• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Fanconi Anemia

Synonym: Fanconi Pancytopenia. Includes: BRCA2-Related Fanconi Anemia, BRIP1-Related Fanconi Anemia, FANCA-Related Fanconi Anemia, FANCB-Related Fanconi Anemia, FANCC-Related Fanconi Anemia, FANCD2-Related Fanconi Anemia, FANCE-Related Fanconi Anemia, FANCF-Related Fanconi Anemia, FANCG-Related Fanconi Anemia, FANCI-Related Fanconi Anemia, FANCL-Related Fanconi Anemia, FANCM-Related Fanconi Anemia, PALB2-Related Fanconi Anemia, RAD51C-Related Fanconi Anemia, SLX4-Related Fanconi Anemia

, MD, MPH, FAAP and , MD.

Author Information
, MD, MPH, FAAP
Clinical Genetics Branch
Division of Cancer Epidemiology and Genetics
National Cancer Institute
Department of Health and Human Services
Bethesda, Maryland
, MD
Departments of Pediatrics and Pathology
Section of Pediatric Hematology-Oncology
Yale University School of Medicine
New Haven, Connecticut

Initial Posting: ; Last Revision: February 7, 2013.

Summary

Disease characteristics. Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk of malignancy. Physical abnormalities, present in 60%-75% of affected individuals, include one or more of the following: short stature; abnormal skin pigmentation; malformations of the thumbs, forearms, skeletal system, eyes, kidneys and urinary tract, ears (and decreased hearing), heart, gastrointestinal system, central nervous system; hypogonadism; and developmental delay. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. By age 40 to 50 years, the estimated cumulative incidence of bone marrow failure is 90%; the incidence of hematologic malignancies (primarily acute myeloid leukemia) 10%-30%; and of nonhematologic malignancies (solid tumors, particularly of the head and neck, skin, GI tract, and genital tract) 25%-30%.

Diagnosis/testing. The diagnosis of FA rests upon the detection of chromosomal aberrations (breaks, rearrangements, radials, exchanges) in cells after culture with a DNA interstrand cross-linking agent such as diepoxybutane (DEB) or mitomycin C (MMC). Molecular genetic testing is complicated by the presence of at least 15 genes, which are responsible for the known FA complementation groups (A, B, C, D1 [BRCA2], D2, E, F, G, I, J [BRIP1], L, M, N [PALB2], O [RAD51C], and P [SLX4]). The latter two genes are still thought of as tentative as they do not fall within a very easily characterized compartment biologically and have very few representative individuals. If the relevant complementation group is identified, molecular genetic testing can be directed to the appropriate gene.

Management. Treatment of manifestations: Administration of oral androgens (e.g., oxymetholone) improves blood counts (red cell, white cell, and platelets) in approximately 50% of individuals with FA; subcutaneous administration of G-CSF improves the neutrophil count in some; hematopoietic stem cell transplantation (HSCT) is the only curative therapy for the hematologic manifestations of FA, but the high risk of solid tumors remains and may even be increased in those undergoing HSCT. All these treatments have potential significant toxicity.

Surveillance: Monitoring of growth and pubertal development; monitoring for evidence of bone marrow failure (regular blood counts; at least annual bone marrow aspirate/biopsy to evaluate morphology, cellularity, and cytogenetics); for those receiving androgen therapy, monitoring liver chemistry profile and regular ultrasound examination of the liver; monitoring for solid tumors (oropharyngeal and gynecologic examinations).

Agents/circumstances to avoid: Transfusions of red cells or platelets for persons who are candidates for HSCT; family members as blood donors if HSCT is being considered; blood products that are not filtered (leukodepleted) or irradiated; toxic agents that have been implicated in tumorigenesis; radiographic studies solely for the purpose of surveillance (i.e., in the absence of clinical indications).

Evaluation of relatives at risk: DEB/MMC testing of all siblings of a proband for early diagnosis, treatment, and monitoring for physical abnormalities, bone marrow failure, and related cancers.

Genetic counseling. Abnormalities of Fanconi anemia (FA) genes are inherited in an autosomal recessive manner except for mutations in FANCB, which are inherited in an X-linked manner.

Autosomal recessive FA: Each sibling of an affected individual has a 25% chance of inheriting both mutations and being affected, a 50% chance of inheriting one mutated gene and being a carrier, and a 25% chance of inheriting both normal genes and not being a carrier. Carriers (heterozygotes) for autosomal recessive FA are asymptomatic.

X-linked FA: For carrier females the chance of transmitting the mutation in each pregnancy is 50%; males who inherit the mutation will be affected; females who inherit the mutation will be carriers and will usually not be affected.

For both autosomal recessive and X-linked FA: Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants in the family are known.

Diagnosis

Clinical Diagnosis

Recommendations for diagnosis were agreed upon at a 2008 consensus conference [Eiler et al 2008; click Image guidelines.jpg for full text].

Fanconi anemia (FA) is suspected in individuals with the following:

  • Physical abnormalities including short stature; abnormal skin pigmentation (e.g., café au lait spots or hypopigmentation); malformations of the thumbs, forearms, skeletal system, eye, kidneys and urinary tract, ear, heart, gastrointestinal system, oral cavity, and central nervous system; hearing loss; hypogonadism; and developmental delay. These findings are variable; approximately 25%-40% of individuals with Fanconi anemia have no physical abnormalities. Thus, the absence of physical abnormalities does NOT rule out the diagnosis of Fanconi anemia.
  • Progressive bone marrow failure, manifest as thrombocytopenia, leukopenia, and anemia, typically presenting by age seven to eight years, often initially with either thrombocytopenia or leukopenia. Bone marrow, initially normocellular, becomes progressively hypoplastic with time.
  • Adult-onset aplastic anemia, in which red cell macrocytosis and elevated hemoglobin F levels may be seen.
  • Myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML). On occasion, MDS or AML is the initial manifestation.
  • Solid tumors presenting at an atypically young age and in the absence of other risk factors. These tumors include squamous cell carcinomas of the head and neck, esophagus, and vulva; cervical cancer; and liver tumors (usually but not exclusively associated with treatment with oral androgens). Solid tumors may be the first manifestation of Fanconi anemia in individuals who have no birth defects and have not experienced bone marrow failure.
  • Inordinate toxicities from chemotherapy or radiation

Testing

Chromosomal breakage studies. The diagnosis of FA rests on cytogenetic testing for increased chromosomal breakage or rearrangement in the presence of diepoxybutane (DEB), a bifunctional DNA interstrand cross-linking agent [Auerbach 1993] or radial figures with mitomycin C (MMC) [Cervenka et al 1981]. The background rate of chromosomal breakage in control chromosomes is more variable with MMC; thus, some centers prefer to use DEB while other centers use both DEB and MMC.

Peripheral blood is cultured with a T-cell mitogen, phytohemagglutinin, in the presence and absence of the cross-linking agent. A total of 50 cells in metaphase are scored and analyzed for chromosomal breakage as well as the formation of radials. Results are compared with those from normal control cells and FA-positive control cells.

  • Cultures without the DNA clastogenic agent may be used to measure the spontaneous breakage rate.
  • Results are reported as either the average number of breaks/cell or as x number of cells with 1,2,3...>8 breaks.
  • The number of cells with radial forms is recorded.

In response to DEB or MMC, individuals with FA show:

  • Increased rates of spontaneous chromosomal breakage (may be seen in FA as well as other chromosomal breakage syndromes; see Differential Diagnosis)
  • Increased breakage and radial forms that distinguish FA from other chromosomal breakage syndromes

The increased sensitivity to DEB/MMC is present regardless of phenotype, congenital anomalies, or severity of the disease.

Note: Interpretation of the results of the chromosomal breakage test may be complicated by mosaicism, defined as the presence of two populations of lymphocytes: one showing increased sensitivity to DEB/MMC and the other showing normal levels of chromosomal breakage in response to DEB/MMC. This normal cellular phenotype has been attributed to gene conversion events, back mutations, or compensatory deletions/insertions leading to selective advantage of the gene-corrected lymphocytes [Lo Ten Foe et al 1997, Waisfisz et al 1999, Gross et al 2002]. Lymphocyte mosaicism can develop in individuals initially found to be sensitive to DEB/MMC. These individuals may have a falsely normal DEB/MMC test. In individuals with a normal DEB/MMC test in whom a high degree of clinical suspicion of FA remains, DEB/MMC testing to establish the diagnosis could be performed on an alternative cell type, such as skin fibroblasts. Tabulation of the number of cells with chromosomal breaks and radials can assist in diagnosis in the presence of lymphocyte mosaicism.

FA heterozygotes cannot be detected by the DEB/MMC test because their results are within the normal range.

Other cytogenetic testing. Abnormal bone marrow cytogenetic findings may develop. Cytogenetic abnormalities can wax and wane or the patient may progress to myelodysplastic syndrome (MDS) and leukemia [Alter et al 2000]. Clonal amplifications of chromosome 3q26-q29 were reported in association with an increased risk of progression to MDS or acute myelogenous leukemia (AML) [Tonnies et al 2003, Cioc et al 2010].

Immunoblot assay of FANCD2 protein monoubiquitination. The Fanconi anemia proteins A, B, C, E, F, G, I, L, and M form the core complex required for the monoubiquitination of the downstream FANCD2 protein. FANCD2 protein monoubiquitination is essential for the functional integrity of the FA pathway as measured by resistance to MMC or DEB. Because FANCD2 protein monoubiquitination is intact in other bone marrow failure syndromes and chromosomal breakage syndromes tested to date [Shimamura et al 2002], evaluation of FANCD2 protein monoubiquitination by immunoblotting provides a rapid diagnostic test for Fanconi anemia. Note that the rare FA subtypes FA-D1 (BRCA2), FA-J (BACH1/BRIP1), and FA-N (PALB2) would be missed by this approach (because they are downstream of FANCD2), as might individuals with somatic mosaicism.

Cell cycle arrest. MMC also induces cell cycle arrest in the G2 phase. Flow cytometric assessment of G2 arrest has been used diagnostically [Pulsipher et al 1998]. In this test, primary skin fibroblasts are exposed to MMC and analyzed by flow cytometry for the percentage of cells in the G2 phase of the cell cycle. FA is suspected when a large fraction of cells accumulate in G2.

Determination of complementation groups. Based on somatic cell fusion studies, at least 15 complementation FA groups have been identified [A, B, C, D1 (BRCA2), D2, E, F, G, I, J (BRIP1/BACH1), L, M, N (PALB2), O (RAD51C), and P (SLX4). The FA complementation group can be identified by identifying which of the cDNA of the 15 FA-related genes, when expressed in the cells of the affected individual, corrects the DEB/MMC sensitivity phenotype [Pulsipher et al 1998]. Such testing is now possible [Chandra et al 2005].

Laboratory findings that may be found in association with FA:

  • Macrocytic red blood cells, often with increased fetal hemoglobin. These changes, which have no prognostic significance, often precede the onset of anemia.
  • Normal or usually increased serum erythropoietin concentration

Molecular Genetic Testing

Genes. Genes in which mutation is responsible for all of the 15 FA complementation groups have been identified:

Clinical testing

  • Targeted mutation analysis for the common Ashkenazi Jewish FANCC mutation (c.456+4A>C; previously known as IVS4+4A>T)
  • Sequence analysis for all the known genes associated with Fanconi anemia. Sequence analysis is complicated by the number of genes to be analyzed, the large number of possible mutations in each gene, the presence of large insertions or deletions in some genes, and the large size of many of the FA-related genes. If the complementation group has been established, the responsible mutation can be determined by sequencing the corresponding gene.
  • Deletion/duplication analysis to detect deletions of one or more exons or of an entire gene

Table 1. Summary of Molecular Genetic Testing Used in Fanconi Anemia

Complementation GroupGene 1Proportion of FA Attributable to Mutations in This Gene 2Test MethodMutations Detected 3
FA-AFANCA60%-70%Sequence analysisSequence variants 4
Deletion/duplication analysis 5Exonic or whole-gene deletions
FA-BFANCB~2% Sequence analysisSequence variants 4
Deletion/duplication analysis 5Exonic or whole-gene deletions
FA-CFANCC~14%Targeted mutation analysis c.456+4A>T, 67delG 6
Sequence analysisSequence variants 4 incl those in targeted analysis
Deletion/duplication analysis 3Exonic or whole-gene deletions
FA-D1BRCA2~3% Sequence analysisSequence variants 4
FA-D2FANCD2~3%
FA-EFANCE~3%
FA-FFANCF~2%
FA-GFANCG~10%
FA-IFANCI~1%
FA-JBRIP1~2%
FA-LFANCL~0.2%
FA-M 7FANCM~0.2%
FA-NPALB2~0.7%
Deletion/duplication analysis 3Exonic or whole-gene deletions
FA-O 8RAD51C~0.2%Sequence analysisSequence variants 4
FA-P 9SLX4~0.2%

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. Shimamura & Alter [2010]

3. See Molecular Genetics for information on allelic variants.

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

6. Mutation panel may vary by laboratory.

7. FA-M: Assignment of a formal complementation group for persons with FANCM mutations is still controversial since only one reference family/cell line has been identified and that cell line has been determined to have biallelic mutations in both FANCA and FANCM. Of note, under experimental conditions specific knockdown of FANCM alone results in an FA phenotype [Singh et al 2009].

8. FA-O: Assignment of a formal complementation group for persons with RAD51C mutations is still controversial, as only one reference consanguineous family has been identified [Vaz et al 2010].

9. FA-P: Assignment of a formal complementation group for persons with SLX4 mutations is still controversial as only a handful of reference families have been identified and SLX4 biology falls outside previously characterized FA proteins [Kim et al 2011, Stoepker et al 2011].

Testing Strategy

To confirm/establish the diagnosis in a proband

  • Perform cytogenetic testing in blood for increased chromosomal breakage, rearrangements, and radials in the presence of diepoxybutane (DEB) or mitomycin C (MMC).
  • Perform cytogenetic testing in the presence of diepoxybutane (DEB) or mitomycin C (MMC) in skin fibroblasts if blood is normal or inconclusive and mosaicism is suspected.
  • Once cytogenetic testing has confirmed the diagnosis of FA, obtain complementation analysis (in a CLIA-certified laboratory) to identify the mutated gene [Chandra et al 2005], then obtain sequence analysis of the appropriate gene.

    Note: Although some centers recommend sequencing of all genes without prior evaluation by complementation analysis [Ameziane et al 2008], this is prohibitively expensive at this time in the United States using conventional sequencing methods.
  • Targeted mutation analysis of FANCC or sequencing of specific genes can be performed in ethnic groups in which there is a founder effect, as in the Ashkenazi Jewish mutation c.456+4A>T.

Carrier testing for relatives at risk for the autosomal recessive forms of Fanconi anemia requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Carrier testing for relatives at risk for X-linked form of Fanconi anemia (FANCB mutations) requires prior identification of the disease-causing mutation in the family.

Note: (1) Carriers are female heterozygotes for this X-linked disorder. (2) Identification of female carriers generally requires either (a) prior identification of the disease-causing mutation in the family or (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

The primary clinical features of Fanconi anemia (FA) include physical abnormalities, progressive bone marrow failure manifest as pancytopenia, and cancer susceptibility; however, some individuals with FA have neither physical abnormalities nor bone marrow failure.

Physical abnormalities. Physical anomalies are not generally a cause of mortality in individuals with Fanconi anemia. The likelihood of any physical abnormality is approximately 75%. The ratio of males to females is 1.2:1 (p <0.001 vs expected 1.00). The most commonly reported abnormalities and their frequency (see Note) include the following [Shimamura & Alter 2010]:

  • Low birth weight (5%)
  • Microsomia (40%). Short stature
  • Skin (40%). Generalized hyperpigmentation; café au lait spots, hypopigmented areas
  • Skeletal
    • Upper limbs, unilateral or bilateral (35%)
      • Thumbs (35%). Absent or hypoplastic, bifid, duplicated, rudimentary, attached by a thread, triphalangeal, long, low set
      • Radii (7%). Absent or hypoplastic (only with abnormal thumbs), absent or weak pulse
      • Hands (5%). Flat thenar eminence, absent first metacarpal, clinodactyly, polydactyly
      • Ulnae (1%). Dysplastic, short
    • Lower limbs (5%)
      • Feet. Toe syndactyly, abnormal toes, club feet
      • Legs. Congenital hip dislocation
    • Neck (1%). Sprengel deformity, Klippel-Fiel anomaly, short, low hairline, webbed
    • Spine (2%). Spina bifida, scoliosis, hemivertebrae, abnormal ribs, coccygeal aplasia
  • Craniofacial
    • Head (20%). Microcephaly
    • Face (2%). Triangular, birdlike, dysmorphic, micrognathia, mid-face hypoplasia
  • Eyes (20%). Small, cataracts, astigmatism; strabismus, epicanthal folds, hypotelorism, hypertelorism, ptosis
  • Renal (20%). Kidneys: horseshoe, ectopic or pelvic, abnormal, hypoplastic or dysplastic, absent; hydronephrosis or hydroureter
  • Gonads
    • Males (25%). Hypospadias, micropenis; undescended testes, absent testes
    • Females (2%). bicornuate uterus, malposition, small ovaries

      Note: Fertility is reduced in males (albeit not entirely absent) due to hypo- or azospermia. Pregnancy is possible in females, whether or not they have undergone hematopoietic stem cell transplantation [Alter et al 1991, Dalle et al 2004].
  • Developmental delay (10%). Intellectual disability, developmental delay
  • Ears (10%). Hearing loss (usually conductive secondary to middle ear bony anomalies); abnormal shape (dysplastic, atretic, narrow ear canal [i.e., external auditory meatus], abnormal pinna)
  • Cardiopulmonary (6%). Congenital heart defect: patent ductus arteriosus, atrial septal defect, ventricular septal defect, coarctation of the aorta, truncus arteriosus, situs inversus
  • Gastrointestinal (5%). Esophageal, duodenal, jejunal atresia; imperforate anus; tracheoesophageal fistula; annular pancreas; malrotation of the gut
  • Central nervous system (3%). Small pituitary, pituitary stalk interruption syndrome, absent corpus callosum, cerebellar hypoplasia, hydrocephalus, dilated ventricles

Note: Percentages are calculated from 2000 cases reported in the literature from 1927 to 2009. Frequencies are approximate, since many reports did not mention physical descriptions.

Bone marrow failure. The hematologic complications of FA typically occur within the first decade of life but are highly variable. Pancytopenia can present as early as the newborn period [Landmann et al 2004, Shimamura & Alter 2010].

  • Thrombocytopenia or leukopenia may precede anemia.
  • Pancytopenia generally worsens over time.
  • Neutropenia is associated with an increased risk for infections.
  • Sweet syndrome (neutrophilic skin infiltration) has been reported in a few individuals with FA and myelodysplastic syndrome (MDS) [Baron et al 1989].
  • Severe bone marrow failure (defined as severe enough to lead to death or hematopoietic stem cell transplantation) has a peak hazard rate of about 5% per year at age ten years. In a competing risk analysis, the cumulative incidence of this complication as the first event is 55% by age 50 years [Rosenberg et al 2003, Alter et al 2010]; in a non-competing risk model, the cumulative risk of any hematologic finding (not necessarily severe) was 90% by age 50 years [Kutler et al 2003].

Cancer susceptibility. In a review of individuals reported in the literature with FA, 9% developed leukemia (primarily acute myeloid leukemia [AML]) and 7% developed myelodysplastic syndrome (MDS) [Alter 2003a]. The relative risk for AML was increased approximately 500-fold in four different cohorts [Rosenberg et al 2003, Rosenberg et al 2008, Alter et al 2010, Tamary et al 2010]. In a competing risk analysis of the combined cohorts, the cumulative incidence of AML was 13% by age 50 years, with most cases between ages 15 and 35 years.

The risk of developing solid tumors, particularly of the head and neck, skin, esophagus, and gynecologic area is also increased [Kutler et al 2003, Rosenberg et al 2003, Rosenberg et al 2008, Alter et al 2010, Tamary et al 2010].

The head and neck, esophageal, and vulvar tumors are squamous cell carcinomas. An increased incidence of human papillomavirus DNA reported in squamous cell carcinoma samples from individuals with FA in one cohort [Kutler et al 2003] was not confirmed in a separate report [van Zeeburg et al 2008]. The relative risk of solid tumors in the four cohorts was about 40-fold and the cumulative incidence 30% by age 50 years in a competing risk analysis.

Individuals with FA receiving androgen treatment for bone marrow failure are at increased risk for liver tumors; however, two individuals out of about 45 with liver tumors had never received androgens.

Malignancies are very difficult to treat (except surgically) because individuals with FA are sensitive to DNA-damaging agents such as chemotherapy and radiation.

Genotype-Phenotype Correlations

FANCA. Among individuals with mutations in FANCA, those who are homozygous for null mutations (no protein production) may have earlier onset of anemia and higher incidence of leukemia than individuals with mutations that permit production of an abnormal FANCA protein [Faivre et al 2000].

FANCC

BRCA2. Biallelic mutations in BRCA2 (also known as FANCD1) are associated with early-onset acute leukemia [Wagner et al 2004] and solid tumors [Hirsch et al 2004]. All persons with mutations in IVS7 developed AML by age three years; those with other BRCA2 mutations who developed AML did so by age six years [Alter 2006]. The cumulative probability of any malignancy was 97% by age six years, including AML, medulloblastomas, and Wilms tumor [Alter et al 2007].

FANCG. Mutations in FANCG may be associated with more severe cytopenia and a higher incidence of leukemia than other mutations; null mutations were in general more severe than mutations that produced an altered protein [Faivre et al 2000].

Prevalence

The incidence of FA is estimated at 1:360,000 births, based on an assumed carrier frequency of 1:300 and an autosomal recessive model [Swift 1971].

In some populations (Ashkenazi Jewish, Spanish Gypsy, and black South African) the carrier frequency of FA is estimated at around 1:100 [Kutler & Auerbach 2004, Callen et al 2005, Morgan et al 2005].

Differential Diagnosis

Fanconi anemia (FA) is the most common genetic cause of aplastic anemia and one of the most common genetic causes of hematologic malignancy.

Cells derived from individuals with other chromosomal breakage syndromes, such as Bloom syndrome or ataxia-telangiectasia, may also exhibit high rates of spontaneous chromosomal breakage; however, only FA cells exhibit increased chromosomal breakage in response to DEB.

Nijmegen breakage syndrome (NBS), characterized by short stature, progressive microcephaly with loss of cognitive skills, premature ovarian failure in females, recurrent sinopulmonary infections, and an increased risk for cancer, particularly lymphoma, may also manifest increased chromosomal breakage with MMC [Nakanishi et al 2002, Gennery et al 2004]. Inheritance is autosomal recessive. NBS may be distinguished from FA by DNA-based testing of NBS1, which detects mutations in almost 100% of individuals with NBS.

Seckel syndrome, characterized by growth retardation, microcephaly with intellectual disability, and a characteristic 'bird-headed' facial appearance, may also show increased chromosome breakage with DNA cross-linking agents (MMC, DEB) [Andreassen et al 2004]. Some individuals with Seckel syndrome also develop pancytopenia and/or AML. Mutations in at least three genes are responsible for Seckel syndrome, only one of which (ATR) has been identified [O'Driscoll et al 2003].

Other disorders including neurofibromatosis 1 (which could be considered because of café au lait spots), TAR syndrome (thrombocytopenia with absent radii), and non-FA-related VACTERL association [Faivre et al 2005] (which could be considered because of radial ray defects) can be distinguished from FA by the DEB or MMC test.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Management focuses on surveillance and treatment of physical abnormalities, bone marrow failure, leukemia, and solid tumors.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Fanconi anemia (FA), the following evaluations are recommended as needed:

Physical abnormalities

  • Ultrasound examination of the kidneys and urinary tract
  • Formal hearing test
  • Developmental assessment (particularly important for toddlers and school-age children)
  • Referral to an ophthalmologist, otolaryngologist, endocrinologist, hand surgeon, gynecologist (for females as indicated), gastroenterologist, urologist
  • Evaluation by a medical geneticist and genetic counseling

Bone marrow failure

  • Evaluation by a hematologist, to include complete blood count, fetal hemoglobin, and bone marrow aspirate for cell morphology and cytogenetics, as well as biopsy for cellularity
  • HLA typing of the affected individual, sibs, and parents for consideration of hematopoietic stem cell transplantation
  • Full blood typing
  • Blood chemistries (assessing liver, kidney, and iron status)

Treatment of Manifestations

Recommendations for treatment were agreed upon at a 2008 consensus conference [Eiler et al 2008 (full text)].

Androgen administration. Androgens improve the blood counts in approximately 50% of individuals with FA. The earliest response is seen in red cells, with reticulocytosis and increase in hemoglobin generally occurring within the first month or two of treatment. Responses in the white cell count and platelet count are variable. Platelet responses are generally incomplete and may not be seen before several months of therapy. Such responses may be transient and improvement is generally greatest for the red cell count. Resistance to therapy may develop over time (generally years). The standard recommended androgen is oxymetholone at a starting dose of 2-5 mg/kg/day given orally. Androgen doses may be slowly tapered to the minimal effective dose with careful monitoring of the blood counts. Side effects of androgen administration include liver toxicity such as elevated liver enzymes, cholestasis, peliosis hepatis (vascular lesion with multiple blood-filled cysts), and hepatic tumors [Shimamura & Alter 2010].

Hematopoietic growth factors. Granulocyte colony-stimulating factor (G-CSF), generally administered subcutaneously, improves the neutrophil count in some individuals. Note: A bone marrow aspirate and biopsy should be performed prior to the initiation of hematopoietic growth factor therapy and monitored regularly throughout treatment. Hematopoietic growth factors should be administered cautiously or not at all in the setting of a clonal cytogenetic bone marrow abnormality.

Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for the hematologic manifestations of FA, including aplastic anemia, myelodysplastic syndrome, and acute leukemia. Donor stem cells may be obtained from bone marrow, peripheral blood (following stimulation of donor hematopoiesis with G-CSF), or cord blood. Ideally the HSCT is performed prior to onset of MDS/leukemia and before multiple transfusions are given for hematopoietic support [MacMillan & Wagner 2010]. HSCT should be performed at centers with expertise in HSCT for FA.

Because individuals with FA are exquisitely sensitive to the toxicity of the usual chemotherapy and radiation regimens used in preparation for BMT, reduced doses are typically used. Graft failure, historically a major impediment to FA transplantation, has been largely ameliorated by use of fludaribine. Additionally, improvements in disease prophylaxis and treatment have led to greater use of alternative donors and decreased differences in the outcomes between sibling transplants and unrelated donor transplants.

Individuals whose hematologic manifestations have been successfully treated with HSCT appear to be at an increased risk for solid tumors, particularly tongue squamous cell carcinomas. In one study the risk was increased fourfold and the median age of onset was 16 years younger than in persons with FA who were not transplanted [Rosenberg et al 2005].

Cancer treatment. Treatment of malignancies is challenging secondary to the increased toxicity associated with chemotherapy and radiation in FA. When possible, care should be obtained from centers experienced in the treatment of FA.

Prevention of Secondary Complications

Vaccination of females and males with the human papilloma virus vaccine (HPV) starting at age nine years is recommended in order to reduce the risk of gynecologic cancer in females (proven), and possibly reduce the risk of oral cancer in all individuals (not proven).

Surveillance

Physical abnormalities. Growth and pubertal development must be monitored carefully and early referral to an endocrinologist should be made as indicated.

Bone marrow failure. General recommendations vary.

  • Regular blood counts, every two to three months while stable, more often as needed.
  • Bone marrow aspirate/biopsy recommended at least annually to evaluate morphology, cellularity (from the biopsy), and cytogenetics (the latter for emergence of a malignant clone).

Recommendations for monitoring of blood and bone marrow parameters were agreed upon at a 2008 consensus conference [Eiler et al 2008 (full text)].

Androgen administration. For individuals receiving androgen therapy:

  • Monitoring of liver chemistry profile
  • Ultrasound examination of the liver every six to 12 months for androgen-related changes, including tumors.

Cancer surveillance. The majority of solid tumors develop after the first or second decade of life. Prompt and aggressive workup for any symptoms suggestive of a malignancy should be pursued. Detection and surgical removal of early-stage cancers remains the mainstay of therapy.

Surveillance regimens should include the following:

  • Annual gynecologic examination and Pap smears, beginning at menarche or age16 years, whichever is first
  • Frequent dental and oropharyngeal examinations, including nasolaryngoscopy starting at age ten years, or within the first year after HSCT
  • Annual esophageal endoscopy may be considered, but there are no guidelines, and currently most centers require anesthesia for this procedure.

Agents/Circumstances to Avoid

Blood transfusions. Transfusions of red cells or platelets should be avoided or minimized for individuals who are candidates for HSCT.

To reduce the chances of sensitization, family members must not act as blood donors if HSCT is being considered.

All blood products should be filtered (leukodepleted) and irradiated.

Cancer prevention. Given the increased susceptibility of individuals with FA to developing leukemias and other malignancies, affected individuals are advised to avoid toxic agents including smoking, second-hand smoke, and alcohol, which have been implicated in tumorigenesis.

Due to the sensitivity of individuals with FA to radiation, radiographic studies for the purpose of surveillance should be minimized in the absence of clinical indications. However, baseline skeletal surveys may be considered, in order to document bony anomalies that may lead to problems with age, such as anomalies of the wrist, hip, and vertebrae.

Evaluation of Relatives at Risk

It is appropriate to perform DEB/MMC testing or molecular genetic testing (if the family specific mutations are known) on all sibs of an affected individual for early diagnosis and appropriate monitoring for physical abnormalities, bone marrow failure, and related cancers.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Pregnancy is possible in females with FA, whether or not they have undergone hematopoietic stem cell transplantation [Alter et al 1991, Dalle et al 2004]. Pregnancy needs to be managed by a high-risk maternal fetal obstetrician along with a hematologist.

Therapies Under Investigation

Gene therapy, a theoretic possibility, is at a research stage only. Theoretically FA is an ideal disease for gene therapy, because the cells would gain a growth advantage by acquisition of a normal (wild type) allele. However, gene therapy used in hematopoietic cells would not reduce the risk of solid tumors in other tissues. Early phase trials of gene therapy for individuals with mutations in FANCC described transient retroviral FANCC transduction in hematopoietic cells [Liu et al 1999]. Because previous clinical trials failed to accomplish permanent gene correction of stem cells, current work is focusing on development of novel vector and delivery strategies.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Abnormalities of Fanconi anemia (FA)-related genes are inherited in an autosomal recessive manner except for mutations in FANCB, which are inherited in an X-linked manner.

Risk to Family Members — Autosomal Recessive FA

Parents of a proband

  • The parents of a child with autosomal recessive FA are obligate carriers of an FA-causing Allelic variant.
  • Carriers (heterozygotes) are asymptomatic.

Sibs of a proband

  • Each sib of an individual with autosomal recessive FA has a 25% chance of inheriting both pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being a carrier, and a 25% chance of inheriting both normal genes and not being a carrier.
  • Unaffected sibs who have had a normal DEB/MMC test have a 2/3 chance of being carriers.
  • Heterozygotes (carriers) are asymptomatic. Whether FA heterozygotes have an increased risk of developing malignancies is under investigation (with the exception of FANCD1/ BRCA2, in which heterozygotes may be at risk for breast, ovarian, or other cancers). See Hereditary Breast and Ovarian Cancer.

Offspring of a proband. The offspring of an individual with autosomal recessive FA are obligate heterozygotes (carriers).

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Risk to Family Members — X-Linked FA

Parents of a proband

  • The father of a male with X-linked FA will not have the disease nor will he be a carrier of the pathogenic variant.
  • In a family with more than one affected individual, the mother of an affected male is an obligate carrier.
  • If pedigree analysis reveals that the proband is the only affected family member, the mother may be a carrier or the affected male may have a de novo gene mutation, in which case the mother is not a carrier.
  • If a woman has more than one affected son and the pathogenic variant cannot be detected in DNA from leukocytes, she has germline mosaicism.

Sibs of a proband

  • The risk to sibs depends on the carrier status of the mother.
  • If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Male sibs who inherit the pathogenic variant will be affected; female sibs who inherit the pathogenic variant will be carriers and will usually not be affected.
  • If the pathogenic variant cannot be detected in the DNA extracted from leukocytes of the mother of the only affected male in the family, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Males will pass the pathogenic variant to all of their daughters and none of their sons. However, to date no male with FA-B has been old enough to have children; furthermore, they may be infertile as are many males with FA.

Other family members of a proband. The proband's maternal aunts may be at risk of being carriers and the aunt's offspring, depending on their gender, may be at risk of being carriers or of being affected.

Carrier Detection

Carriers of FA cannot be detected by the DEB/MMC test.

Carrier testing is possible once the pathogenic variant(s) have been identified in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Sibs of a proband. Because 25%-40% of individuals with FA may have no physical abnormalities, it is appropriate to perform DEB/MMC testing on all sibs of an affected individual for early diagnosis and appropriate monitoring for physical abnormalities, bone marrow failure, and related cancers.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. If the family-specific pathogenic variant(s) have been identifie, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation.

Chromosomal breakage. Prenatal testing is also possible for pregnancies at increased risk for FA by performing cytogenetic testing in the presence of DEB/MMC to evaluate for increased chromosomal breakage in fetal cells obtained by chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation or amniocentesis usually performed at approximately 15 to 18 weeks' gestation; however, if the pathogenic variant(s) are known in the family, molecular genetic testing is the method of choice for prenatal diagnosis.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Fetal ultrasound evaluation. Ultrasound examination can be used to evaluate for fetal anomalies consistent with FA. However, ultrasound examination is not a diagnostic test for FA. Many congenital anomalies characteristic of FA may not be detectable by ultrasound examination, and those that can be seen may be associated with diagnoses other than FA.

Preimplantation genetic diagnosis has successfully identified at-risk embryos to be unaffected with FA and HLA-matched to affected sibs [Verlinsky et al 2001, Bielorai et al 2004, Grewal et al 2004].

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Fanconi Anemia Cell Repository
    Department of Medical and Molecular Genetics
    3181 Southwest Sam Jackson Park Road L103
    Oregon Health & Science University
    Portland OR 97201
    Phone: 503-494-6888
  • Fanconi Anemia Research Fund, Inc. (FARF)
    1801 Williamette Street
    Suite 200
    Eugene OR 97401
    Phone: 888-326-2664 (Toll-free Family Support Line); 541-687-4658
    Fax: 541-687-0548
    Email: info@fanconi.org
  • International Fanconi Anemia Registry (IFAR)
    The Rockefeller University
    1230 York Avenue
    New York NY 10065
    Phone: 212-327-8862
    Fax: 212-327-8262
    Email: auerbac@rockefeller.edu
  • NCI Inherited Bone Marrow Failure Syndromes (IBMFS) Cohort Registry
    National Cancer Institute
    Phone: 800-518-8474
    Email: lisaleathwood@westat.com

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Fanconi Anemia: Genes and Databases

Complementation GroupGene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
FA-CFANCC9q22​.32Fanconi anemia group C proteinFanconi Anemia Mutation Database (FANCC)FANCC
FA-AFANCA16q24​.3Fanconi anemia group A proteinFanconi Anemia Mutation Database (FANCA)FANCA
FA-BFANCBXp22​.2Fanconi anemia group B proteinFANCB @ LOVD
Fanconi Anaemia Mutation Database (FANCB)
FANCB
FA-D2FANCD23p25​.3Fanconi anemia group D2 proteinFanconi Anaemia Mutation Database (FANCD2)FANCD2
FA-EFANCE6p21​.31Fanconi anemia group E proteinFanconi Anaemia Mutation Database (FANCE)FANCE
FA-FFANCF11p14​.3Fanconi anemia group F proteinFanconi Anaemia Mutation Database (FANCF)FANCF
FA-GFANCG9p13​.3Fanconi anemia group G proteinFanconi Anaemia Mutation Database (FANCG)FANCG
FA-D1BRCA213q13​.1Breast cancer type 2 susceptibility proteinBRCA2 homepage - LOVD
Fanconi Anaemia Mutation Database (FANCD1 - BRCA2)
Breast Cancer Information Core (BRCA2)
BRCA2 @ ZAC-GGM
BRCA2
FA-JBRIP117q23​.2Fanconi anemia group J proteinBRIP1 @ LOVD
Fanconi Anaemia Mutation Database (FANCJ - BRIP1)
BRIP1
FA-LFANCL2p16​.1E3 ubiquitin-protein ligase FANCLFanconi Anaemia Mutation Database (FANCL)FANCL
FA-IFANCI15q26​.1Fanconi anemia group I proteinFanconi Anemia Mutation Database (FANCI)FANCI
FA-NPALB216p12​.2Partner and localizer of BRCA2Fanconi Anaemia Mutation Database (FANCN - PALB2)
Fanconi anemia database (FANCN)
PALB2 database
PALB2
FA-MFANCM14q21​.2Fanconi anemia group M proteinFanconi Anaemia Mutation Database (FANCM)FANCM
FA-ORAD51C17q22DNA repair protein RAD51 homolog 3RAD51C @ LOVDRAD51C
FA-PSLX416p13​.3Structure-specific endonuclease subunit SLX4SLX4 @ LOVDSLX4

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Fanconi Anemia (View All in OMIM)

227645FANCONI ANEMIA, COMPLEMENTATION GROUP C; FANCC
227646FANCONI ANEMIA, COMPLEMENTATION GROUP D2; FANCD2
227650FANCONI ANEMIA, COMPLEMENTATION GROUP A; FANCA
300514FANCONI ANEMIA, COMPLEMENTATION GROUP B; FANCB
300515FANCB GENE; FANCB
600185BRCA2 GENE; BRCA2
600901FANCONI ANEMIA, COMPLEMENTATION GROUP E; FANCE
602774RAD51, S. CEREVISIAE, HOMOLOG OF, C; RAD51C
602956FANCG GENE; FANCG
603467FANCONI ANEMIA, COMPLEMENTATION GROUP F; FANCF
605724FANCONI ANEMIA, COMPLEMENTATION GROUP D1; FANCD1
605882BRCA1-INTERACTING PROTEIN 1; BRIP1
607139FANCA GENE; FANCA
608111FANCL GENE; FANCL
609053FANCONI ANEMIA, COMPLEMENTATION GROUP I; FANCI
609054FANCONI ANEMIA, COMPLEMENTATION GROUP J; FANCJ
609644FANCM GENE; FANCM
610355PARTNER AND LOCALIZER OF BRCA2; PALB2
610832FANCONI ANEMIA, COMPLEMENTATION GROUP N; FANCN
611360FANCI GENE; FANCI
613278SLX4, S. CEREVISIAE, HOMOLOG OF; SLX4
613390FANCONI ANEMIA, COMPLEMENTATION GROUP O; FANCO
613897FANCF GENE; FANCF
613899FANCC GENE; FANCC
613951FANCONI ANEMIA, COMPLEMENTATION GROUP P; FANCP
613976FANCE GENE; FANCE
613984FANCD2 GENE; FANCD2
614082FANCONI ANEMIA, COMPLEMENTATION GROUP G; FANCG
614083FANCONI ANEMIA, COMPLEMENTATION GROUP L; FANCL
614087FANCONI ANEMIA, COMPLEMENTATION GROUP M; FANCM

Note: The detailed discussion of protein interactions and signaling described in this section and Figure 1 has been simplified by replacing the long names of the proteins with their non-italicized gene acronym (e.g., FANCA instead of Fanconi anemia group A protein; BRCA2 instead of breast cancer type 2 susceptibility protein). See Table A for gene and protein names.

Figure 1

Figure

Figure 1. Current model of the Fanconi anemia pathway. Eight FA proteins (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, and FANCM), along with FAAP100 and FAAP24 form a nuclear protein complex (the FA core complex) with E3 ubiquitin ligase activity. (more...)

Molecular Genetic Pathogenesis

Thirteen genes that are involved in Fanconi anemia (FA) and also account for each of the 13 phenotypic complementation groups, have been identified. The FA-M group has been further refined to be complex in that the only reference cell line is actually a double FANCA and FANCM mutant, clouding the notion that FANCM is a bona fide FA-related gene [Singh et al 2009]. The proteins encoded by the FA-related genes are considered to work together in a common pathway/network called "the FA pathway" or "the FA-BRCA pathway/network," which regulates cellular resistance to DNA cross-linking agents [Taniguchi & D'Andrea 2006]. Disruption of this pathway leads to the common cellular and clinical abnormalities observed in FA [Garcia-Higuera et al 2001].

Eight of the FA proteins (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, and FANCM), along with proteins FAAP24 [Ciccia et al 2007] and FAAP100 [Ling et al 2007] are assembled in a nuclear complex (FA core complex). This complex is a multi-subunit ubiquitin ligase complex; monoubiquitination of two FA proteins (FANCD2 and FANCI) depends on the FA core complex [Garcia-Higuera et al 2001, Smogorzewska et al 2007]. In response to DNA damage or in S phase of the cell cycle, this FA core complex activates the monoubiquitination of the FANCD2 and FANCI proteins. Monoubiquitinated FANCD2 and monoubiquitinated FANCI are translocated to nuclear foci containing the proteins BRCA1, BRCA2, PALB2, and RAD51. FANCI shares sequence similarity with FANCD2; together they form a protein complex (ID complex) [Smogorzewska et al 2007]. Monoubiquitination of FANCD2 and FANCI depend on each other [Smogorzewska et al 2007]. A nuclease, FAN1, has been shown to bind to monoubiquitylated FANCD2, which directs its enzymatic activity [Huang & D'Andrea 2010]. A cell-free system has been used to recapitulate cross-link repair in vitro [Knipscheer et al 2009].

One of the components of the FA core complex, FANCL, has a PHD (plant homeodomain) finger (a variant RING finger) domain with ubiquitin ligase activity [Meetei et al 2003a]. FANCL associates through its PHD/RING finger domain with UBE2T, a ubiquitin conjugating enzyme (E2), which is also required for FANCD2 monoubiquitination [Machida et al 2006]. Recombinant FANCL, the E2 UBE2T, FANCD2, FANCI, and FANCE recapitulate the monoubiquitination reaction in vitro [Alpi et al 2008].

Another component of the FA core complex, FANCM, is homologous to the archaeal DNA helicase/nuclease known as HEF. FANCM has DNA helicase motifs and a degenerate nuclease motif and exhibits DNA-stimulated ATPase activity and DNA translocase activity [Meetei et al 2005]. A FANCM-interacting protein, FAAP24, preferentially binds to single-stranded DNA and branched DNA structures [Ciccia et al 2007]. Therefore, it has been speculated that FANCM DNA translocase activity could play an important role in displacing the FA core complex along the DNA, allowing DNA damage recognition, or that FAAP24 may play a role in targeting the FA core complex to abnormal, branched DNA structures. This complex is thought to be responsible for a replication-associated checkpoint response involving RPA [Huang et al 2010] and the BLM helicase [Deans & West 2009]. As is true for multiple FA proteins, the complex appears to be regulated through ATR [Collis et al 2008].

Furthermore, the FA core complex forms a larger complex with BLM, RPA, and topoisomerase IIIα, called BRAFT (BLM, RPA, FA, and topoisomerase IIIα) [Meetei et al 2003b] in a further link to Bloom syndrome. FANCM is found in both separable complexes: the FA core complex as well as the BLM complex [Deans & West 2009].

A DNA damage-activated signaling kinase, ATR, a single-strand DNA-binding protein complex, RPA, and an ATR-associated protein, HCLK2, are required for DNA damage-inducible monoubiquitnation and foci formation of FANCD2 [Andreassen et al 2004, Collis et al 2007]. BRCA1 [Garcia-Higuera et al 2001, Vandenberg et al 2003] and histone H2AX [Bogliolo et al 2007] are required for DNA damage-inducible foci formation of FANCD2, but not for monoubiquitination of FANCD2. These factors are considered to be upstream positive regulators of the FA pathway. ATR has been shown to directly phosphorylate FANCA and indirectly phosphorylate FANCD2 through CHK1 [Zhi et al 2009]. As described, ATR is also necessary for assembly of FANCM and recruitment of RPA at the ICL-induced checkpoint [Collis et al 2008].

BRCA2 (previously known as FANCD1) is a tumor suppressor that confers breast cancer susceptibility [Howlett et al 2002]. BRCA2 protein stability and localization is regulated by PALB2 (partner and localizer of BRCA2) [Xia et al 2006]. PALB2, another breast cancer susceptibility gene [Rahman et al 2007], is responsible for FA complementation group FA-N and the gene sometimes called FANCN [Reid et al 2007, Xia et al 2007]. Another breast cancer susceptibility gene [Seal et al 2006], BRIP1 (originally known as BACH1 for BRCA1-associated C-terminal helicase 1) [Cantor et al 2001], is also an FA-related gene and is the basis for complementation group FA-J [Levitus et al 2005, Levran et al 2005, Litman et al 2005]. BRCA2, PALB2, and BRIP1 are not required for FANCD2 protein monoubiquitination or FANCD2 nuclear foci formation, but are still required for cellular resistance to MMC or DEB. BRCA2 has been found to act in multiple subcomplexes of FA proteins, including FANCG and FANCD2 [Wilson et al 2010], suggesting that the notion of acting downstream of FANCD2 monoubiquitination may be too simplistic. Phosphorylation of FANCD2 by CHK1 has been shown to be necessary for interaction with BRCA2 [Zhi et al 2009]. FANCJ and FANCD2 have also been shown to be functionally linked in foci formation [Zhang et al 2010].

USP1 is a deubiquitinating enzyme that removes ubiquitin from monoubiquitinated FANCD2, and negatively regulates the FA pathway along with its coactivator UAF1 [Nijman et al 2005, Cohn et al 2007]. USP1 also removes ubiquitin from monoubiquitylated PCNA (proliferating cell nuclear antigen) [Huang et al 2006]. This may not be coincidental, since FANCD2 and PCNA have been shown to bind [Howlett et al 2009]. The deubiquitination event has been shown to be vital for FA function [Oestergaard et al 2007]. Hematopoeitic defects have been noted in knockout mice [Parmar et al 2010].

In nuclear foci, FANCD2 colocalizes with FANCI, BRCA1, BRCA2, PALB2, RAD51, BLM, RPA, ATR, FANCC, and FANCE [Garcia-Higuera et al 2001, Pace et al 2002, Taniguchi et al 2002a, Andreassen et al 2004, Wang et al 2004, Matsushita et al 2005, Xia et al 2006, Smogorzewska et al 2007]. FANCD2 also colocalizes partially with BRIP1 [Litman et al 2005] and NBS1 [Nakanishi et al 2002]. All of these factors are required for cellular resistance to DNA cross-linking agents and are considered to work together to repair interstrand DNA cross-links, although the precise mechanism is not understood. Recently, pathogenic variants in RAD51C have been detected in several FA-like cases in a consanguineous family, also associated with breast and ovarian cancer susceptibility [Meindl et al 2010, Vaz et al 2010].

Among FA proteins, BRCA2 has a clear role in regulating homologous recombination by controlling the activity of RAD51, the eukaryotic homolog of bacterial RecA [Davies et al 2001, Moynahan et al 2001]. PALB2 regulates BRCA2 stability and localization in nuclear structures (chromatin and nuclear matrix) and, thus, is required for homologous recombination [Xia et al 2006]. The FA core complex, FANCD2, FANCI [Smogorzewska et al 2007], and FANCJ [Litman et al 2005] are also reported to be required for efficient homologous recombination, although conflicting reports exist [Taniguchi & D'Andrea 2006].

FANCD2 protein is also phosphorylated by the ataxia-telangiectasia kinase, ATM, in a process that regulates a radiation-induced S phase checkpoint [Taniguchi et al 2002b, Ho et al 2006]. While required for resistance to ionizing radiation, this phosphorylation event is dispensable for cross-linker resistance, implying a separation of or dual function for FANCD2. FANCD2 appears to be phosphorylated by CHK1, which is downstream of ATR, at serine 331 in a manner that results in activation by cross-links [Zhi et al 2009].

Importantly, a number of studies have shown defects in the FA-BRCA pathway to be implicated in cancer:

These findings underscore the importance of the FA-BRCA pathway in tumor suppression. Because the FA pathway is required for cellular resistance to interstrand DNA cross-linking agents (e.g., cisplatin, MMC, melphalan), tumors with defects in the FA pathway are expected to be hypersensitive to these widely used anti-cancer agents. Therefore, the FA-BRCA pathway is an attractive target for developing small molecule inhibitors that may be useful as chemosensitizers [Chirnomas et al 2006].

Other manipulators of the FA pathway include curcumin, which has been demonstrated to inhibit the FA pathway and, thus, increase the sensitivity of tumors to cisplatin [Chirnomas et al 2006]. Another avenue of recent excitement has been the use of poly adenosine diphosphate ribose polymerase inhibitors, which target alternative pathways of homologous recombination repair and again enable better response to cross-linkers [Martin et al 2010]. Anti-oxidative agents have been shown to delay the onset of tumors in mouse models of FA [Zhang et al 2008].

Amelioration of FA pathology has been implicated in reports of downregulation of elements of the non-homologous end joining pathway [Adamo et al 2010]. These data propose that much of FA pathophysiology results from the unfettered work of NHEJ promoting inaccurate repair. On the other hand, FA involvement in homologous recombinatorial repair has been well established in interactions with BRCA1, BRCA2, and RAD51C. FANCD2 has also been shown to interact with PCNA and pol K, suggesting that translesion synthesis, a variant of HR, may be the most direct function of FA proteins in bypass of the lesion as an intermediate to HRR [Ho & Schärer 2010, Song et al 2010].

For reviews of the molecular biology of FA, see D'Andrea & Grompe [2003], Venkitaraman [2004], Collins & Kupfer [2005], Kennedy & D'Andrea [2005], Niedernhofer et al [2005], Bagby & Alter [2006], Gurtan & D'Andrea [2006], Lyakhovich & Surralles [2006], Mathew [2006], Mirchandani & D'Andrea [2006], Taniguchi & D'Andrea [2006], Green & Kupfer [2009], and Thompson & Hinz [2009].

FANCA

Gene structure. FANCA has two isoforms. Reference sequence NM_000135.2 has 43 exons and encodes the longer isoform. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. The pathogenic alleles of FANCA are numerous and highly variable among families [Levran et al 1997, Morgan et al 1999, Wijker et al 1999]. A small percentage of families share the pathogenic variants p.Phe1263del and p.Val372AlafsTer42; the latter is found in affected individuals of northern European ancestry. See Table A.

Table 2. Selected FANCA Pathologic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.1115_1118delp.Val372AlafsTer42NM_000135​.2
NP_000126​.2
c.3788_3790delp.Phe1263del

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. FANCA encoded by the longer isoform has 1455 amino acids (reference sequence NM_000126). FANCA is a component of the FA core complex. FANCA contains two overlapping bipartite nuclear localization signals (NLS), five functional leucine-rich nuclear export sequences (NESs) and a partial leucine zipper sequence [Fanconi Anaemia/Breast Cancer Consortium 1996, Lo Ten Foe et al 1996, Ferrer et al 2005]. The nuclear export of FANCA is regulated in a CRM1-dependent manner [Ferrer et al 2005]. FANCA is a phosphoprotein. FANCA is a client of Hsp90 [Oda et al 2007]. Recent reports suggest that FANCA is phosphorylated by the ATR kinase at serine 1449 [Collins et al 2009].

Abnormal gene product. See Molecular Genetic Pathogenesis.

FANCB

Gene structure. FANCB has ten exons with the translation start in exon 3 (reference sequence NM_001018113.1). FAAP95 is an alias for FANCB. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. See Table A.

Normal gene product. FANCB comprises 853 amino acids; some sequences have 859 residues, depending on the initiating methionine. FANCB is a component of the FA core complex and contains a putative bipartite NLS [Meetei et al 2004].

Abnormal gene product. See Molecular Genetic Pathogenesis.

FANCC

Gene structure. FANCC has 15 exons (reference sequence NM_000136.2). For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. Three common pathogenic variants in FANCC have been identified (c.456+4A>T, p.Arg548Ter, and c.67delG) [Whitney et al 1993], as well as several rare variants (p.Gln13Ter, p.Arg185Ter, and p.Leu554Pro). The pathogenic variant c.456+4A>T has been found primarily in the Ashkenazi Jewish population; recently, it has also been reported in a Japanese cohort. The pathogenic variants p.Arg548Ter, c.67delG, p.Arg185Ter, and p.Leu554Pro are prevalent in individuals of northern European ancestry; p.Gln13Ter is found in individuals from southern Italy. See Table A.

Table 3. Selected FANCC Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
c.456+4A>T
(IVS4+4A>T)
--NM_000136​.2
NP_000127​.2
c.37C>Tp.Gln13Ter
c.67delG
(322delG)
p.Asp23IlefsTer23
c.553C>Tp.Arg185Ter
c.1642C>Tp.Arg548Ter
c.1661T>Cp.Leu554Pro

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

Normal gene product. FANCC has 558 amino acids. It is a component of the FA core complex, but localizes both to both the nucleus and the cytoplasm [Yamashita et al 1994]. Some functions of FANCC outside of the FA core complex have been also proposed [Fagerlie et al 2004]. Reports suggest that STAT1 binds to FANCC to modulate JAK-STAT signaling and to protect cells from interferon gamma toxic effects [Pang et al 2000, Fagerlie et al 2004].

Abnormal gene product. See Molecular Genetic Pathogenesis.

BRCA2

Gene structure. BRCA2, also known as FANCD1, has 27 exons (reference sequence NM_000059.3). For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. See Table A.

Normal gene product. The breast cancer type 2 susceptibility protein (BRCA2) has 3418 amino acids. BRCA2 regulates homologous recombination repair through control of RAD51 recombinase (eukaryotic homologue of bacterial RecA) [Davies et al 2001, Moynahan et al 2001]. BRCA2 also has other functions including stabilization of stalled replication forks and regulation of cytokinesis [Daniels et al 2004]. BRCA2 has been demonstrated to work in concert with RAD51 to orchestrate the repair of double strand break ends, prompting the nucleation of each end by RAD51. BRCA2 has been found in various subcomplexes with other FA proteins, including FANCG, FANCD2, and PALB2 [Xia et al 2007, Wilson et al 2010].

Abnormal gene product. See Molecular Genetic Pathogenesis.

FANCD2

Gene structure. FANCD2 has two isoforms. Isoform a (reference sequence NM_033084.3) has 43 exons. Isoform b (reference sequence NM_001018115.1) has 44 exons and an alternate 3' coding sequence resulting in a shorter and distinct C-terminus. FANCD2 protein encoded by isoform b (exon 44 form) is the functional FANCD2, and the protein encoded by isoform a (exon 43 form) is not functional [Montes de Oca et al 2005]. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. See Table A.

Normal gene product. FANCD2 has 1451 amino acids (isoform b) and shares sequence similarity with FANCI. FANCD2 and FANCI form a protein complex (ID complex). FANCD2 can be monoubiquitinated on lysine 561 in an FA core complex-, UBE2T-, and FANCI-dependent manner. Monoubiquitinated FANCD2 is translocated to chromatin fraction, and form nuclear foci with FANCI, BRCA1, BRCA2, RAD51, etc. FANCD2 can be phosphorylated by ATM [Taniguchi et al 2002b, Ho et al 2006] and possibly by ATR [Andreassen et al 2004, Pichierri & Rosselli 2004] in response to DNA damage. A recent report suggests that FANCD2 is phosphorylated at serine 331 by CHK1 in a manner that is required for binding to BRCA2 [Zhi et al 2009]. Important studies have shown FANCD2 to have a function in resection of ends surrounding a cross-link in the repair process [Knipscheer et al 2009]. A nuclease, FAN1, has been demonstrated to bind to FANCD2 [Huang & D'Andrea 2010].

Abnormal gene product. See Molecular Genetic Pathogenesis.

FANCE

Gene structure. FANCE has 14 exons (reference sequence NM_021922.2). For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. See Table A.

Normal gene product. FANCE has 536 amino acids and is a component of the FA core complex. FANCE directly binds to FANCD2. FANCE contains two nuclear localization signals (NLS). FANCE has five tandem repeats of a short helical motif (FANC repeats) [Nookala et al 2007]. It purportedly has function as a shuttle protein between the FA core complex and FANCD2 in a fashion dependent on phosphorylation [Wang et al 2007].

Abnormal gene product. See Molecular Genetic Pathogenesis.

FANCF

Gene structure. FANCF has a single exon (reference sequence NM_022725.2). For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. See Table A.

Normal gene product. FANCF has 374 amino acids and is a component of the FA core complex. FANCF acts as a flexible adaptor protein required for the assembly of the FA core complex [Léveillé et al 2004]. Crystallographic studies of the C-terminal domain revealed a helical repeat structure similar to the Cand1 regulator of the Cul1-Rbx1-Skp1-Fbox(Skp2) ubiquitin ligase complex [Kowal et al 2007].

Abnormal gene product. See Molecular Genetic Pathogenesis.

FANCG

Gene structure. FANCG has 14 exons (reference sequence NM_004629.1). For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. The pathogenic variants in FANCG are highly variable, but more common variant alleles have been described in specific populations: c.307+1G>C (Korean/Japanese); c.925-2A>G (Brazilian); c.1480+1G>C (French Canadian); p.Gly395TrpfsTer5 (northern European); and p.Trp599ProfsTer49 (northern European) [Demuth et al 2000, Nakanishi et al 2002]. See Table A.

Table 4. Selected FANCG Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
c.307+1G>C
(IVS3+1G>C)
--NM_004629​.1
NP_004620​.1
c.925-2A>G
(IVS8-2A>G)
--
c.1183-1192del
(1184-1194del)
p.Glu395TrpfsTer5
c.1480+1G>C
(IVS11+1G>C)
p.Trp599ProfsTer49
c.1794_1803del

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

Normal gene product. FANCG has 622 amino acids. It is a component of the FA core complex. FANCG has seven tetratricopeptide repeat motifs (TPRs) [Blom et al 2004]. FANCG is a phosphoprotein; serines 383 and 387 on FANCG are phosphorylated in M phase, presumably by cdc2 [Mi et al 2004]. These two sites are important for exclusion of FANCG from chromatin in mitosis. Phosphorylation of serine 7 of FANCG is upregulated after MMC treatment [Qiao et al 2004]. FANCA and FANCG stabilize each other. Recent data have demonstrated FANCG, FANCD1/BRCA2, FANCD2, and XRCC3 participate in the same protein complex. This implies multifunctionality of FANCG by its presence in the core complex as well as in homologous recombinatorial repair [Wang et al 2007].

Abnormal gene product. See Molecular Genetic Pathogenesis.

FANCI

Gene structure. FANCI has 37 exons (reference sequence NM_018193.2). For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. See Table A.

Normal gene product. FANCI has 1268 amino acids and shares sequence similarity with FANCD2. FANCD2 and FANCI form a protein complex (ID complex). FANCI can be monoubiquitinated on lysine 523 in an FA core complex-, UBE2T-, and FANCD2-dependent manner. Monoubiquitinated FANCI is translocated to nuclear foci and colocalizes with BRCA1, BRCA2, RAD51, FANCD2, etc. FANCI is a phosphoprotein. DNA damage-induced phosphorylation of p.Ser730, p.Thr952, and p.Ser1121 of human FANCI can be detected [Smogorzewska et al 2007]. FANCI functions in an analogous manner as FANCD2 and can be analyzed in the same fashion in assays including DNA repair foci, cell survival, and monoubiquitylation [Ishiai et al 2008].

Abnormal gene product. See Molecular Genetic Pathogenesis.

BRIP1

Gene structure. BRIP1 (BRCA1 interacting protein C-terminal helicase 1) has 20 exons. This gene has also been called FANCJ or BACH1. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. See Table A.

Normal gene product. The Fanconi anemia group J protein (BRIP1 or FANCJ) has 1249 amino acids and is a DNA-dependent ATPase and a 5'-to-3' DNA helicase (DEAH helicase) that binds directly to the BRCT domain of BRCA1 [Cantor et al 2001]. FANCJ contains the seven helicase-specific motifs and C-terminal extension, which has 39% homology with synaptonemal complex protein 1, a major component of the transverse filaments of developing meiotic chromosomes [Cantor et al 2001]. FANCJ helicase domain clearly is important for FA pathway function [Wu & Brosh 2009]. FANCJ also appears to interdigitate with the mismatch repair pathway in binding to MLH1 [Cantor & Xie 2010].

Abnormal gene product. See Molecular Genetic Pathogenesis.

FANCL

Gene structure. FANCL has 14 exons (reference sequence NM_018062.2). For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. See Table A.

Normal gene product. The E3 ubiquitin-protein ligase FANCL has 375 amino acids. It is a component of the FA core complex with three WD40 (Tryptophan-Aspartate -40) repeats and a PHD finger motif (a variant RING finger motif) [Meetei et al 2003a] and is presumed to be the catalytic subunit of the FA core complex as an ubiquitin ligase for FANCD2 and FANCI. FANCL directly interact with UBE2T (E2 ubiquitin conjugating enzyme) [Machida et al 2006]. A baculoviral generated protein has been shown to have in vitro monoubiquitylation activity [Alpi et al 2008].

Abnormal gene product. See Molecular Genetic Pathogenesis.

FANCM

Gene structure. FANCM has 23 exons (reference sequence NM_020937.1). For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. See Table A.

Normal gene product. The Fanconi anemia group M protein (FANCM) has 2048 animo acids. It is a component of the FA core complex, contains the seven helicase-specific motifs, one degenerate endonuclease domain, and ssDNA and dsDNA-stimulated ATPase activity and DNA translocase activity [Meetei et al 2005]. FANCM is phosphorylated in response to DNA damage. In concert with FAAP24, a FANCM binding protein, FANCM participates in a checkpoint reaction to DNA damage [Huang et al 2010].

Abnormal gene product. See Molecular Genetic Pathogenesis.

PALB2

Gene structure. PALB2 (also known as FANCN) has 13 exons (reference sequence NM_024675.3). For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. See Table A.

Normal gene product. The partner and localizer of BRCA2 protein (PALB2) has 1186 amino acids. It regulates localization and stability of BRCA2 protein. Short sections of the PALB2 N-terminus share homologies with a segment of prefoldin and the light chain 3 (LC3) of microtubule-associated protein MAP1. PALB2 also has two WD40 repeat-like segments at the C terminus [Xia et al 2006]. PALB2 is one of the FA-related genes that is also a breast cancer susceptibility gene. It is a known protein partner of FANCD1/BRCA2 and plays a role in the homologous recombination repair pathway [Xia et al 2007].

Abnormal gene product. See Molecular Genetic Pathogenesis.

RAD51C (FANCO)

Gene structure. RAD51C has 9 exons (reference sequence NM_058216). For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. See Table A.

Normal gene product. RAD51C is a protein of 376 amino acids shown to participate in several distinct protein complexes involved in homologous recombination. RAD51 variants have been demonstrated to bind to single strand overhangs that occur after processing of DNA lesions in concert with BRCA2 [Somyajit et al 2010].

Abnormal gene product. See Molecular Genetic Pathogenesis.

SLX4 (FANCP)

Gene structure. SLX4 has 15 exons (reference sequence NM_032444). For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. See Table A.

Normal gene product. SLX4 is a protein of 1834 amino acids that appears to be involved in resolution of homologous recombination intermediates, such as Holliday junctions. SLX4 appears to interact with other endonuclease complexes, including MUS81-EME1 and XPF-ERCC1 [Kim et al 2011, Stoepker et al 2011].

Abnormal gene product. See Molecular Genetic Pathogenesis.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Published Guidelines/Consensus Statements

  1. Eiler ME, Frohnmayer D, Frohnmayer L, Larsen K, Olsen J, eds. Fanconi Anemia: Guidelines for Diagnosis and Management. 3 ed. Eugene, OR: Fanconi Anemia Research Fund, Inc. Available online. 2008. Accessed 2-28-14.

Literature Cited

  1. Adamo A, Collis SJ, Adelman CA, Silva N, Horejsi Z, Ward JD, Martinez-Perez E, Boulton SJ, La Volpe A. Preventing nonhomologous end joining suppresses DNA repair defects of Fanconi anemia. Mol Cell. 2010;39:25–35. [PubMed: 20598602]
  2. Alpi AF, Pace PE, Babu MM, Patel KJ. Mechanistic insight into site-restricted monoubiquitination of FANCD2 by Ube2t, FANCL, and FANCI. Mol Cell. 2008;32:767–77. [PubMed: 19111657]
  3. Alter BP. Cancer in Fanconi anemia, 1927-2001. Cancer. 2003a;97:425–40. [PubMed: 12518367]
  4. Alter BP. Inherited bone marrow failure syndromes. In: Nathan DG, Orkin SH, Look AT, Ginsburg D, eds. Nathan and Oski's Hematology of Infancy and Childhood. 6 ed. Philadelphia, PA: WB Saunders; 2003b:280-365.
  5. Alter BP. The association between FANCD1/BRCA2 mutations and leukaemia. Br J Haematol. 2006;133:446–8. [PubMed: 16643458]
  6. Alter BP, Caruso JP, Drachtman RA, Uchida T, Velagaleti GV, Elghetany MT. Fanconi anemia: myelodysplasia as a predictor of outcome. Cancer Genet Cytogenet. 2000;117:125–31. [PubMed: 10704682]
  7. Alter BP, Frissora CL, Halpérin DS, Freedman MH, Chitkara U, Alvarez E, Lynch L, Adler-Brecher B, Auerbach AD. Fanconi's anaemia and pregnancy. Br J Haematol. 1991;77:410–8. [PubMed: 2012768]
  8. Alter BP, Giri N, Savage SA, Peters JA, Loud JT, Leathwood L, Carr AG, Greene MH, Rosenberg PS. Malignancies and survival patterns in the National Cancer Institute inherited bone marrow failure syndromes cohort study. Br J Haematol. 2010;150:179–88. [PMC free article: PMC3125983] [PubMed: 20507306]
  9. Alter BP, Rosenberg PS, Brody LC. Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2. J Med Genet. 2007;44:1–9. [PMC free article: PMC2597904] [PubMed: 16825431]
  10. Ameziane N, Errami A, Léveillé F, Fontaine C, de Vries Y, van Spaendonk RM, de Winter JP, Pals G, Joenje H. Genetic subtyping of Fanconi anemia by comprehensive mutation screening. Hum Mutat. 2008;29:159–66. [PubMed: 17924555]
  11. Andreassen PR, D'Andrea AD, Taniguchi T. ATR couples FANCD2 monoubiquitination to the DNA-damage response. Genes Dev. 2004;18:1958–63. [PMC free article: PMC514175] [PubMed: 15314022]
  12. Apostolou S, Whitmore SA, Crawford J, Lennon G, Sutherland GR, Callen DF. lanzano L, Savino M, D'Apolito M, Notarangeio A, Memeo E, Piemontese MR, Zelante L, Savoia A, Gibson RA, Tipping AJ, Morgan NV, Hassock S, Jansen S, de Ravel TJ, Van Berkell C, Pronk JC, Easton DF, Mathew CG, Levran O, Verlander PC, Batish SD, Erlich T, Auerbach AD, Cleton-Jansen A-M, Moerland EW, Cornelisse CJ, Doggett NA, Deaven LD, Moyzis RK; Fanconi anaemia/Breast cancer consortium. Positional cloning of the Fanconi anaemia group A gene. Nat Genet. 1996;14:324–8.
  13. Auerbach AD. Fanconi anemia diagnosis and the diepoxybutane (DEB) test. Exp Hematol. 1993;21:731–3. [PubMed: 8500573]
  14. Bagby GC, Alter BP. Fanconi anemia. Semin Hematol. 2006;43:147–56. [PubMed: 16822457]
  15. Baron F, Sybert VP, Andrews RG. Cutaneous and extracutaneous neutrophilic infiltrates (Sweet syndrome) in three patients with Fanconi anemia. J Pediatr. 1989;115:726–9. [PubMed: 2809903]
  16. Bielorai B, Hughes MR, Auerbach AD, Nagler A, Loewenthal R, Rechavi G, Toren A. Successful umbilical cord blood transplantation for Fanconi anemia using preimplantation genetic diagnosis for HLA-matched donor. Am J Hematol. 2004;77:397–9. [PubMed: 15551406]
  17. Blom E, van de Vrugt HJ, de Vries Y, de Winter JP, Arwert F, Joenje H. Multiple TPR motifs characterize the Fanconi anemia FANCG protein. DNA Repair (Amst). 2004;3:77–84. [PubMed: 14697762]
  18. Bogliolo M, Lyakhovich A, Callén E, Castellà M, Cappelli E, Ramírez MJ, Creus A, Marcos R, Kalb R, Neveling K, Schindler D, Surrallés J. Histone H2AX and Fanconi anemia FANCD2 function in the same pathway to maintain chromosome stability. EMBO J. 2007;26:1340–51. [PMC free article: PMC1817623] [PubMed: 17304220]
  19. Callen E, Casado JA, Tischkowitz MD, Bueren JA, Creus A, Marcos R, Dasi A, Estella JM, Munoz A, Ortega JJ, de Winter J, Joenje H, Schindler D, Hanenberg H, Hodgson SV, Mathew CG, Surralles J. A common founder mutation in FANCA underlies the world's highest prevalence of Fanconi anemia in Gypsy families from Spain. Blood. 2005;105:1946–9. [PubMed: 15522956]
  20. Cantor SB, Bell DW, Ganesan S, Kass EM, Drapkin R, Grossman S, Wahrer DC, Sgroi DC, Lane WS, Haber DA, Livingston DM. BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function. Cell. 2001;105:149–60. [PubMed: 11301010]
  21. Cantor SB, Xie J. Assessing the link between BACH1/FANCJ and MLH1 in DNA crosslink repair. Environ Mol Mutagen. 2010;51:500–7. [PubMed: 20658644]
  22. Carreau M. Not-so-novel phenotypes in the Fanconi anemia group D2 mouse model. Blood. 2004;103:2430. [PubMed: 14998919]
  23. Cervenka J, Arthur D, Yasis C. Mitomycin C test for diagnostic differentiation of idiopathic aplastic anemia and Fanconi anemia. Pediatrics. 1981;67:119–27. [PubMed: 7243420]
  24. Chandra S, Levran O, Jurickova I, Maas C, Kapur R, Schindler D, Henry R, Milton K, Batish SD, Cancelas JA, Hanenberg H, Auerbach AD, Williams DA. A rapid method for retrovirus-mediated identification of complementation groups in Fanconi anemia patients. Mol Ther. 2005;12:976–84. [PubMed: 16084127]
  25. Chirnomas D, Taniguchi T, de la Vega M, Vaidya AP, Vasserman M, Hartman AR, Kennedy R, Foster R, Mahoney J, Seiden MV, D'Andrea AD. Chemosensitization to cisplatin by inhibitors of the Fanconi anemia/BRCA pathway. Mol Cancer Ther. 2006;5:952–61. [PubMed: 16648566]
  26. Ciccia A, Ling C, Coulthard R, Yan Z, Xue Y, Meetei AR. Identification of FAAP24, a Fanconi anemia core complex protein that interacts with FANCM. Mol Cell. 2007;25:331–43. [PubMed: 17289582]
  27. Cioc AM, Wagner JE, MacMillan ML, DeFor T, Hirsch B. Diagnosis of myelodysplastic syndrome among a cohort of 119 patients with Fanconi anemia: morphologic and cytogenetic characteristics. Am J Clin Pathol. 2010;133:92–100. [PubMed: 20023263]
  28. Cohn MA, Kowal P, Yang K, Haas W, Huang TT, Gygi SP, D'Andrea AD. A UAF1-containing multisubunit protein complex regulates the Fanconi anemia pathway. Mol Cell. 2007;28:786–97. [PubMed: 18082604]
  29. Collins N, Kupfer GM. Molecular pathogenesis of Fanconi anemia. Int J Hematol. 2005;82:176–83. [PubMed: 16207587]
  30. Collins NB, Wilson JB, Bush T, Thomashevski A, Roberts KJ, Jones NJ, Kupfer GM. ATR-dependent phosphorylation of FANCA on serine 1449 after DNA damage is important for FA pathway function. Blood. 2009;113:2181–90. [PMC free article: PMC2652366] [PubMed: 19109555]
  31. Collis SJ, Ciccia A, Deans AJ, Horejsí Z, Martin JS, Maslen SL, Skehel JM, Elledge SJ, West SC, Boulton SJ. FANCM and FAAP24 function in ATR-mediated checkpoint signaling independently of the Fanconi anemia core complex. Mol Cell. 2008;32:313–24. [PubMed: 18995830]
  32. Collis SJ, Barber LJ, Clark AJ, Martin JS, Ward JD, Boulton SJ. HCLK2 is essential for the mammalian S-phase checkpoint and impacts on Chk1 stability. Nat Cell Biol. 2007;9:391–401. [PubMed: 17384638]
  33. D'Andrea AD, Grompe M. The Fanconi anaemia/BRCA pathway. Nat Rev Cancer. 2003;3:23–34. [PubMed: 12509764]
  34. Dalle JH, Huot C, Duval M, Rousseau P, Francoeur D, Champagne J, Vachon MF, Champagne MA. Successful pregnancies after bone marrow transplantation for Fanconi anemia. Bone Marrow Transplant. 2004;34:1099–100. [PubMed: 15489874]
  35. Daniels MJ, Wang Y, Lee M, Venkitaraman AR. Abnormal cytokinesis in cells deficient in the breast cancer susceptibility protein BRCA2. Science. 2004;306:876–9. [PubMed: 15375219]
  36. Davies AA, Masson JY, McIlwraith MJ, Stasiak AZ, Stasiak A, Venkitaraman AR, West SC. Role of BRCA2 in control of the RAD51 recombination and DNA repair protein. Mol Cell. 2001;7:273–82. [PubMed: 11239456]
  37. de Winter JP, Rooimans MA, van Der Weel L, van Berkel CG, Alon N, Bosnoyan-Collins L, de Groot J, Zhi Y, Waisfisz Q, Pronk JC, Arwert F, Mathew CG, Scheper RJ, Hoatlin ME, Buchwald M, Joenje H. The Fanconi anaemia gene FANCF encodes a novel protein with homology to ROM. Nat Genet. 2000;24:15–6. [PubMed: 10615118]
  38. Deans AJ, West SC. FANCM connects the genome instability disorders Bloom's Syndrome and Fanconi Anemia. Mol Cell. 2009;36:943–53. [PubMed: 20064461]
  39. Demuth I, Wlodarski M, Tipping AJ, Morgan NV, de Winter JP, Thiel M, Gräsl S, Schindler D, D'Andrea AD, Altay C, Kayserili H, Zatterale A, Kunze J, Ebell W, Mathew CG, Joenje H, Sperling K, Digweed M. Spectrum of mutations in the Fanconi anaemia group G gene, FANCG/XRCC9. Eur J Hum Genet. 2000;8:861–8. [PubMed: 11093276]
  40. Dorsman JC, Levitus M, Rockx D, Rooimans MA, Oostra AB, Haitjema A, Bakker ST, Steltenpool J, Schuler D, Mohan S, Schindler D, Arwert F, Pals G, Mathew CG, Waisfisz Q, de Winter JP, Joenje H. Identification of the Fanconi anemia complementation group I gene, FANCI. Cell Oncol. 2007;29:211–8. [PubMed: 17452773]
  41. Eiler ME, Frohnmayer D, Frohnmayer L, Larsen K, Olsen J, eds. Fanconi Anemia: Guidelines for Diagnosis and Management. 3 ed. Eugene, OR: Fanconi Anemia Research Fund, Inc. Available online. 2008. Accessed 2-28-14.
  42. Erkko H, Xia B, Nikkilä J, Schleutker J, Syrjäkoski K, Mannermaa A, Kallioniemi A, Pylkäs K, Karppinen SM, Rapakko K, Miron A, Sheng Q, Li G, Mattila H, Bell DW, Haber DA, Grip M, Reiman M, Jukkola-Vuorinen A, Mustonen A, Kere J, Aaltonen LA, Kosma VM, Kataja V, Soini Y, Drapkin RI, Livingston DM, Winqvist R. A recurrent mutation in PALB2 in Finnish cancer families. Nature. 2007;446:316–9. [PubMed: 17287723]
  43. Fagerlie SR, Koretsky T, Torok-Storb B, Bagby GC. Impaired type I IFN-induced Jak/STAT signaling in FA-C cells and abnormal CD4+ Th cell subsets in Fancc-/- mice. J Immunol. 2004;173:3863–70. [PubMed: 15356134]
  44. Faivre L, Guardiola P, Lewis C, Dokal I, Ebell W, Zatterale A, Altay C, Poole J, Stones D, Kwee ML, van Weel-Sipman M, Havenga C, Morgan N, de Winter J, Digweed M, Savoia A, Pronk J, de Ravel T, Jansen S, Joenje H, Gluckman E, Mathew CG. Association of complementation group and mutation type with clinical outcome in Fanconi anemia. European Fanconi Anemia Research Group. Blood. 2000;96:4064–70. [PubMed: 11110674]
  45. Faivre L, Portnoi MF, Pals G, Stoppa-Lyonnet D, Le Merrer M, Thauvin-Robinet C, Huet F, Mathew CG, Joenje H, Verloes A, Baumann C. Should chromosome breakage studies be performed in patients with VACTERL association? Am J Med Genet A. 2005;137:55–8. [PubMed: 16015582]
  46. Fanconi Anaemia/Breast Cancer Consortium; Positional cloning of the Fanconi anaemia group A gene. Nat Genet. 1996;14:324–8. [PubMed: 8896564]
  47. Ferrer M, Rodriguez JA, Spierings EA, de Winter JP, Giaccone G, Kruyt FA. Identification of multiple nuclear export sequences in Fanconi anemia group A protein that contribute to CRM1-dependent nuclear export. Hum Mol Genet. 2005;14:1271–81. [PubMed: 15790592]
  48. Futaki M, Yamashita T, Yagasaki H, Toda T, Yabe M, Kato S, Asano S, Nakahata T. The IVS4 + 4 A to T mutation of the Fanconi anemia gene FANCC is not associated with a severe phenotype in Japanese patients. Blood. 2000;95:1493–8. [PubMed: 10666230]
  49. Garcia-Higuera I, Taniguchi T, Ganesan S, Meyn MS, Timmers C, Hejna J, Grompe M, D'Andrea AD. Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway. Mol Cell. 2001;7:249. [PubMed: 11239454]
  50. Gennery AR, Slatter MA, Bhattacharya A, Barge D, Haigh S, O'Driscoll M, Coleman R, Abinun M, Flood TJ, Cant AJ, Jeggo PA. The clinical and biological overlap between Nijmegen Breakage Syndrome and Fanconi anemia. Clin Immunol. 2004;113:214–9. [PubMed: 15451479]
  51. Gillio AP, Verlander PC, Batish SD, Giampietro PF, Auerbach AD. Phenotypic consequences of mutations in the Fanconi anemia FAC gene: an International Fanconi Anemia Registry study. Blood. 1997;90:105–10. [PubMed: 9207444]
  52. Green AM, Kupfer GM. Fanconi anemia. Hematol Oncol Clin North Am. 2009;23:193–214. [PubMed: 19327579]
  53. Grewal SS, Kahn JP, MacMillan ML, Ramsay NK, Wagner JE. Successful hematopoietic stem cell transplantation for Fanconi anemia from an unaffected HLA-genotype-identical sibling selected using preimplantation genetic diagnosis. Blood. 2004;103:1147–51. [PubMed: 14504102]
  54. Gross M, Hanenberg H, Lobitz S, Friedl R, Herterich S, Dietrich R, Gruhn B, Schindler D, Hoehn H. Reverse mosaicism in Fanconi anemia: natural gene therapy via molecular self-correction. Cytogenet Genome Res. 2002;98:126–35. [PubMed: 12697994]
  55. Gurtan AM, D'Andrea AD. Dedicated to the core: understanding the Fanconi anemia complex. DNA Repair (Amst). 2006;5:1119–25. [PubMed: 16784902]
  56. Hirsch B, Shimamura A, Moreau L, Baldinger S, Hag-alshiekh M, Bostrom B, Sencer S, D'Andrea AD. Association of biallelic BRCA2/FANCD1 mutations with spontaneous chromosomal instability and solid tumors of childhood. Blood. 2004;103:2554–9. [PubMed: 14670928]
  57. Ho GP, Margossian S, Taniguchi T, D'Andrea AD. Phosphorylation of FANCD2 on two novel sites is required for mitomycin C resistance. Mol Cell Biol. 2006;26:7005–15. [PMC free article: PMC1592857] [PubMed: 16943440]
  58. Ho TV, Schärer OD. Translesion DNA synthesis polymerases in DNA interstrand crosslink repair. Environ Mol Mutagen. 2010;51:552–66. [PubMed: 20658647]
  59. Houghtaling S, Timmers C, Noll M, Finegold MJ, Jones SN, Meyn MS, Grompe M. Epithelial cancer in Fanconi anemia complementation group D2 (Fancd2) knockout mice. Genes Dev. 2003;17:2021–35. [PMC free article: PMC196256] [PubMed: 12893777]
  60. Howlett NG, Taniguchi T, Olson S, Cox B, Waisfisz Q, De Die-Smulders C, Persky N, Grompe M, Joenje H, Pals G, Ikeda H, Fox EA, D'Andrea AD. Biallelic inactivation of BRCA2 in Fanconi anemia. Science. 2002;297:606–9. [PubMed: 12065746]
  61. Howlett NG, Harney JA, Rego MA, Kolling FW, Glover TW. Functional interaction between the Fanconi Anemia D2 protein and proliferating cell nuclear antigen (PCNA) via a conserved putative PCNA interaction motif. J Biol Chem. 2009;284:28935–42. [PMC free article: PMC2781439] [PubMed: 19704162]
  62. Huang M, D'Andrea AD. A new nuclease member of the FAN club. Nat Struct Mol Biol. 2010;17:926–8. [PMC free article: PMC2945811] [PubMed: 20683477]
  63. Huang M, Kim JM, Shiotani B, Yang K, Zou L, D'Andrea AD. The FANCM/FAAP24 complex is required for the DNA interstrand crosslink-induced checkpoint response. Mol Cell. 2010;39:259–68. [PMC free article: PMC2928996] [PubMed: 20670894]
  64. Huang TT, Nijman SM, Mirchandani KD, Galardy PJ, Cohn MA, Haas W, Gygi SP, Ploegh HL, Bernards R, D'Andrea AD. Regulation of monoubiquitinated PCNA by DUB autocleavage. Nat Cell Biol. 2006;8:339–47. [PubMed: 16531995]
  65. Ishiai M, Kitao H, Smogorzewska A, Tomida J, Kinomura A, Uchida E, Saberi A, Kinoshita E, Kinoshita-Kikuta E, Koike T, Tashiro S, Elledge SJ, Takata M. FANCI phosphorylation functions as a molecular switch to turn on the Fanconi anemia pathway. Nat Struct Mol Biol. 2008;15:1138–46. [PMC free article: PMC3293454] [PubMed: 18931676]
  66. Kennedy RD, D'Andrea AD. The Fanconi Anemia/BRCA pathway: new faces in the crowd. Genes Dev. 2005;19:2925–40. [PubMed: 16357213]
  67. Kim Y, Lach FP, Desetty R, Hanenberg H, Auerbach AD, Smogorzewska A. Mutations of the SLX4 gene in Fanconi anemia. Nat Genet. 2011;43:142–6. [PMC free article: PMC3345287] [PubMed: 21240275]
  68. Knipscheer P, Räschle M, Smogorzewska A, Enoiu M, Ho TV, Schärer OD, Elledge SJ, Walter JC. The Fanconi anemia pathway promotes replication-dependent DNA interstrand cross-link repair. Science. 2009;326:1698–701. [PMC free article: PMC2909596] [PubMed: 19965384]
  69. Kowal P, Gurtan AM, Stuckert P, D'Andrea AD, Ellenberger T. Structural determinants of human FANCF protein that function in the assembly of a DNA damage signaling complex. J Biol Chem. 2007;282:2047–55. [PubMed: 17082180]
  70. Kutler DI, Auerbach AD. Fanconi anemia in Ashkenazi Jews. Fam Cancer. 2004;3:241–8. [PubMed: 15516848]
  71. Kutler DI, Singh B, Satagopan J, Batish SD, Berwick M, Giampietro PF, Hanenberg H, Auerbach AD. A 20-year perspective on the International Fanconi Anemia Registry (IFAR). Blood. 2003;101:1249–56. [PubMed: 12393516]
  72. Landmann E, Bluetters-Sawatzki R, Schindler D, Gortner L. Fanconi anemia in a neonate with pancytopenia. J Pediatr. 2004;145:125–7. [PubMed: 15238921]
  73. Léveillé F, Blom E, Medhurst AL, Bier P. The Fanconi anemia gene product FANCF is a flexible adaptor protein. J Biol Chem. 2004;279:39421–30. [PubMed: 15262960]
  74. Levitus M, Waisfisz Q, Godthelp BC, de Vries Y, Hussain S, Wiegant WW, Elghalbzouri-Maghrani E, Steltenpool J, Rooimans MA, Pals G, Arwert F, Mathew CG, Zdzienicka MZ, Hiom K, De Winter JP, Joenje H. The DNA helicase BRIP1 is defective in Fanconi anemia complementation group J. Nat Genet. 2005;37:934–5. [PubMed: 16116423]
  75. Levran O, Attwooll C, Henry RT, Milton KL, Neveling K, Rio P, Batish SD, Kalb R, Velleuer E, Barral S, Ott J, Petrini J, Schindler D, Hanenberg H, Auerbach AD. The BRCA1-interacting helicase BRIP1 is deficient in Fanconi anemia. Nat Genet. 2005;37:931–3. [PubMed: 16116424]
  76. Levran O, Erlich T, Magdalena N, Gregory JJ, Batish SD, Verlander PC, Auerbach AD. Sequence variation in the Fanconi anemia gene FAA. Proc Natl Acad Sci U S A. 1997;94:13051–6. [PMC free article: PMC24261] [PubMed: 9371798]
  77. Ling C, Ishiai M, Ali AM, Medhurst AL, Neveling K, Kalb R, Yan Z, Xue Y, Oostra AB, Auerbach AD, Hoatlin ME, Schindler D, Joenje H, de Winter JP, Takata M, Meetei AR, Wang W. FAAP100 is essential for activation of the Fanconi anemia-associated DNA damage response pathway. EMBO J. 2007;26:2104–14. [PMC free article: PMC1852792] [PubMed: 17396147]
  78. Litman R, Peng M, Jin Z, Zhang F, Zhang J, Powell S, Andreassen PR, Cantor SB. BACH1 is critical for homologous recombination and appears to be the Fanconi anemia gene product FANCJ. Cancer Cell. 2005;8:255–65. [PubMed: 16153896]
  79. Liu JM, Kim S, Read EJ, Futaki M, Dokal I, Carter CS, Leitman SF, Pensiero M, Young NS, Walsh CE. Engraftment of hematopoietic progenitor cells transduced with the Fanconi anemia group C gene (FANCC). Hum Gene Ther. 1999;10:2337–46. [PubMed: 10515453]
  80. Lo Ten Foe JR, Kwee ML, Rooimans MA, Oostra AB, Veerman AJ, van Weel M, Pauli RM, Shahidi NT, Dokal I, Roberts I, Altay C, Gluckman E, Gibson RA, Mathew CG, Arwert F, Joenje H. Somatic mosaicism in Fanconi anemia: molecular basis and clinical significance. Eur J Hum Genet. 1997;5:137–48. [PubMed: 9272737]
  81. Lo Ten Foe JR, Rooimans MA, Bosnoyan-Collins L, Alon N, Wijker M, Parker L, Lightfoot J, Carreau M, Callen DF, Savoia A, Cheng NC, van Berkel CG, Strunk MH, Gille JJ, Pals G, Kruyt FA, Pronk JC, Arwert F, Buchwald M, Joenje H. Expression cloning of a cDNA for the major Fanconi anaemia gene, FAA. Nat Genet. 1996;14:320–3. [PubMed: 8896563]
  82. Lyakhovich A, Surralles J. Disruption of the Fanconi anemia/BRCA pathway in sporadic cancer. Cancer Lett. 2006;232:99–106. [PubMed: 16246487]
  83. MacMillan ML, Wagner JE. Haematopoeitic cell transplantation for Fanconi anaemia - when and how? Br J Haematol. 2010;149:14–21. [PubMed: 20136826]
  84. Machida YJ, Machida Y, Chen Y, Gurtan AM, Kupfer GM, D'Andrea AD, Dutta A. UBE2T is the E2 in the Fanconi anemia pathway and undergoes negative autoregulation. Mol Cell. 2006;23:589–96. [PubMed: 16916645]
  85. Marsit CJ, Liu M, Nelson HH, Posner M, Suzuki M, Kelsey KT. Inactivation of the Fanconi anemia/BRCA pathway in lung and oral cancers: implications for treatment and survival. Oncogene. 2004;23:1000–4. [PubMed: 14647419]
  86. Martin SA, Hewish M, Lord CJ, Ashworth A. Genomic instability and the selection of treatments for cancer. J Pathol. 2010;220:281–9. [PubMed: 19890832]
  87. Mathew CG. Fanconi anaemia genes and susceptibility to cancer. Oncogene. 2006;25:5875–84. [PubMed: 16998502]
  88. Matsushita N, Kitao H, Ishiai M, Nagashima N, Hirano S, Okawa K, Ohta T, Yu DS, McHugh PJ, Hickson ID, Venkitaraman AR, Kurumizaka H, Takata M. A FancD2-monoubiquitin fusion reveals hidden functions of Fanconi anemia core complex in DNA repair. Mol Cell. 2005;19:841–7. [PubMed: 16168378]
  89. Meetei AR, de Winter JP, Medhurst AL, Wallisch M, Waisfisz Q, van de Vrugt HJ, Oostra AB, Yan Z, Ling C, Bishop CE, Hoatlin ME, Joenje H, Wang W. A novel ubiquitin ligase is deficient in Fanconi anemia. Nat Genet. 2003a;35:165–70. [PubMed: 12973351]
  90. Meetei AR, Levitus M, Xue Y, Medhurst AL, Zwaan M, Ling C, Rooimans MA, Bier P, Hoatlin M, Pals G, de Winter JP, Wang W, Joenje H. X-linked inheritance of Fanconi anemia complementation group B. Nat Genet. 2004;36:1219–24. [PubMed: 15502827]
  91. Meetei AR, Medhurst AL, Ling C, Xue Y, Singh TR, Bier P, Steltenpool J, Stone S, Dokal I, Mathew CG, Hoatlin M, Joenje H, de Winter JP, Wang W. A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M. Nat Genet. 2005;37:958–63. [PMC free article: PMC2704909] [PubMed: 16116422]
  92. Meetei AR, Sechi S, Wallisch M, Yang D, Young MK, Joenje H, Hoatlin ME, Wang W. A multiprotein nuclear complex connects Fanconi anemia and Bloom syndrome. Mol Cell Biol. 2003b;23:3417–26. [PMC free article: PMC164758] [PubMed: 12724401]
  93. Meindl A, Hellebrand H, Wiek C, Erven V, Wappenschmidt B, Niederacher D, Freund M, Lichtner P, Hartmann L, Schaal H, Ramser J, Honisch E, Kubisch C, Wichmann HE, Kast K, Deissler H, Engel C, Müller-Myhsok B, Neveling K, Kiechle M, Mathew CG, Schindler D, Schmutzler RK, Hanenberg H. Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat Genet. 2010;42:410–4. [PubMed: 20400964]
  94. Mi J, Qiao F, Wilson JB, High AA, Schroeder MJ, Stukenberg PT, Moss A, Shabanowitz J, Hunt DF, Jones NJ, Kupfer GM. FANCG is phosphorylated at serines 383 and 387 during mitosis. Mol Cell Biol. 2004;24:8576–85. [PMC free article: PMC516759] [PubMed: 15367677]
  95. Mirchandani KD, D'Andrea AD. The Fanconi anemia/BRCA pathway: a coordinator of cross-link repair. Exp Cell Res. 2006;312:2647–53. [PubMed: 16859679]
  96. Montes de Oca R, Andreassen PR, Margossian SP, Gregory RC, Taniguchi T, Wang X, Houghtaling S, Grompe M, D'Andrea AD. Regulated interaction of the Fanconi anemia protein, FANCD2, with chromatin. Blood. 2005;105:1003–9. [PubMed: 15454491]
  97. Morgan NV, Essop F, Demuth I, de Ravel T, Jansen S, Tischkowitz M, Lewis CM, Wainwright L, Poole J, Joenje H, Digweed M, Krause A, Mathew CG. A common Fanconi anemia mutation in black populations of sub-Saharan Africa. Blood. 2005;105:3542–4. [PubMed: 15657175]
  98. Morgan NV, Tipping AJ, Joenje H, Mathew CG. High frequency of large intragenic deletions in the Fanconi anemia group A gene. Am J Hum Genet. 1999;65:1330–41. [PMC free article: PMC1288285] [PubMed: 10521298]
  99. Moynahan ME, Pierce AJ, Jasin M. BRCA2 is required for homology-directed repair of chromosomal breaks. Mol Cell. 2001;7:263–72. [PubMed: 11239455]
  100. Nakanishi K, Taniguchi T, Ranganathan V, New HV, Moreau LA, Stotsky M, Mathew CG, Kastan MB, Weaver DT, D'Andrea AD. Interaction of FANCD2 and NBS1 in the DNA damage response. Nat Cell Biol. 2002;4:913–20. [PubMed: 12447395]
  101. Narayan G, Arias-Pulido H, Nandula SV, Basso K, Sugirtharaj DD, Vargas H, Mansukhani M, Villella J, Meyer L, Schneider A, Gissmann L, Dürst M, Pothuri B, Murty VV. Promoter hypermethylation of FANCF: disruption of Fanconi Anemia-BRCA pathway in cervical cancer. Cancer Res. 2004;64:2994–7. [PubMed: 15126331]
  102. Niedernhofer LJ, Lalai AS, Hoeijmakers JH. Fanconi anemia (cross) linked to DNA repair. Cell. 2005;123:1191–8. [PubMed: 16377561]
  103. Nijman SM, Huang TT, Dirac AM, Brummelkamp TR, Kerkhoven RM, D'Andrea AD, Bernards R. The deubiquitinating enzyme USP1 regulates the Fanconi anemia pathway. Mol Cell. 2005;17:331–9. [PubMed: 15694335]
  104. Nookala RK, Hussain S, Pellegrini L. Insights into Fanconi Anaemia from the structure of human FANCE. Nucleic Acids Res. 2007;35:1638–48. [PMC free article: PMC1865054] [PubMed: 17308347]
  105. O'Driscoll M, Ruiz-Perez VL, Woods CG, Jeggo PA, Goodship JA. A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome. Nat Genet. 2003;33:497–501. [PubMed: 12640452]
  106. Oda T, Hayano T, Miyaso H, Takahashi N, Yamashita T. Hsp90 regulates the Fanconi anemia DNA damage response pathway. Blood. 2007;109:5016–26. [PubMed: 17327415]
  107. Oestergaard VH, Langevin F, Kuiken HJ, Pace P, Niedzwiedz W, Simpson LJ, Ohzeki M, Takata M, Sale JE, Patel KJ. Deubiquitination of FANCD2 is required for DNA crosslink repair. Mol Cell. 2007;28:798–809. [PMC free article: PMC2148256] [PubMed: 18082605]
  108. Olopade OI, Wei M. FANCF methylation contributes to chemoselectivity in ovarian cancer. Cancer Cell. 2003;3:417–20. [PubMed: 12781358]
  109. Pace P, Johnson M, Tan WM, Mosedale G, Sng C, Hoatlin M, de Winter J, Joenje H, Gergely F, Patel KJ. FANCE: the link between Fanconi anaemia complex assembly and activity. EMBO J. 2002;21:3414–23. [PMC free article: PMC125396] [PubMed: 12093742]
  110. Pang Q, Fagerlie S, Christianson TA, Keeble W, Faulkner G, Diaz J, Rathbun RK, Bagby GC. The Fanconi anemia protein FANCC binds to and facilitates the activation of STAT1 by gamma interferon and hematopoietic growth factors. Mol Cell Biol. 2000;20:4724–35. [PMC free article: PMC85895] [PubMed: 10848598]
  111. Parmar K, Kim J, Sykes SM, Shimamura A, Stuckert P, Zhu K, Hamilton A, Deloach MK, Kutok JL, Akashi K, Gilliland DG. Hematopoietic stem cell defects in mice with deficiency of Fancd2 or Usp1. Stem Cells. 2010;28:1186–95. [PMC free article: PMC2910804] [PubMed: 20506303]
  112. Pichierri P, Rosselli F. The DNA crosslink-induced S-phase checkpoint depends on ATR-CHK1 and ATR-NBS1-FANCD2 pathways. EMBO J. 2004;23:1178–87. [PMC free article: PMC380971] [PubMed: 14988723]
  113. Pulsipher M, Kupfer GM, Naf D, Suliman A, Lee J-S, Jakobs P, Grompe M, Joenje H, Sieff C, Guinan E, Mulligan R, D'Andrea AD. Subtyping analysis of Fanconi anemia by immunoblotting and retroviral gene transfer. Mol Med. 1998;4:468. [PMC free article: PMC2230330] [PubMed: 9713825]
  114. Qiao F, Mi J, Wilson JB, Zhi G, Bucheimer NR, Jones NJ, Kupfer GM. Phosphorylation of Fanconi anemia (FA) complementation group G protein, FANCG, at serine 7 is important for function of the FA pathway. J Biol Chem. 2004;279:46035–45. [PubMed: 15299017]
  115. Rahman N, Seal S, Thompson D, Kelly P, Renwick A, Elliott A, Reid S, Spanova K, Barfoot R, Chagtai T, Jayatilake H, McGuffog L, Hanks S, Evans DG, Eccles D. PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet. 2007;39:165–7. [PMC free article: PMC2871593] [PubMed: 17200668]
  116. Reid S, Schindler D, Hanenberg H, Barker K, Hanks S, Kalb R, Neveling K, Kelly P, Seal S, Freund M, Wurm M, Batish SD, Lach FP, Yetgin S, Neitzel H, Ariffin H, Tischkowitz M, Mathew CG, Auerbach AD, Rahman N. Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat Genet. 2007;39:162–4. [PubMed: 17200671]
  117. Rosenberg PS, Alter BP, Ebell W. Cancer risks in Fanconi anemia: findings from the German Fanconi Anemia Registry. Haematologica. 2008;93:511–7. [PubMed: 18322251]
  118. Rosenberg PS, Greene MH, Alter BP. Cancer incidence in persons with Fanconi anemia. Blood. 2003;101:822–6. [PubMed: 12393424]
  119. Rosenberg PS, Socié G, Alter BP, Gluckman E. Risk of head and neck squamous cell cancer and death in patients with Fanconi anemia who did and did not receive transplants. Blood. 2005;105:67–73. [PubMed: 15331448]
  120. Seal S, Thompson D, Renwick A, Elliott A, Kelly P, Barfoot R, Chagtai T, Jayatilake H, Ahmed M, Spanova K, North B, McGuffog L, Evans DG, Eccles D. Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat Genet. 2006;38:1239–41. [PubMed: 17033622]
  121. Shimamura A, Alter BP. Pathophysiology and management of inherited bone marrow failure syndromes. Blood Rev. 2010;24:101–22. [PMC free article: PMC3733544] [PubMed: 20417588]
  122. Shimamura A, de Oca RM, Svenson JL, Haining N, Moreau LA, Nathan DG, D'Andrea AD. A novel diagnostic screen for defects in the Fanconi anemia pathway. Blood. 2002;100:4649–54. [PubMed: 12393398]
  123. Sims AE, Spiteri E, Sims RJ, Arita AG, Lach FP, Landers T, Wurm M, Freund M, Neveling K, Hanenberg H, Auerbach AD, Huang TT. FANCI is a second monoubiquitinated member of the Fanconi anemia pathway. Nat Struct Mol Biol. 2007;14:564–7. [PubMed: 17460694]
  124. Singh TR, Bakker ST, Agarwal S, Jansen M, Grassman E, Godthelp BC, Ali AM, Du CH, Rooimans MA, Fan Q, Wahengbam K, Steltenpool J, Andreassen PR, Williams DA, Joenje H, de Winter JP, Meetei AR. Impaired FANCD2 monoubiquitination and hypersensitivity to camptothecin uniquely characterize Fanconi anemia complementation group M. Blood. 2009;114:174–80. [PMC free article: PMC2710946] [PubMed: 19423727]
  125. Smogorzewska A, Matsuoka S, Vinciguerra P, McDonald ER, Hurov KE, Luo J, Ballif BA, Gygi SP, Hofmann K, D'Andrea AD, Elledge SJ. Identification of the FANCI protein, a monoubiquitinated FANCD2 paralog required for DNA repair. Cell. 2007;129:289–301. [PMC free article: PMC2175179] [PubMed: 17412408]
  126. Somyajit K, Subramanya S, Nagaraju G. RAD51C: a novel cancer susceptibility gene is linked to Fanconi anemia and breast cancer. Carcinogenesis. 2010;31:2031–8. [PMC free article: PMC2994284] [PubMed: 20952512]
  127. Song IY, Palle K, Gurkar A, Tateishi S, Kupfer GM, Vaziri C. Rad18-mediated translesion synthesis of bulky DNA adducts is coupled to activation of the Fanconi anemia DNA repair pathway. J Biol Chem. 2010;285:31525–36. [PMC free article: PMC2951227] [PubMed: 20675655]
  128. Stoepker C, Hain K, Schuster B, Hilhorst-Hofstee Y, Rooimans MA, Steltenpool J, Oostra AB, Eirich K, Korthof ET, Nieuwint AW, Jaspers NG, Bettecken T, Joenje H, Schindler D, Rouse J, de Winter JP. SLX4, a coordinator of structure-specific endonucleases, is mutated in a new Fanconi anemia subtype. Nat Genet. 2011;43:138–41. [PubMed: 21240277]
  129. Strathdee CA, Gavish H, Shannon WR, Buchwald M. Cloning of cDNAs for Fanconi's anaemia by functional complementation. Nature. 1992;356:763–7. [PubMed: 1574115]
  130. Swift M. Fanconi's anaemia in the genetics of neoplasia. Nature. 1971;230:370–3. [PubMed: 4927726]
  131. Tamary H, Nishri D, Yacobovich J, Zilber R, Dgany O, Krasnov T, Aviner S, Stepensky P, Ravel-Vilk S, Bitan M, Kaplinsky C, Ben Barak A, Elhasid R, Kapelusnik J, Koren A, Levin C, Attias D, Laor R, Yaniv I, Rosenberg PS, Alter BP. Frequency and natural history of inherited bone marrow failure syndromes: the Israeli Inherited Bone Marrow Failure Registry. Haematologica. 2010;95:1300–7. [PMC free article: PMC2913078] [PubMed: 20435624]
  132. Taniguchi T, D'Andrea AD. Molecular pathogenesis of Fanconi anemia: recent progress. Blood. 2006;107:4223–33. [PubMed: 16493006]
  133. Taniguchi T, Garcia-Higuera I, Andreassen PR, Gregory RC, Grompe M, D'Andrea AD. S-phase-specific interaction of the Fanconi anemia protein, FANCD2, with BRCA1 and RAD51. Blood. 2002a;100:2414–20. [PubMed: 12239151]
  134. Taniguchi T, Garcia-Higuera I, Xu B, Andreassen PR, Gregory RC, Kim ST, Lane WS, Kastan MB, D'Andrea AD. Convergence of the Fanconi anemia and ataxia-telangiectasia signaling pathways. Cell. 2002b;109:459–72. [PubMed: 12086603]
  135. Taniguchi T, Tischkowitz M, Ameziane N, Hodgson SV, Mathew CG, Joenje H, Mok SC, D'Andrea AD. Disruption of the Fanconi anemia-BRCA pathway in cisplatin-sensitive ovarian tumors. Nat Med. 2003;9:568–74. [PubMed: 12692539]
  136. Thompson LH, Hinz JM. Cellular and molecular consequences of defective Fanconi anemia proteins in replication-coupled DNA repair: mechanistic insights. Mutat Res. 2009;668:54–72. [PMC free article: PMC2714807] [PubMed: 19622404]
  137. Timmers C, Taniguchi T, Hejna J, Reifsteck C, Lucas L, Bruun D, Thayer M, Cox B, Olson S, D'Andrea A, Moses R, Grompe M. Positional cloning of a novel Fanconi Anemia gene, FANCD2. Mol Cell. 2001;7:241. [PubMed: 11239453]
  138. Tischkowitz M, Xia B, Sabbaghian N, Reis-Filho JS, Hamel N, Li G, van Beers EH, Li L, Khalil T, Quenneville LA, Omeroglu A, Poll A, Lepage P, Wong N, Nederlof PM, Ashworth A, Tonin PN, Narod SA, Livingston DM, Foulkes WD. Analysis of PALB2/FANCN-associated breast cancer families. Proc Natl Acad Sci U S A. 2007;104:6788–93. [PMC free article: PMC1871863] [PubMed: 17420451]
  139. Tonnies H, Huber S, Kuhl JS, Gerlach A, Ebell W, Neitzel H. Clonal chromosomal aberrations in bone marrow cells of Fanconi anemia patients: gains of the chromosomal segment 3q26q29 as an adverse risk factor. Blood. 2003;101:3872–4. [PubMed: 12511406]
  140. Turner N, Tutt A, Ashworth A. Hallmarks of 'BRCAness' in sporadic cancers. Nat Rev Cancer. 2004;4:814–9. [PubMed: 15510162]
  141. van Der Heijden MS, Yeo CJ, Hruban RH, Kern SE. Fanconi anemia gene mutations in young-onset pancreatic cancer. Cancer Res. 2003;63:2585–8. [PubMed: 12750283]
  142. van Zeeburg HJ, Snijders PJ, Wu T, Gluckman E, Soulier J, Surralles J, Castella M, van der Wal JE, Wennerberg J, Califano J, Velleuer E, Dietrich R, Ebell W, Bloemena E, Joenje H, Leemans CR, Brakenhoff RH. Clinical and molecular characteristics of squamous cell carcinomas from Fanconi anemia patients. J Natl Cancer Inst. 2008;100:1649–53. [PMC free article: PMC3299207] [PubMed: 19001603]
  143. Vandenberg CJ, Gergely F, Ong CY, Pace P, Mallery DL, Hiom K, Patel KJ. BRCA1-independent ubiquitination of FANCD2. Mol Cell. 2003;12:247–54. [PubMed: 12887909]
  144. 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 RG, Schaal H, Mohammed S, Rahman N, Schindler D, Mathew CG. Mutation of the RAD51C gene in a Fanconi anemia-like disorder. Nat Genet. 2010;42:406–9. [PubMed: 20400963]
  145. Venkitaraman AR. Tracing the network connecting BRCA and Fanconi anaemia proteins. Nat Rev Cancer. 2004;4:266–76. [PubMed: 15057286]
  146. Verlinsky Y, Rechitsky S, Schoolcraft W, Strom C, Kuliev A. Preimplantation diagnosis for Fanconi anemia combined with HLA matching. JAMA. 2001;285:3130–3. [PubMed: 11427142]
  147. Wagner JE, Tolar J, Levran O, Scholl T, Deffenbaugh A, Satagopan J, Ben-Porat L, Mah K, Batish SD, Kutler DI, MacMillan ML, Hanenberg H, Auerbach AD. Germline mutations in BRCA2: shared genetic susceptibility to breast cancer, early onset leukemia, and Fanconi anemia. Blood. 2004;103:3226–9. [PubMed: 15070707]
  148. Waisfisz Q, Morgan NV, Savino M, de Winter JP, van Berkel CG, Hoatlin ME, Ianzano L, Gibson RA, Arwert F, Savoia A, Mathew CG, Pronk JC, Joenje H. Spontaneous functional correction of homozygous Fanconi anaemia alleles reveals novel mechanistic basis for reverse mosaicism. Nat Genet. 1999;22:379–83. [PubMed: 10431244]
  149. Wang X, Andreassen PR, D'Andrea AD. Functional interaction of monoubiquitinated FANCD2 and BRCA2/FANCD1 in chromatin. Mol Cell Biol. 2004;24:5850–62. [PMC free article: PMC480901] [PubMed: 15199141]
  150. Wang X, Kennedy RD, Ray K, Stuckert P, Ellenberger T, D'Andrea AD. Chk1-mediated phosphorylation of FANCE is required for the Fanconi anemia/BRCA pathway. Mol Cell Biol. 2007;27:3098–108. [PMC free article: PMC1899922] [PubMed: 17296736]
  151. Wang Z, Li M, Lu S, Zhang Y, Wang H. Promoter hypermethylation of FANCF plays an important role in the occurrence of ovarian cancer through disrupting Fanconi anemia-BRCA pathway. Cancer Biol Ther. 2006;5:256–60. [PubMed: 16418574]
  152. Whitney MA, Saito H, Jakobs PM, Gibson RA, Moses RE, Grompe M. A common mutation in the FACC gene causes Fanconi anaemia in Ashkenazi Jews. Nat Genet. 1993;4:202–5. [PubMed: 8348157]
  153. Wijker M, Morgan NV, Herterich S, van Berkel CG, Tipping AJ, Gross HJ, Gille JJ, Pals G, Savino M, Altay C, Mohan S, Dokal I, Cavenagh J, Marsh J, van Weel M, Ortega JJ, Schuler D, Samochatova E, Karwacki M, Bekassy AN, Abecasis M, Ebell W, Kwee ML, de Ravel T, Mathew CG. Heterogeneous spectrum of mutations in the Fanconi anaemia group A gene. Eur J Hum Genet. 1999;7:52–9. [PubMed: 10094191]
  154. Wilson JB, Blom E, Cunningham R, Xiao Y, Kupfer GM, Jones NJ. Several tetratricopeptide repeat (TPR) motifs of FANCG are required for assembly of the BRCA2/D1-D2-G-X3 complex, FANCD2 monoubiquitylation and phleomycin resistance. Mutat Res. 2010;689:12–20. [PMC free article: PMC2903733] [PubMed: 20450923]
  155. Wong JC, Alon N, McKerlie C, Huang JR, Meyn MS, Buchwald M. Targeted disruption of exons 1 to 6 of the Fanconi Anemia group A gene leads to growth retardation, strain-specific microphthalmia, meiotic defects and primordial germ cell hypoplasia. Hum Mol Genet. 2003;12:2063–76. [PubMed: 12913077]
  156. Wu Y, Brosh RM. FANCJ helicase operates in the Fanconi Anemia DNA repair pathway and the response to replicational stress. Curr Mol Med. 2009;9:470–82. [PMC free article: PMC2763586] [PubMed: 19519404]
  157. Xia B, Dorsman JC, Ameziane N, de Vries Y, Rooimans MA, Sheng Q, Pals G, Errami A, Gluckman E, Llera J, Wang W, Livingston DM, Joenje H, de Winter JP. Fanconi anemia is associated with a defect in the BRCA2 partner PALB2. Nat Genet. 2007;39:159–61. [PubMed: 17200672]
  158. Xia B, Sheng Q, Nakanishi K, Ohashi A, Wu J, Christ N, Liu X, Jasin M, Couch FJ, Livingston DM. Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol Cell. 2006;22:719–29. [PubMed: 16793542]
  159. Yamashita T, Barber DL, Zhu Y, Wu N, D'Andrea AD. The Fanconi anemia polypeptide FACC is localized to the cytoplasm. Proc Natl Acad Sci U S A. 1994;91:6712–6. [PMC free article: PMC44273] [PubMed: 7517562]
  160. Yamashita T, Wu N, Kupfer G, Corless C, Joenje H, Grompe M, D'Andrea AD. The Clinical variability of Fanconi Anemia (Type C) results from expression of an amino terminal truncated FAC polypeptide with partial activity. Blood. 1996;87:4424. [PubMed: 8639804]
  161. Zhang F, Fan Q, Ren K, Auerbach AD, Andreassen PR. FANCJ/BRIP1 recruitment and regulation of FANCD2 in DNA damage responses. Chromosoma. 2010;119:637–49. [PubMed: 20676667]
  162. Zhang QS, Eaton L, Snyder ER, Houghtaling S, Mitchell JB, Finegold M, Van Waes C, Grompe M. Tempol protects against oxidative damage and delays epithelial tumor onset in Fanconi anemia mice. Cancer Res. 2008;68:1601–8. [PubMed: 18316625]
  163. Zhi G, Wilson JB, Chen X, Krause DS, Xiao Y, Jones NJ, Kupfer GM. Fanconi anemia complementation group FANCD2 protein serine 331 phosphorylation is important for Fanconi anemia pathway function and BRCA2 interaction. Cancer Res. 2009;69:8775–83. [PubMed: 19861535]

Suggested Reading

  1. Auerbach AD, Buchwald M, Joenje H. Fanconi anemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 31. Available online. Accessed 2-28-14.
  2. Huret JL. Fanconi anaemia. Atlas of Genetics and Cytogenetics Oncology and Haematology. Available online. 2002. Accessed 2-28-14.

Chapter Notes

Author Notes

Comprehensive Center for Fanconi Anemia
Dana Farber Cancer Institute
Mayer 676
44 Binney Street
Boston, MA 02115
Phone: 617-632-6302

Author History

Blanche P Alter, MD, MPH (2011-present)
Alan D'Andrea, MD; Dana Farber Cancer Institute (2002-2007)
Gary Kupfer, MD (2011-present)
Lisa Moreau, MS; Dana Farber Cancer Institute (2002-2007)
Akiko Shimamura, MD, PhD; Dana Farber Cancer Institute (2002-2007)
Toshiyasu Taniguchi, MD, PhD; Fred Hutchinson Cancer Research Center (2007-2011)

Revision History

  • 7 February 2013 (cd) Revision: deletion/duplication analysis available clinically for FANCC
  • 6 September 2012 (cd) Revision: sequence analysis for mutations in RAD51C and SLX4 available clinically
  • 3 November 2011 (cd) Revision: deletion/duplication analysis available clinically for PALB2 deletions
  • 10 February 2011 (me) Comprehensive update posted live
  • 27 March 2008 (cd) Revision: sequence analysis and prenatal testing available clinically for FANCB-, FANCE-, FANCF- and FANCI-related Fanconi anemia
  • 29 January 2008 (cd) Revision: sequence analysis of entire coding region of FANCG and prenatal testing available
  • 7 November 2007 (cd) Revision: molecular genetic testing and prenatal diagnosis no longer available on a clinical basis for FANCF and FANCG
  • 22 June 2007 (me) Comprehensive update posted to live Web site
  • 1 March 2006 (cd) Revision: FANCB mutations: X-linked inheritance
  • 3 January 2006 (as) Revision: deletion/duplication testing clinically available
  • 13 September 2004 (me) Comprehensive update posted to live Web site
  • 14 February 2002 (me) Review posted to live Web site
  • 31 May 2001 (as) Original submission
Copyright © 1993-2014, University of Washington, Seattle. All rights reserved.

For more information, see the GeneReviews Copyright Notice and Usage Disclaimer.

For questions regarding permissions: ude.wu@tssamda.

Bookshelf ID: NBK1401PMID: 20301575
PubReader format: click here to try

Views

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to pubmed
  • Gene
    Gene records cited in chapters on the NCBI bookshelf. Links are provided by the authors or the NCBI Bookshelf staff.

Related citations in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...