs. The infant died 2 months later and the abnormalities were confirmed by postmortem examination. Family history included 2 previous fetuses with congenital malformations; data available for 1 in which the pregnancy had been terminated revealed similar features. In the second family, a female Dutch infant (case 2) showed intrauterine growth retardation, hydrocephalus, facial dysmorphism with depressed nasal tip, microtia, microphthalmia, cleft palate, short neck, short forearms, radial club hands with absent thumbs, hypoplastic sacrum, and anal atresia with rectovaginal fistula. She also had cardiac defects and renal hypoplasia. She died at age 2 days. Cells derived from both patients showed increased chromosomal breakage with DEB or MMC, consistent with a diagnosis of Fanconi anemia.
The transmission pattern of FANCL in the families reported by Vetro et al. (2015) was consistent with autosomal recessive inheritance.
In a cell line (EUFA868) from an individual with Fanconi anemia of complementation group FANCL, Meetei et al. (2003) found little or no PHF9 protein. PHF9 cDNA from this cell line lacked exon 11, thus removing the conserved PHD finger and part of the third WD40 repeat. The genomic DNA from this individual showed a homo- or hemizygous insertion of 177 bp into a pyrimidine-rich sequence at the splice junction between intron 10 and exon 11 (608111.0001).
In a male patient with FANCL, Ali et al. (2009) identified compound heterozygous mutations in the FANCL gene (608111.0002-608111.0003).
In 2 unrelated infants with lethal FANCL, Vetro et al. (2015) identified 2 different homozygous truncating mutations in the FANCL gene (608111.0004 and 608111.0005). The mutation in the first patient was found by whole-exome sequencing and segregated with the disorder in the family. The mutation in the second patient was found by targeted sequencing of known Fanconi anemia genes. Cell lines from both patients showed increased chromosomal breakage and increased sensitivity to MMC, which was rescued after transfection with wildtype FANCL.
Ali, A. M., Kirby, M., Jansen, M., Lach, F. P., Schulte, J., Singh, T. R., Batish, S. D., Auerbach, A. D., Williams, D. A., Meetei, A. R. Identification and characterization of mutations in FANCL gene: a second case of Fanconi anemia belonging to FA-L complementation group. Hum. Mutat. 30: E761-E770, 2009. Note: Electronic Article. [PubMed: 19405097] [Full Text: https://doi.org/10.1002/humu.21032]
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]
Meetei, A. R., de Winter, J. P., Medhurst, A. L., Wallisch, M., Waisfisz, Q., van de Vrugt, H. J., Oostra, A. B., Yan, Z., Ling, C., Bishop, C. E., Hoatlin, M. E., Joenje, H., Wang, W. A novel ubiquitin ligase is deficient in Fanconi anemia. Nature Genet. 35: 165-170, 2003. [PubMed: 12973351] [Full Text: https://doi.org/10.1038/ng1241]
Vetro, A., Iascone, M., Limongelli, I., Ameziane, N., Gana, S., Della Mina, E., Giussani, U., Ciccone, R., Forlino, A., Pezzoli, L., Rooimans, M. A., van Essen, A. J., Messa, J., Rizzuti, T., Bianchi, P., Dorsman, J., de Winter, J. P., Lalatta, F., Zuffardi, O. Loss-of-function FANCL mutations associate with severe Fanconi anemia overlapping the VACTERL association. Hum. Mutat. 36: 562-568, 2015. [PubMed: 25754594] [Full Text: https://doi.org/10.1002/humu.22784]