A number sign (#) is used with this entry because Fanconi anemia of complementation group Q (FANCQ) is caused by compound heterozygous mutation in the ERCC4 gene (133520) on chromosome 16p13.

Fanconi anemia (FA) is a rare genomic instability disorder characterized by bone marrow failure, congenital malformations, hypersensitivity to DNA interstrand crosslink-inducing agents, chromosome fragility, and high susceptibility to cancer (summary by Bogliolo et al., 2013).

For additional general information and a discussion of genetic heterogeneity of Fanconi anemia, see 227650.

Bogliolo et al. (2013) reported 2 unrelated patients, of Spanish and German origin, respectively, with an unclassified form of Fanconi anemia. The first patient presented in the neonatal period with bilateral absent thumbs, microsomy, esophageal atresia, a ventrally translocated anus, and dysplastic, low-set ears. She did not have skin hyperpigmentation, photosensitivity, sunlight-induced scarring, or atrophy. She developed bone marrow failure at age 2 years and died from complications of a bone marrow transplant at age 4 years. The second patient was diagnosed at age 5 years due to the presence of multiple FA features such as perinatal growth retardation, short stature, microcephaly, cafe-au-lait spots, an ostium primum defect, biliary atresia with liver fibrosis, and bone marrow failure. The patient had red hair and pale skin, but had no spontaneous or UV light-induced skin lesions. Laboratory studies of cells derived from both patients showed increased chromosome breakage in response to certain agents, such as diepoxybutane, mitomycin-C, and melphalan, indicating a defect in interstrand crosslink (ICL) DNA repair. In contrast, patient cells did not show increased sensitivity to UV-induced damage, suggesting that nucleotide excision repair (NER) was intact.

The transmission pattern of FANCQ in the families reported by Bogliolo et al. (2013) was consistent with autosomal recessive inheritance.

By exome sequencing of a girl with Fanconi anemia, Bogliolo et al. (2013) identified compound heterozygous mutations in the ERCC4 gene (133520.0004 and 133520.0005). Direct sequencing of this gene in 18 patients with unclassified Fanconi anemia revealed 1 patient with compound heterozygous mutations (133520.0006 and 133520.0007). Transduction of wildtype ERCC4 into patient cells complemented the mitomycin-C sensitivity. Detailed cellular studies showed that the Fanconi anemia cells with ERCC4 mutations were completely deficient in ICL repair, but retained significant levels of NER activity to prevent skin photosensitivity from UV damage. Functional studies showed that the mutations resulted either in impaired nuclease incision activity or in abnormal aggregation of the protein in the cytoplasm.