Fanconi Anemia, Complementation Group I
A number sign (#) is used with this entry because Fanconi anemia complementation group I (FANCI) is caused by homozygous or compound heterozygous mutation in the FANCI gene (611360) on chromosome 15q26.
DescriptionFanconi 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.
Clinical FeaturesLevitus et al. (2004) provided a tabulation of 11 genetically distinct FA subtypes. They reported 8 unrelated FA patients who were excluded from the known subtypes on the basis of phenotypic correction (complementation) or genetic data. Four of these cell lines failed to complement each other in somatic cell hybrids and therefore represented a new group, termed complementation group I (FANCI). The remaining cell lines complemented group FANCI but did not complement each other, thus representing a second new group, FANCJ (609054). Both the FANCI and FANCJ cell lines were capable of forming an FA multiprotein core complex. This complex is required for activation of the FANCD2 protein (227646) by monoubiquitination, a key downstream event in the FA pathway. In FANCI cells, FANCD2 was not monoubiquitinated, indicating a defect upstream in the FA pathway, whereas in FANCJ cells, FANCD2 was monoubiquitinated, indicating a downstream defect. The results suggested that the FA pathway of genome stabilization may be controlled by at least 11 different genes, including FANCI and FANCJ.
Savage et al. (2015) reported 3 patients with molecularly confirmed FANCI who also had features of VACTERL/VACTERL-H association (see 192350, 276950, 314390). One patient (NCI-82-1) had short stature with height and weight below the 1st centile for age, microcephaly, and a small triangular face (Fanconi facies). She also had fused cervical vertebrae, atrial septal defect (ASD), ventricular septal defect (VSD), duodenal atresia, small kidneys, and absent thumbs. She had mild thrombocytopenia, and her bone marrow was hypocellular (30%) with a 47,XX,+i(1)(q10)[2]/46,XX[48] clonal abnormality. She died at age 11.5 years from complications of hematopoietic stem cell transplantation. Another patient (NCI-253-1) had hypothyroidism, marked short stature, microcephaly, and a short triangular face. She also had cervical vertebral anomaly, VSD, patent foramen ovale, horseshoe kidney, and absent thumb. Her blood counts were normal, but her bone marrow was hypocellular (40%) with normal cytogenetics. The third patient (NCI-309-1) had bilateral hypoplastic thumbs, microcephaly, congenital heart disease (ASD, VSD, and patent ductus arteriosus, all of which closed spontaneously), microcephaly, a small, triangular face, small eyes, small neck, narrow C5 vertebra, bilateral hypoplastic thumbs, absent radial pulses, Chiari malformation, and a small pituitary gland with poorly visualized pituitary stalk. She had previously undergone a bilateral ureteric reimplantation for grade three vesicoureteral reflux. She had normal stature and normal hormone function. She had mild neutropenia, and a bone marrow biopsy revealed 20 to 50% cellularity with trilineage hematopoiesis and normal cytogenetics.
MappingFA complementation group I results from mutations in the FANCI gene, which maps to chromosome 15q25-q26 (Dorsman et al., 2007).
Molecular GeneticsDorsman et al. (2007) identified several mutations in the FANCI gene (e.g., 611360.0001-611360.0004) in 8 patients with FA complementation group I. Western blot analysis confirmed that functionally active FANCI protein was absent in patients with FA complementation group I. Sims et al. (2007) and Smogorzewska et al. (2007) also reported mutations in the FANCI gene in patients with FA complementation group I.