Fanconi Anemia, Complementation Group W

A number sign (#) is used with this entry because of evidence that Fanconi anemia complementation group W (FANCW) is caused by compound heterozygous mutation in the RFWD3 gene (614151) on chromosome 16q23. One such patient has been reported.

For a discussion of genetic heterogeneity of Fanconi anemia, see FANCA (227650).

Clinical Features

Knies et al. (2017) reported a 12-year-old German girl (patient 1143), born of unrelated parents, with typical Fanconi anemia. She was born with intrauterine growth retardation at 35 weeks' gestation and showed duodenal atresia, radial ray malformations, bilateral absent thumbs, and small midface. Ultrasound showed enlarged brain ventricles, hypoplastic left kidney, and polysplenia. Brain MRI showed rarefied periventricular white matter, narrow corpus callosum, abnormal pituitary, and Chiari malformation type I, but cognitive development was normal and she had no neurologic signs. She had poor overall growth and microcephaly, and she was treated for hypothalamic partial growth hormone deficiency. From age 10 years, she developed bone marrow abnormalities, including cytopenia, reduced hematopoiesis, and mild dysplastic features, such as dysmyelopoiesis, dysmegakaryopoiesis, and megaloblastoid erythropoiesis. Myelodysplastic syndrome was excluded on several occasions. The cytopenia was restricted to the bone marrow; peripheral blood counts remained stable. Cultured lymphocytes and fibroblasts showed hypersensitivity to DNA cross-linking agents, confirming the diagnosis of Fanconi anemia.

Inheritance

The transmission pattern of FANCW in the family reported by Knies et al. (2017) was consistent with autosomal recessive inheritance.

Molecular Genetics

In a 12-year-old German girl (patient 1143) with FANCW, Knies et al. (2017) identified compound heterozygous mutations in the RFWD3 gene (c.205_206dupCC, 614151.0001 and I639K, 614151.0002). Patient cells showed increased chromosomal breakage, reduced survival, and cell cycle arrest in G2 following exposure to mitomycin C (MMC) and additional DNA cross-linking agents, and these defects could be restored by expression of wildtype RFWD3. The specific results suggested a defect in BRCA2 (600185)-dependent homologous recombination (HR). In vitro studies of the I639K variant indicated that it had less relocalization to the nucleus and to chromatin compared to wildtype, had disrupted physical interaction with RPA proteins (see, e.g., RPA2, 179836), and caused impaired HR in transduced cells. Three different cellular models with generation of RFWD3 mutants recapitulated the defects observed in patient cells, indicating that RFWD3 normally promotes HR induced by DNA interstrand cross-links. Knies et al. (2017) concluded that RFWD3 is positioned late in the FA/BRCA pathway, downstream of BRCA2/FANCD1.

Animal Model

Knies et al. (2017) found that Rfwd3-null mice were viable and did not show overt phenotypic abnormalities, although there was some evidence for increased embryonic lethality, earlier death, and subfertility, associated with testicular and ovarian atrophy in mutant mice. Mutant mouse embryonic fibroblasts were hypersensitive to DNA cross-linking agents and showed increased chromosomal breakage compared to controls.