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Fanconi Anemia

Synonym: Fanconi Pancytopenia

, MD and , MD, PhD.

Author Information

Initial Posting: ; Last Update: September 22, 2016.

Summary

Clinical characteristics.

Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors –particularly of the head and neck, skin, gastrointestinal tract, and genitourinary tract – are more common in individuals with FA.

Diagnosis/testing.

The diagnosis of FA is established in a proband with increased chromosome breakage and radial forms on cytogenetic testing of lymphocytes with diepoxybutane (DEB) and mitomycin C (MMC). The diagnosis is confirmed by identification of one of the following:

  • Biallelic pathogenic variants in one of the 16 genes known to cause autosomal recessive FA
  • A heterozygous pathogenic variant in RAD51, known to cause autosomal dominant FA
  • A hemizygous pathogenic variant in FANCB, known to cause X-linked FA

Management.

Treatment of manifestations: Administration of oral androgens (e.g., oxymetholone) improves blood counts (red cell and platelets) in approximately 50% of individuals with FA; 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 for solid tumors remains and may even be increased in those undergoing HSCT. All these treatments have potential significant toxicity. Early detection and surgical removal remains the mainstay of therapy for solid tumors.

Prevention of primary manifestations: Human papilloma virus (HPV) vaccination to reduce the risk of gynecologic cancer in females, and possibly reduce the risk of oral cancer in all individuals.

Prevention of secondary complications: T-cell depletion of the donor graft to minimize the risk of graft vs host disease; conditioning regimen without radiation prior to HSCT to reduce the risk of subsequent solid tumors.

Surveillance: Annual evaluation with a multidisciplinary team including an endocrinologist; 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 function tests 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; unsafe sex practices, which increase the risk of HPV-associated malignancy; radiographic studies solely for the purpose of surveillance (i.e., in the absence of clinical indications).

Evaluation of relatives at risk: DEB/MMC testing or molecular genetic testing (if the family-specific pathogenic variants are known) of all sibs of a proband for early diagnosis, treatment, and monitoring for physical abnormalities, bone marrow failure, and related cancers.

Genetic counseling.

Fanconi anemia (FA) can be inherited in an autosomal recessive manner, an autosomal dominant manner (RAD51-related FA), or an X-linked manner (FANCB-related FA).

Autosomal recessive FA: Each sib of an affected individual has a 25% chance of inheriting both pathogenic allelic variants and being affected, a 50% chance of inheriting one pathogenic allelic variant and being a carrier, and a 25% chance of inheriting both normal alleles and not being a carrier. Carriers (heterozygotes) for autosomal recessive FA are asymptomatic.

Autosomal dominant FA: Given that all affected individuals with RAD51-related FA reported to date have the disorder as a result of a de novo RAD51 pathogenic variant, the risk to other family members is presumed to be low.

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

Carrier testing for at-risk relatives (for autosomal recessive and X-linked FA) and prenatal testing for pregnancies at increased risk are possible if the pathogenic variant(s) in the family are known.

Diagnosis

Recommendations for diagnosis were agreed upon at a 2013 consensus conference (see Fanconi Anemia: Guidelines for Diagnosis and Management).

Suggestive Findings

Fanconi anemia (FA) should be suspected in individuals with the following clinical and laboratory features:

Physical features (in ~75% of affected persons)

  • Prenatal and/or postnatal short stature
  • Abnormal skin pigmentation (e.g., café au lait macules, hypopigmentation)
  • Skeletal malformations (e.g., hypoplastic thumb, hypoplastic radius)
  • Microcephaly
  • Ophthalmic anomalies
  • Genitourinary tract anomalies

Laboratory findings

  • Macrocytosis
  • Increased fetal hemoglobin (often precedes anemia)
  • Cytopenia (especially thrombocytopenia, leukopenia and neutropenia)

Pathology findings

  • Progressive bone marrow failure
  • Adult-onset aplastic anemia
  • Myelodysplastic syndrome (MDS)
  • Acute myelogenous leukemia (AML)
  • Early-onset solid tumors (e.g., squamous cell carcinomas of the head and neck, esophagus, and vulva; cervical cancer; and liver tumors)
  • Inordinate toxicities from chemotherapy or radiation

Establishing the Diagnosis

The diagnosis of FA is established in a proband with the following findings:

  • Increased chromosome breakage and radial forms on cytogenetic testing of lymphocytes with diepoxybutane (DEB) and mitomycin C (MMC)
    Note: (1) The background rate of chromosome breakage in control chromosomes is more variable with MMC; thus, some centers use DEB while other centers use both DEB and MMC. (2) If results of lymphocyte testing are normal or inconclusive and mosaicism is suspected, testing can be performed on an alternative cell type, such as skin fibroblasts. See Fanconi Anemia: Guidelines for Diagnosis and Management.
  • Identification of biallelic pathogenic variants in one of the 16 genes known to cause autosomal recessive FA, or a heterozygous pathogenic variant in RAD51 known to cause autosomal dominant FA, or a hemizygous pathogenic variant in FANCB, known to cause X-linked FA (see Table 1)

Molecular testing approaches can include serial single-gene testing, use of a multi-gene panel, and more comprehensive genomic testing.

  • Serial single-gene testing. Sequence analysis of FANCA can be performed first, and followed by gene-targeted FANCA deletion/duplication analysis if only one or no pathogenic variant is found.
  • A multi-gene panel that includes the genes in Table 1a and Table 1b and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multi-gene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multi-gene panel provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost while limiting secondary findings. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing based tests.
  • More comprehensive genomic testing (when available) including whole-exome sequencing (WES) and whole-genome sequencing (WGS) may be considered if serial single-gene testing (and/or use of a multi-gene panel) fails to confirm a diagnosis in an individual with features of Fanconi anemia. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For issues to consider in interpretation of genomic test results, click here.

Table 1a.

Molecular Genetics of Fanconi Anemia: Most Common Genetic Causes

Gene 1, 2Complementation Group 3% of FA Attributed to Pathogenic Variants in This Gene 4Proportion of Pathogenic Variants 5 Detected by Test Method
Sequence analysis 6Gene-targeted deletion/duplication analysis 7
BRCA2FA-D1~3%>90%None reported
BRIP1FA-J~2%>90%None reported
FANCAFA-A60%-70%~60%>20 deletion/duplication variants reported; see HGMD
FANCBFA-B~2%UnknownDeletion/duplication variants reported; see HGMD
FANCCFA-C~14%UnknownSeveral deletion/duplication variants reported; see HGMD
FANCD2FA-D2~3%UnknownMultiple deletion/duplication variants reported; see HGMD
FANCEFA-E~3%>90%None reported
FANCFFA-F~2%UnknownDeletion/duplication variants reported; see HGMD
FANCGFA-G~10%>90%None reported
FANCIFA-I~1%UnknownDeletion/duplication variant reported; see HGMD

Pathogenic variants of any one of the genes included in this table account for >1% of FA

1.

Genes are listed in alphabetic order.

2.
3.

Prior to identification of the genes, complementation groups were defined based on somatic cell-based methods. While complementation analysis testing has been supplanted by multi-gene panels; this terminology continues to be used in some contexts.

4.
5.

See Molecular Genetics for information on pathogenic allelic variants detected.

6.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

7.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

Table 1b.

Molecular Genetics of Fanconi Anemia: Less Common Genetic Causes

Gene 1, 2, 3Complementation Group 4Comment
ERCC4FA-Q2 individuals w/FA & biallelic ERCC4 pathogenic variants reported [Bogliolo et al 2013]; functional studies of ERCC4 missense variants reported by Osorio et al [2013].
FANCLFA-L13 FANCL pathogenic variants reported [Chandrasekharappa et al 2013, Nicchia et al 2015, Vetro et al 2015]
FANCMFA-MAssignment of a formal complementation group for persons w/FANCM pathogenic variants still controversial as only 1 reference family/cell line has been identified & that cell line has been determined to have biallelic pathogenic variants in both FANCA & FANCM. Of note, under experimental conditions specific knockdown of FANCM alone results in an FA phenotype [Singh et al 2009]
PALB2FA-N14 PALB2 pathogenic variants reported including a deletion of exons 1-10 [Reid et al 2007, Xia et al 2007, Byrd et al 2016]
RAD51FA-R2 individuals w/features of FA & a de novo RAD51 pathogenic variant reported [Ameziane et al 2015, Wang et al 2015]
RAD51CFA-OAssignment of a formal complementation group for persons w/RAD51C pathogenic variants still controversial as only 1 reference consanguineous family identified [Vaz et al 2010]
SLX4FA-PAssignment of a formal complementation group for persons with SLX4 pathogenic variants still controversial as only a handful of reference families have been identified & SLX4 biology falls outside previously characterized FA proteins [Kim et al 2011, Stoepker et al 2011]
UBE2TFA-T1 individual w/biallelic UBE2T pathogenic variants including a large paternal deletion & a maternal duplication reported [Rickman et al 2015, Virts et al 2015]

Pathogenic variants of any one of the genes listed in this table are reported in only a few families (i.e., <1% of FA)

1.

Genes are listed in alphabetic order.

2.
3.

Genes are not described in detail in Molecular Genetics but may be included here (pdf).

4.

Prior to identification of the genes, complementation groups were defined based on somatic cell-based methods this terminology continues to be used in some contexts.

Clinical Characteristics

Clinical Description

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

Physical features occur in approximately 75% of individuals with FA.

  • Growth deficiency: prenatal and/or postnatal short stature, low birth weight
  • Abnormal skin pigmentation (40%): generalized hyperpigmentation; café au lait macules, hypopigmentation
  • Skeletal malformations of upper limbs, unilateral or bilateral (35%):
    • Thumbs (35%): absent, hypoplastic, bifid, duplicated, triphalangeal, long, proximally placed
    • 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
  • Skeletal malformations of lower limbs (5%)
    • Syndactyly, abnormal toes, club feet
    • Congenital hip dislocation
  • Microcephaly (20%)
  • Ophthalmic (20%): microphthalmia, cataracts, astigmatism, strabismus, epicanthal folds, hypotelorism, hypertelorism, ptosis
  • Genitourinary tract anomalies:
    • Renal (20%): horseshoe, ectopic, pelvic, hypoplastic, dysplastic, or absent kidney; hydronephrosis or hydroureter
    • Males (25%). Hypospadias, micropenis, cryptorchidism, anorchia, hypo- or azoospermia, reduced fertility
    • Females (2%). bicornuate or uterus malposition, small ovaries
      Note: Pregnancy is possible in females, whether or not they have undergone hematopoietic stem cell transplantation.
  • Endocrine: hypothyroidism, glucose/insulin abnormalities
  • Hearing loss, usually conductive secondary to middle ear bony anomalies; abnormal ear shape: dysplastic, narrow ear canal, abnormal pinna (10%)
  • Congenital heart defect (6%): patent ductus arteriosus, atrial septal defect, ventricular septal defect, coarctation of the aorta, truncus arteriosus, situs inversus
  • Gastrointestinal (5%): esophageal, duodenal, or jejunal atresia, imperforate anus, tracheoesophageal fistula, annular pancreas, malrotation
  • Central nervous system (3%): small pituitary, pituitary stalk interruption syndrome, absent corpus callosum, cerebellar hypoplasia, hydrocephalus, dilated ventricles
  • Other
    • Facial features (2%): triangular, micrognathia, mid-face hypoplasia
    • Spine anomalies (2%): spina bifida, scoliosis, hemivertebrae, rib anomalies, coccygeal aplasia
    • Neck anomalies (1%): Sprengel deformity, Klippel-Feil anomaly, short or webbed neck, low hairline

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

Developmental delay and/or intellectual disability (10%)

Bone marrow failure. The age of onset is highly variable, even among siblings. An analysis of 754 individuals with pathogenic variants in FANCA, FANCC, and FANCG identified an average age of onset of 7.6 years. Rarely, bone marrow failure can present in infants and small children [Shimamura & Alter 2010]. The risk of developing any hematologic abnormality is 90% by age 40 years [Kutler et al 2003].

  • Thrombocytopenia or leukopenia usually precede anemia. These are commonly associated with macrocytosis and elevated fetal hemoglobin.
  • Pancytopenia generally worsens over time.
  • Sweet syndrome (neutrophilic skin infiltration) was associated with progression of hematologic disease in six out of seven individuals with FA [Giulino et al 2011].
  • The severity of bone marrow failure can be classified by the degree of cytopenia(s) (Table 3). Importantly, to meet these criteria for marrow failure, the cytopenias must be persistent and unexplained by other causes.

Table 2.

Severity of Bone Marrow Failure in Fanconi Anemia

MildModerateSevere
Absolute neutrophil count (ANC)<1,500/mm3<1,000/mm3<500/mm3
Platelet count150,000-50,000/mm3<50,000/mm3<30,000/mm3
Hemoglobin (Hb) level≥8 g/dL<8 g/dL<8 g/dL

Cancer susceptibility. The relative risk for acute myelogenous leukemia (AML) is increased approximately 500-fold [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 individuals diagnosed between ages 15 and 35 years.

An increased risk of developing myelodysplastic syndrome (MDS)/AML is associated with monosomy 7 and most 7q deletions. Clonal amplifications of chromosome 3q26-q29 were reported in association with an increased risk of progression to MDS/AML [Neitzel et al 2007, Mehta et al 2010].

Solid tumors may be the first manifestation of FA in individuals who have no birth defects and have not experienced bone marrow failure.

  • Head and neck squamous cell carcinomas (HNSCCs) are the most common solid tumor in individuals with FA. The incidence is 500- to 700-fold higher than in the general population. The HNSCCs in FA show distinct differences compared to HNSCCs seen in the general population. HNSCCs:
    • Occur at an earlier age (20-40 years) than in the general population;
    • Are most commonly in the the oral cavity (e.g., tongue);
    • Present at an advanced stage;
    • Respond poorly to therapy.
  • Individuals with FA are at increased risk for second primary cancers in the skin and genitourinary tract. The pattern of second primaries resembles that observed in HPV-associated HNSCC in the general population [Morris et al 2011].
  • Individuals with FA receiving androgen treatment for bone marrow failure are also at increased risk for liver tumors.

Phenotype Correlations by Gene

BRCA2. Biallelic pathogenic variants in BRCA2 are associated with early-onset acute leukemia and solid tumors [Hirsch et al 2004, Wagner et al 2004, Myers et al 2012]. The cumulative probability of any malignancy was 97% by age six years, including AML, medulloblastoma, and Wilms tumor [Alter et al 2007].

FANCG. Pathogenic variants in FANCG may be associated with severe marrow failure and a higher incidence of leukemia compared to FANCC [Faivre et al 2000].

PALB2. Solid tumors (e.g., medulloblastoma, Wilms tumor) are associated with PALB2 pathogenic variants [Reid et al 2007].

Genotype-Phenotype Correlations

The clinical spectrum of FA remains heterogenous. There are no clearcut genotype-phenotype correlations [Neveling et al 2009]. In general, null variants lead to a more severe phenotype (e.g., congenital anomalies, early-onset bone marrow failure, and MDS/AML) than hypomorphic variants.

BRCA2. All persons with an IVS7 pathogenic variant in BRCA2 developed AML by age three years; those with other BRCA2 pathogenic variants who developed AML did so by age six years [Alter 2006].

FANCA. Individuals who are homozygous for null pathogenic variants in FANCA may have earlier onset of anemia and higher incidence of leukemia than individuals with pathogenic variants that permit production of an abnormal FANCA protein [Faivre et al 2000].

FANCC

Prevalence

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

The ratio of males to females is 1.2:1 (p <0.001 vs expected 1.00).

Rosenberg et al [2011] showed higher carrier rates for FA than previously reported. Carrier frequency was 1:181 in North Americans and 1:93 in Israel. Specific populations have founder variants with increased carrier frequencies (<1:100), including Ashkenazi Jews (FANCC, BRCA2), northern Europeans (FANCC), Afrikaners (FANCA), sub-Saharan Blacks (FANCG), Spanish Gypsies (FANCA), and others.

Differential Diagnosis

Cells derived from individuals with other chromosome breakage syndromes, such as Bloom syndrome or ataxia-telangiectasia, may also exhibit high rates of spontaneous chromosome breakage; however, only FA cells exhibit increased chromosome breakage in response to diepoxybutane (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 chromosome breakage with mitomycin C (MMC) [Chrzanowska et al 2012]. Inheritance is autosomal recessive. NBS may be distinguished from FA by NBN molecular genetic testing, which identifies pathogenic variants 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. Inheritance is autosomal recessive. Biallelic pathogenic variants in ATR, NIN, ATRIP, RBBP8, CEP152, CENPJ, and CEP63 are causative.

Other disorders including neurofibromatosis 1 (which could be considered because of café au lait macules), TAR syndrome (thrombocytopenia with absent radii), and VACTERL association (radial ray defects) (OMIM) can be distinguished from FA by testing for chromosome breakage with DEB and MMC.

Management

Evaluations Following Initial Diagnosis

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

  • Evaluation by a hematologist, to include complete blood count, fetal hemoglobin, full blood typing, blood chemistries (assessing liver, kidney, and iron status), and bone marrow aspirate for cell morphology, FISH and cytogenetics, as well as biopsy for cellularity
    Note: The bone marrow of individuals with FA can exhibit signs of dysplasia, such as nuclear/cytoplasmic dys-synchrony, hypo-lobulated megakaryocytes, and bi-nucleated erythroid cells. These features must be distinguished from true forms of MDS by a hematopathologist experienced in the evaluation of MDS in individuals with FA.
  • HLA typing of the affected individual, sibs, and parents for consideration of hematopoietic stem cell transplantation
  • Examination by an ophthalmologist
  • Ultrasound examination of the kidneys and urinary tract
  • Formal hearing evaluation
  • Echocardiogram
  • Referral to an endocrinologist
  • Developmental assessment (particularly important for toddlers and school-age children)
  • Referrals as indicated to an otolaryngologist, hand surgeon, gastroenterologist, gynecologist, and urologist
  • Evaluation by a clinical geneticist and genetic counseling

Treatment of Manifestations

Recommendations for treatment were agreed upon at a 2014 consensus conference (full text).

Androgens improve (at least transiently) the red cell and platelet counts in approximately 50% of individuals. Androgen therapy can be considered when the hemoglobin drops below 8 g/dL or the platelet count falls below 30,000/mm3 ('severe' – see Table 2). Although only 10%-20% of individuals receiving continuous low-dose androgen therapy are long-term responders, this option can be particularly useful for individuals who do not have access to or are not ready for hematopoietic stem cell transplant (HSCT), or to individuals for whom of a suitable donor is not available.

  • Oxymetholone, given orally at a starting dose of 2 mg/kg/day, may be increased up to 5 mg/kg/day.
  • Doses may be slowly tapered to the minimal effective dose with careful monitoring of the blood counts.
  • Other synthetic androgens used in FA include stanazolol in Asia, and oxandrolone and danazol in North America.

Side effects of androgen administration include virilization and liver toxicity such as elevated liver enzymes, cholestasis, peliosis hepatis (vascular lesion with multiple blood-filled cysts), and hepatic tumors. Individuals taking androgens should be monitored for liver tumors and undergo regular liver function tests (LFT) for abnormalities. Blood tests for LFTs should be performed every three to six months; liver ultrasound should be performed every six to 12 months. If no response is seen after three to four months, androgens should be discontinued [Scheckenbach et al 2012, Rose et al 2014].

Granulocyte colony-stimulating factor (G-CSF) improves the neutrophil count in some individuals. G-CSF dose should be titrated to the lowest possible dose and frequency to keep ANC above 1,000/mm3. Note: (1) A bone marrow aspirate and biopsy should be performed prior to the initiation of G-CSF and monitored every six months throughout treatment, given the theoretic risk of stimulating the growth of a leukemic clone. (2) G-CSF should be administered in consultation with an FA expert.

Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for the hematologic manifestations, including aplastic anemia, myelodysplastic syndrome, and acute leukemia. Ideally, HSCT is performed prior to onset of MDS/AML and before multiple transfusions [MacMillan & Wagner 2010, Mehta et al 2010]. Individuals with FA are sensitive to chemotherapy and radiation, need special transplant regimens, and should be cared for and transplanted at centers with the most experience in HSCT in FA.

A multi-institutional study reported a one-year probability of overall survival of 80% in 43 individuals with FA transplanted for marrow failure and/or MDS, using alternative donors (including mismatched related and unrelated donors) and chemotherapy-only preparative regimen. Survival for individuals younger than age ten years transplanted for marrow failure was even better, at 91.3% (±5.9%) [Mehta et al 2015].

Fludarabine reduced the incidence of graft failure and allowed for removal of radiation from the preparative regimens in a matched sib donor setting [MacMillan et al 2015].

MDS/AML treatment remains challenging. Options include chemotherapy, HSCT with or without prior induction chemotherapy, and investigational trials. Chemotherapy should be undertaken in coordination with centers experienced with FA, as it can cause severe, prolonged, or irreversible myelosuppression. Plans for HSCT should be in place prior to starting chemotherapy. Published reports of chemotherapy regimens for AML in individuals with FA are sparse and limited by the unclear benefit to the overall outcome due to the lack of longitudinal follow up [Mehta et al 2007, Talbot et al 2014, Beier et al 2015].

Solid tumors. Prompt, aggressive workup for any symptoms suggestive of a malignancy is indicated. Early detection and surgical removal remains the mainstay of therapy. Treatment is challenging secondary to the increased toxicity associated with chemotherapy and radiation in FA. Data is limited on use of chemotherapy at standard doses or reduced doses and schedules in individuals with FA, and there are reports of severe or fatal toxicities and poor treatment outcomes [Masserot et al 2008, Hosoya et al 2010, Tan et al 2011, Spanier et al 2012]. Individuals diagnosed with a genital tract cancer should be referred to a gynecologic oncologist immediately, and care should be coordinated with FA experts.

Prevention of Primary Manifestations

Human papilloma virus (HPV) vaccination should be initiated at age nine years in order to reduce the risk of gynecologic cancer in females, and possibly reduce the risk of oral cancer in all individuals.

Prevention of Secondary Complications

Individuals with FA treated with HSCT who developed graft vs host disease (GVHD) had a 28% incidence of head and neck cancers in the ten years following treatment (vs 0% in those without GVHD); this finding points to the importance of minimizing the risk of GVHD [Guardiola et al 2004]. Increased risk for GVHD observed in earlier studies was reduced significantly by T-cell depletion of the donor graft [Chaudhury et al 2008, MacMillan et al 2015].

Individuals successfully treated with HSCT are at increased risk for solid tumors, in addition to the baseline increased risk [Rosenberg et al 2005]. Due to the known contribution of radiation to the long-term complication of secondary solid tumors most recent efforts have focused on using a conditioning regimen without radiation even in an unrelated donor setting. German and Brazilian groups now report excellent outcomes with alternative donors with a 'chemotherapy-only' preparative regimen in single-center studies. The study from Germany showed 88% survival and normal hematopoiesis at a median follow up of 30 months [Bonfim et al 2015, Chao et al 2015].

Surveillance

See 2014 consensus guidelines [Frohnmayer et al 2014] (full text).

  • Annual evaluation with a multidisciplinary team including an endocrinologist
  • Regular blood counts, every three to four months while stable and more often as needed
  • Bone marrow aspirate/biopsy at least annually to evaluate morphology, cellularity (from the biopsy), FISH, and cytogenetics (the latter two for emergence of a malignant clone). Individuals on GCSF need to have a bone marrow aspirate/biopsy every six months, if possible.
  • In individuals who develop Sweet syndrome (neutrophilic skin infiltration), prompt investigation for hematologic disease progression including bone marrow evaluation

Notes: (1) Progressively changing blood counts without a potential cause (e.g., acute infection or suppression from medication) require immediate evaluation with a complete blood count and bone marrow examination with FISH and cytogenetics. (2) It is important to recognize that rising blood counts can be due to either the development of MDS/AML or, rarely, reversion of a germline mutation in a stem cell, which repopulates the marrow with normal cells (somatic stem cell mosaicism). These individuals may require immediate HSCT (for MDS/AML) or continued close monitoring with complete blood counts at least every one to two months and a bone marrow examination with cytogenetics every six months.

Individuals receiving androgen therapy

  • Liver function tests every three to six months
  • Liver ultrasound examination every six to 12 months for androgen-related changes, including tumors

Cancer surveillance

  • Annual gynecologic assessment for genital lesions beginning at age 13. Thorough vulvo-vaginal examinations and Pap smear can begin when women become sexually active or by age 18 years, whichever is earlier. Suspicious genital tract lesions should be biopsied.
  • Examination every six months for oral, head, and neck cancers beginning by age nine to ten years. Screening should be performed by a dentist, oral surgeon, or ENT familiar with FA. Nasolaryngoscopy starting at age ten years, or within the first year after HSCT. Individuals with difficulty or pain with swallowing should be evaluated for esophageal cancer.
  • For individuals with a history of premalignant or malignant lesions: surveillance examinations every two to three months
  • For individuals with biallelic pathogenic variants in BRCA2: screening for neuroblastomas, brain tumors, and kidney tumors every six months (see also Risk to Family Members – Autosomal Recessive FA)

Agents/Circumstances to Avoid

Blood transfusions. Blood products should be cytomegalovirus (CMV)-safe and irradiated. To reduce the chances of sensitization, family members must not act as blood donors. Once an individual requires transfusions, he/she should be referred for transplantation.

Toxic agents to avoid include smoking, second-hand smoke, and alcohol, which have been implicated in tumorigenesis.

Unsafe sex practices increase the risk for HPV-associated malignancy.

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 evaluate all sibs of an affected individual in order to identify as early as possible those who would benefit from appropriate monitoring for physical abnormalities, bone marrow failure, and related cancers.

  • DEB/MMC testing can be used to clarify the disease status of at-risk sibs.
  • If the pathogenic variant(s) in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs.

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 [Dalle et al 2004, Nabhan et al 2010].

Pregnancy needs to be managed by a high-risk maternal fetal obstetrician along with a hematologist.

Therapies Under Investigation

Previous clinical trials failed to accomplish permanent gene correction of stem cells; current work is focusing on development of novel vector and delivery strategies [Tolar et al 2011]. The first FA lentiviral gene therapy trial led by the University of Washington/Fred Hutchinson Cancer Research Center is now open [Becker et al 2010]. Dr. Juan Bueren has an open trial of a hematopoietic stem cell mobilization in Madrid, Spain and plans to have their FANCA gene therapy trial opened soon.

A Phase I study of the antioxidant quercetin in children with Fanconi anemia is currently underway at Cincinnati Children's Hospital Medical Center.

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

Fanconi anemia (FA) is inherited in an autosomal recessive manner, an autosomal dominant manner (RAD51-related FA), or an X-linked manner (FANCB-related FA).

Risk to Family Members — Autosomal Recessive FA

Parents of a proband

Sibs of a proband

Offspring of a proband. The offspring of an individual with autosomal recessive FA are obligate heterozygotes (carriers) for a pathogenic variant in an FA-related gene.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier for a pathogenic variant in an FA-related gene.

Carrier (Heterozygote) Detection

  • Carrier testing for at-risk relatives requires prior identification of the FA-related pathogenic variants in the family.
  • Carriers of FA cannot be detected by the DEB/MMC test.

Risk to Family Members — Autosomal Dominant FA

Parents of a proband

  • To date, reported probands with RAD51-related FA have the disorder as a result of a de novo RAD51 pathogenic variant.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include molecular genetic testing.

Sibs of a proband. All affected individuals reported to date have had a de novo RAD51-related FA pathogenic variant, suggesting a low risk to sibs. However, because of the theoretic possibility of germline mosaicism in a parent, the risk is presumed to be greater than in the general population.

Offspring of a proband. Each child of an individual with RAD51-related FA is presumed to have a 50% chance of inheriting the pathogenic variant. However, only one individual with RAD51-related FA has reached adulthood and no offspring have been reported.

Other family members. Given that all probands with RAD51-related FA reported to date have the disorder as a result of a de novo RAD51 pathogenic variant, the risk to other family members is presumed to be low.

Risk to Family Members — X-Linked FA

Parents of a male proband

  • The father of a male with X-linked FA will not have the disorder nor will he be hemizygous for the FANCB pathogenic variant; therefore, he does not require further evaluation/testing.
  • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier).
    Note: If a woman has more than one affected son and if the pathogenic variant cannot be detected in her leukocyte DNA, she has germline mosaicism.
  • If a male is the only affected family member (i.e., a simplex case), the mother may be a carrier or the affected male may have a de novo FANCB pathogenic variant, in which case the mother is not a carrier.

Sibs of a male proband. The risk to sibs depends on the genetic status of the mother:

  • If the mother of the proband has a FANCB 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 proband represents a simplex case (i.e., a single occurrence in a family) and if the FANCB pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is low but greater than that of the general population because of the possibility of maternal germline mosaicism.

Offspring of a male proband

  • Affected males transmit the FANCB pathogenic variant to all of their daughters (who will be carriers and will usually not be affected) and none of their sons.
  • To date, no male with FA-B has been old enough to have children; they may also 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 heterozygotes (carriers) for the FANCB pathogenic variant and the aunt's offspring, depending on their gender, may be at risk of being carriers or of being affected.

Note: Molecular genetic testing may be able to identify the family member in whom a de novo pathogenic variant arose – information that could help determine genetic risk status of the extended family.

Heterozygote (Carrier) Detection

Carrier testing for at-risk female relatives requires prior identification of the FANCB pathogenic variant in the family.

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

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.

Family planning

  • The optimal time for determination of genetic risk, clarification of genetic 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 and Preimplantation Genetic Diagnosis

Molecular genetic testing. Once the FA-related pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk for FA and preimplantation genetic diagnosis are possible options. Preimplantation genetic diagnosis has successfully identified at-risk embryos as unaffected with FA and HLA-matched to affected sibs [Kahraman et al 2014].

Chromosome 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 chromosome breakage in fetal cells obtained by chorionic villus sampling (CVS) or amniocentesis; however, if the pathogenic variants are known in the family, molecular genetic testing is the method of choice for prenatal diagnosis.

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.

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
  • National Cancer Institute Inherited Bone Marrow Failure Syndromes (IBMFS) Cohort Registry
    Phone: 800-518-8474
    Email: NCI.IBMFS@westat.com
  • Prospective Registry of MultiPlex Testing (PROMPT)
    PROMPT is an online research registry for patients and families who have undergone multiplex genetic testing and were found to have a genetic variation which may be linked to an increased risk of having cancer.

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

GeneChromosome LocusProteinLocus SpecificHGMD
BRCA213q13​.1Breast cancer type 2 susceptibility proteinBRCA2 homepage - LOVD
Fanconi Anaemia Mutation Database (FANCD1 - BRCA2)
BRCA2 @ ZAC-GGM
Database of BRCA1 and BRCA2 sequence variants that have been clinically reclassified using a quantitative integrated evaluation
Breast Cancer Information Core (BRCA2)
BRCA2
BRIP117q23​.2Fanconi anemia group J proteinBRIP1 @ LOVD
Fanconi Anaemia Mutation Database (FANCJ - BRIP1)
BRIP1
FANCA16q24​.3Fanconi anemia group A proteinFanconi Anemia Mutation Database (FANCA)FANCA
FANCBXp22​.2Fanconi anemia group B proteinFANCB @ LOVD
Fanconi Anaemia Mutation Database (FANCB)
FANCB
FANCC9q22​.32Fanconi anemia group C proteinFanconi Anemia Mutation Database (FANCC)FANCC
FANCD23p25​.3Fanconi anemia group D2 proteinFanconi Anaemia Mutation Database (FANCD2)FANCD2
FANCE6p21​.31Fanconi anemia group E proteinFanconi Anaemia Mutation Database (FANCE)FANCE
FANCF11p14​.3Fanconi anemia group F proteinFanconi Anaemia Mutation Database (FANCF)FANCF
FANCG9p13​.3Fanconi anemia group G proteinFanconi Anaemia Mutation Database (FANCG)FANCG
FANCI15q26​.1Fanconi anemia group I proteinFanconi Anemia Mutation Database (FANCI)FANCI
FANCL2p16​.1E3 ubiquitin-protein ligase FANCLFanconi Anaemia Mutation Database (FANCL)FANCL
FANCM14q21​.2Fanconi anemia group M proteinFanconi Anaemia Mutation Database (FANCM)FANCM
PALB216p12​.2Partner and localizer of BRCA2Fanconi Anaemia Mutation Database (FANCN - PALB2)
Fanconi anemia database (FANCN)
PALB2 database
PALB2
RAD51C17q22DNA repair protein RAD51 homolog 3RAD51C @ LOVDRAD51C
SLX416p13​.3Structure-specific endonuclease subunit SLX4SLX4 @ LOVDSLX4
UBE2T1q32​.1Ubiquitin-conjugating enzyme E2 TUBE2T

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein 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)

133520EXCISION REPAIR, COMPLEMENTING DEFECTIVE, IN CHINESE HAMSTER, 4; ERCC4
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
610538UBIQUITIN-CONJUGATING ENZYME E2T; UBE2T
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
615272FANCONI ANEMIA, COMPLEMENTATION GROUP Q; FANCQ
616435FANCONI ANEMIA, COMPLEMENTATION GROUP T; FANCT

See Table A for gene and protein names.

For a table of Fanconi anemia-associated proteins and their function, click here and download pdf [Wang & Smogorzewska 2015].

Molecular Genetic Pathogenesis

At least fifteen genes that are involved in Fanconi anemia (FA) and also account for each of the phenotypic complementation groups have been identified. 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, D'Andrea 2010, Deans & West 2011, Kee & D'Andrea 2012]. Disruption of this pathway leads to the common cellular and clinical abnormalities observed in FA [D'Andrea 2010, Nakanishi et al 2011, Williams et al 2011b, Crossan & Patel 2012, Kim & D'Andrea 2012].

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 is interdependent [Smogorzewska et al 2007]. A nuclease, FAN1, has been shown to bind to monoubiquitinated 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 FANCD1) is a tumor suppressor that confers breast cancer susceptibility [Howlett et al 2002] and has a distinct clinical phenotype [Wagner et al 2004, Alter et al 2007, Myers et al 2012]. BRCA2 protein stability and localization is regulated by PALB2 (partner and localizer of BRCA2) [Xia et al 2006] encoded by PALB2 (previously FANCN), another breast cancer susceptibility gene [Rahman et al 2007]. Another breast cancer susceptibility gene [Seal et al 2006], BRIP1 (previously BACH1 or FANCJ) [Cantor et al 2001], is also assoicated with FA [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]. BRIP1 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 monoubiquitinated 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 BRIP1 [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:

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 homologous recombinantion, may be the most direct function of FA proteins in bypass of the lesion [Ho & Schärer 2010, Song et al 2010].

For reviews of the molecular biology of FA, see Nakanishi et al [2011], Williams et al [2011b], Crossan & Patel [2012], Kim & D'Andrea [2012], and Huang et al [2014].

BRCA2 (previously FANCD1)

Gene structure. BRCA2 has 27 exons (NM_000059.3).

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 [Davies et al 2001, Moynahan et al 2001]. Other functions of BRCA2 include stabilizing stalled replication forks and regulating cytokinesis [Daniels et al 2004]. BRCA2 works 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.

BRIP1 (previously FANCJ or BACH1)

Gene structure. BRIP1 (NM_032043.2) has 20 exons.

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, Chen et al 2014, Zou et al 2014]. FANCJ acetylation regulates DNA damage response [Xie et al 2012], and it 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, Wu et al 2012, Brosh & Cantor 2014, Sommers et al 2014]. FANCJ engages stable G4/G-quadruplex structures [Sarkies et al 2012, Castillo Bosch et al 2014], promotes stability of FAND2/FANCI [Zhang et al 2010, Clark et al 2015], and its helicase domain clearly is important for FA pathway function [Wu & Brosh 2009, Guo et al 2014]. FANCJ also appears to interdigitate with the mismatch repair pathway in binding to MLH1 [Cantor & Xie 2010] and centrosome amplification [Zou et al 2013].

Abnormal gene product. See Molecular Genetic Pathogenesis.

FANCA

Gene structure. The longest transcript variant NM_000135.2 has 43 exons.

Pathogenic allelic variants. The pathogenic variants 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 3.

Selected FANCA Pathogenic Allelic Variants

DNA Nucleotide ChangePredicted Protein 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 NM_000135.2 has 1455 amino acids and is a component of the FA core complex. FANCA contains two overlapping bipartite nuclear localization signals (NLS), five functional leucine-rich nuclear export sequences, 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, a client of Hsp90 [Oda et al 2007]; it is phosphorylated by the ATR kinase at serine 1449 [Collins et al 2009]. Reports show that FANCA interacts with FA binding protein FAAP20 [Ali et al 2012, Leung et al 2012], is co-regulated with BRCA1 [Haitjema et al 2014], and its deletion dysregulates murine T regulatory cells [Du et al 2014]. With FANCC it modulates the toll-like receptor pathway [Garbati et al 2013] and – critically – safeguards cell cycle integrity in hematopoietic cells [Abdul-Sater et al 2015].

Abnormal gene product. See Molecular Genetic Pathogenesis.

FANCB

Gene structure. FANCB has ten exons with the translation start in exon 3 (NM_001018113.1).

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]. FANCB is relevant to normal development – as is evidenced by its dysfunction being linked to VACTERL association [McCauley et al 2011, Umaña et al 2011].

Abnormal gene product. See Molecular Genetic Pathogenesis.

FANCC

Gene structure. FANCC has 15 exons.

Pathogenic allelic variants. Three common pathogenic variants in FANCC have been identified (c.456+4A>T, c.1642C>T, and c.67delG) [Whitney et al 1993]. See Table A.

Table 4.

Selected FANCC Pathogenic Allelic Variants

DNA Nucleotide Change
(Alias 1)
Predicted Protein ChangeReference Sequences
c.456+4A>T 2, 3
(IVS4+4A>T)
--NM_000136​.2
NP_000127​.2
c.37C>T 3, 4p.Gln13Ter
c.67delG 4, 5
(322delG)
p.Asp23IlefsTer23
c.1642C>T 4, 5p.Arg548Ter
c.1661T>C 3p.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

2.

Found primarily in the Ashkenazi Jewish population; but also reported in a Japanese cohort.

3.
4.

Prevalent in individuals of northern European ancestry

5.

Found in individuals from southern Italy

Normal gene product. FANCC has 558 amino acids. It is a component of the FA core complex, but localizes to both the nucleus and the cytoplasm [Yamashita et al 1994]. Some functions of FANCC outside of the FA core complex have also been 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]. Further, FANCC binds to microtubule-associated protein stathmin-1 to regulate cytokinesis [Magron et al 2015].

Abnormal gene product. See Molecular Genetic Pathogenesis.

FANCD2

Gene structure. FANCD2 has two transcript variants. Variant 1 (NM_033084.3) has 43 exons; variant 2 (NM_001018115.1) has 44 exons and an alternate 3' coding sequence resulting in a shorter and distinct C-terminus. FANCD2 protein encoded by variant 2 (exon 44 form) is the functional FANCD2 protein, while the other transcript variant encodes a non-functional protein [Montes de Oca et al 2005].

Pathogenic allelic variants. See Table A.

Normal gene product. The functional FANCD2 (NP_001018125.1) 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- (also known as FANCT [Hira et al 2015, Rickman et al 2015, Virts et al 2015]), and FANCI-dependent manner [Sato et al 2012, Rajendra et al 2014]. Reports illuminated the structure of FANCI-FAND2 complex [Joo et al 2011], its coordinate nuclear targeting [Boisvert et al 2013], and its RAD18-mediated chromatin loading [Song et al 2010, Williams et al 2011a]. Monoubiquitinated FANCD2 is translocated to chromatin fraction – recruited by UHRF1 [Liang et al 2015] – to form nuclear foci with FANCI, BRCA1 (FANCS [Sawyer et al 2015]), BRCA2, RAD51, and other partners. FANCD2 can be phosphorylated by ATM [Taniguchi et al 2002b, Ho et al 2006] and by ATR [Andreassen et al 2004, Pichierri & Rosselli 2004] in response to DNA damage. 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], in replication fork processes [Zhu et al 2015b], binding to mini-chromosome maintenance proteins in control of replisome [Lossaint et al 2013]. A nuclease, FAN1, has been demonstrated to bind to FANCD2 [Huang & D'Andrea 2010, Kratz et al 2010, MacKay et al 2010], and to promote DNA interstrand cross-link repair [Smogorzewska et al 2010, Yoshikiyo et al 2010].

Abnormal gene product. See Molecular Genetic Pathogenesis.

FANCE

Gene structure. FANCE has 14 exons (NM_021922.2).

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 and recruits it to the FA E3 ligase complex [Polito et al 2014]. FANCE contains two nuclear localization signals (NLS) and its nuclear accumulation depends on FANCC [Léveillé et al 2006]. FANCE has five tandem repeats of a short helical motif (FANC repeats) [Nookala et al 2007]. It functions as a shuttle protein between the FA core complex and FANCD2 in a fashion dependent on phosphorylation [Wang et al 2007], with functionality dependent on alternative splicing [Bouffard et al 2015].

Abnormal gene product. See Molecular Genetic Pathogenesis.

FANCF

Gene structure. FANCF has a single exon (NM_022725.2).

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], and – recently – next-generation sequencing refined genotype-phenotype correlations [Nicchia et al 2015].

Abnormal gene product. See Molecular Genetic Pathogenesis.

FANCG

Gene structure. FANCG has 14 exons (reference sequence NM_004629.1).

Pathogenic allelic variants. 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), and p.Gly395TrpfsTer5 [Demuth et al 2000] and p.Trp599ProfsTer49 [Auerbach et al 2003] (northern European). See Table A.

Table 5.

Selected FANCG Pathogenic Allelic Variants

DNA Nucleotide Change
(Alias 1)
Predicted Protein 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 [Blom et al 2004, Wilson et al 2010]. 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, and FANCG, 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]. FANCG further associates with Rap80-BRCA1 complex in DNA repair mediated by homologous recombination [Zhu et al 2015a], and it is operational in homing of hematopoietic stem cells [Barroca et al 2012].

Abnormal gene product. See Molecular Genetic Pathogenesis.

FANCI

Gene structure. FANCI has 37 exons (NM_018193.2).

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 [Boisvert & Howlett 2014, Rajendra et al 2014]. 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 monoubiquitination [Ishiai et al 2008]. Reports illuminated the structure of FANCI-FAND2 complex [Joo et al 2011], its coordinate nuclear targeting [Boisvert et al 2013], and – remarkably – its FANCD2-independent function upstream of FA core complex recruitment [Castella et al 2015].

Abnormal gene product. See Molecular Genetic Pathogenesis.

Click here (pdf) for information on the genes less commonly involved in Fanconi Anemia (from Table 1b).

References

Literature Cited

  1. Abdul-Sater Z, Cerabona D, Potchanant ES, Sun Z, Enzor R, He Y, Robertson K, Goebel WS, Nalepa G. FANCA safeguards interphase and mitosis during hematopoiesis in vivo. Exp Hematol. 2015;43:1031–46.e12. [PMC free article: PMC4666759] [PubMed: 26366677]
  2. 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]
  3. Ali AM, Pradhan A, Singh TR, Du C, Li J, Wahengbam K, Grassman E, Auerbach AD, Pang Q, Meetei AR. FAAP20: a novel ubiquitin-binding FA nuclear core-complex protein required for functional integrity of the FA-BRCA DNA repair pathway. Blood. 2012;119:3285–94. [PMC free article: PMC3321854] [PubMed: 22343915]
  4. 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]
  5. 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; 2003:280-365.
  6. Alter BP. The association between FANCD1/BRCA2 mutations and leukaemia. Br J Haematol. 2006;133:446–8. [PubMed: 16643458]
  7. 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]
  8. 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]
  9. Ameziane N, May P, Haitjema A, van de Vrugt HJ, van Rossum-Fikkert SE, Ristic D, Williams GJ, Balk J, Rockx D, Li H, Rooimans MA, Oostra AB, Velleuer E, Dietrich R, Bleijerveld OB, Maarten Altelaar AF, Meijers-Heijboer H, Joenje H, Glusman G, Roach J, Hood L, Galas D, Wyman C, Balling R, den Dunnen J, de Winter JP, Kanaar R, Gelinas R, Dorsman JC. A novel Fanconi anaemia subtype associated with a dominant-negative mutation in RAD51. Nat Commun. 2015;6:8829. [PMC free article: PMC4703882] [PubMed: 26681308]
  10. 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]
  11. Auerbach AD, Greenbaum J, Pujara K, Batish SD, Bitencourt MA, Kokemohr I, Schneider H, Lobitzc S, Pasquini R, Giampietro PF, Hanenberg H, Levran O., International Fanconi Anemia Registry. Spectrum of sequence variation in the FANCG gene: an International Fanconi Anemia Registry (IFAR) study. Hum Mutat. 2003;21:158–68. [PubMed: 12552564]
  12. Barroca V, Mouthon MA, Lewandowski D, Brunet de la Grange P, Gauthier LR, Pflumio F, Boussin FD, Arwert F, Riou L, Allemand I, Romeo PH, Fouchet P. Impaired functionality and homing of Fancg-deficient hematopoietic stem cells. Hum Mol Genet. 2012;21:121–35. [PubMed: 21968513]
  13. Becker PS, Taylor JA, Trobridge GD, Zhao X, Beard BC, Chien S, Adair J, Kohn DB, Wagner JE, Shimamura A, Kiem HP. Preclinical correction of human Fanconi anemia complementation group A bone marrow cells using a safety-modified lentiviral vector. Gene Ther. 2010;17:1244–52. [PMC free article: PMC2927804] [PubMed: 20485382]
  14. Beier R, Maecker-Kolhoff B, Sykora K-W, Chao M, Kratz C, Sauer MG. Minimal antileukaemic treatment followed by reduced-intensity conditioning in three consecutive children with Fanconi anaemia and AML. Bone Marrow Transplant. 2015;50:463–4. [PubMed: 25531282]
  15. Berwick M, Satagopan JM, Ben-Porat L, Carlson A, Mah K, Henry R, Diotti R, Milton K, Pujara K, Landers T, Dev Batish S, Morales J, Schindler D, Hanenberg H, Hromas R, Levran O, Auerbach AD. Genetic heterogeneity among Fanconi anemia heterozygotes and risk of cancer. Cancer Res. 2007;67:9591–6. [PMC free article: PMC3622247] [PubMed: 17909071]
  16. 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]
  17. 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]
  18. Bogliolo M, Schuster B, Stoepker C, Derkunt B, Su Y, Raams A, Trujillo JP, Minguillón J, Ramírez MJ, Pujol R, Casado JA, Baños R, Rio P, Knies K, Zúñiga S, Benítez J, Bueren JA, Jaspers NG, Schärer OD, de Winter JP, Schindler D, Surrallés J. Mutations in ERCC4, encoding the DNA-repair endonuclease XPF, cause Fanconi anemia. Am J Hum Genet. 2013;92:800–6. [PMC free article: PMC3644630] [PubMed: 23623386]
  19. Bonfim C, Riberio L, Nichele S, Loth G, Kuwahara C, Koliski A, Bitencourt M, Scherer F, Rodrigues L, Pilonetto D, Pasquini R. Excellent outcomes for Fanconi anemia patients undergoing hematopoietic stem cell transplantation (HSCT) without radiation: a single center experience on 103 patients. Biol Blood Marrow Transplant. 2015;21:S94a.
  20. Boisvert RA, Howlett NG. The Fanconi anemia ID2 complex: dueling saxes at the crossroads. Cell Cycle. 2014;13:2999–3015. [PMC free article: PMC4612647] [PubMed: 25486561]
  21. Boisvert RA, Rego MA, Azzinaro PA, Mauro M, Howlett NG. Coordinate nuclear targeting of the FANCD2 and FANCI proteins via a FANCD2 nuclear localization signal. PLoS One. 2013;8:e81387. [PMC free article: PMC3836817] [PubMed: 24278431]
  22. Bouffard F, Plourde K, Bélanger S, Ouellette G, Labrie Y, Durocher F. Analysis of a FANCE Splice Isoform in Regard to DNA Repair. J Mol Biol. 2015;427:3056–73. [PubMed: 26277624]
  23. Brosh RM Jr, Cantor SB. Molecular and cellular functions of the FANCJ DNA helicase defective in cancer and in Fanconi anemia. Front Genet. 2014;5:372. [PMC free article: PMC4204437] [PubMed: 25374583]
  24. Byrd PJ, Stewart GS, Smith A, Eaton C, Taylor AJ, Guy C, Eringyte I, Fooks P, Last JI, Horsley R, Oliver AW, Janic D, Dokmanovic L, Stankovic T, Taylor AM. A Hypomorphic PALB2 Allele Gives Rise to an Unusual Form of FA-N Associated with Lymphoid Tumour Development. PLoS Genet. 2016;12:e1005945. [PMC free article: PMC4798644] [PubMed: 26990772]
  25. 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]
  26. 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]
  27. Carreau M. Not-so-novel phenotypes in the Fanconi anemia group D2 mouse model. Blood. 2004;103:2430. [PubMed: 14998919]
  28. Castella M, Jacquemont C, Thompson EL, Yeo JE, Cheung RS, Huang JW, Sobeck A, Hendrickson EA, Taniguchi T. FANCI Regulates Recruitment of the FA Core Complex at Sites of DNA Damage Independently of FANCD2. PLoS Genet. 2015;11:e1005563. [PMC free article: PMC4592014] [PubMed: 26430909]
  29. Castillo Bosch P, Segura-Bayona S, Koole W, van Heteren JT, Dewar JM, Tijsterman M, Knipscheer P. FANCJ promotes DNA synthesis through G-quadruplex structures. EMBO J. 2014;33:2521–33. [PMC free article: PMC4282361] [PubMed: 25193968]
  30. Chao MM, Kuehl JS, Strauss G, Hanenberg H, Schindler D, Neitzel H, Niemeyer C, Baumann I, von Bernuth H, Rascon J, Nagy M, Zimmermann M, Kratz CP, Ebell W. Outcomes of mismatched and unrelated donor hematopoietic stem cell transplantation in Fanconi anemia conditioned with chemotherapy only. Ann Hematol. 2015;94:1311–8. [PubMed: 25862235]
  31. Chandrasekharappa SC, Lach FP, Kimble DC, Kamat A, Teer JK, Donovan FX, Flynn E, Sen SK, Thongthip S, Sanborn E, Smogorzewska A, Auerbach AD, Ostrander EA., NISC Comparative Sequencing Program. Massively parallel sequencing, aCGH, and RNA-Seq technologies provide a comprehensive molecular diagnosis of Fanconi anemia. Blood. 2013;121:e138–48. [PMC free article: PMC3668494] [PubMed: 23613520]
  32. Chaudhury S, Auerbach AD, Kernan NA, Small TN, Prockop SE, Scaradavou A, Heller G, Wolden S, O'Reilly RJ, Boulad F. Fludarabine-based cytoreductive regimen and T-cell-depleted grafts from alternative donors for the treatment of high-risk patients with Fanconi anaemia. Br J Haematol. 2008;140:644–55. [PubMed: 18302713]
  33. Chen X, Wilson JB, McChesney P, Williams SA, Kwon Y, Longerich S, Marriott AS, Sung P, Jones NJ, Kupfer GM. The Fanconi anemia proteins FANCD2 and FANCJ interact and regulate each other's chromatin localization. J Biol Chem. 2014;289:25774–82. [PMC free article: PMC4162179] [PubMed: 25070891]
  34. Chrzanowska KH, Gregorek H, Dembowska-Bagińska B, Kalina MA, Digweed M. Nijmegen breakage syndrome (NBS). Orphanet J Rare Dis. 2012;7:13. [PMC free article: PMC3314554] [PubMed: 22373003]
  35. Ciccia A, Ling C, Coulthard R, Yan Z, Xue Y, Meetei AR. Laghmani el H, Joenje H, McDonald N, de Winter JP, Wang W, West SC. Identification of FAAP24, a Fanconi anemia core complex protein that interacts with FANCM. Mol Cell. 2007;25:331–43. [PubMed: 17289582]
  36. Clark DW, Tripathi K, Dorsman JC, Palle K. FANCJ protein is important for the stability of FANCD2/FANCI proteins and protects them from proteasome and caspase-3 dependent degradation. Oncotarget. 2015;6:28816–32. [PMC free article: PMC4745694] [PubMed: 26336824]
  37. 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]
  38. 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]
  39. 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]
  40. 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]
  41. Crossan GP, Patel KJ. The Fanconi anaemia pathway orchestrates incisions at sites of crosslinked DNA. J Pathol. 2012;226:326–37. [PubMed: 21956823]
  42. D'Andrea AD. Susceptibility pathways in Fanconi's anemia and breast cancer. N Engl J Med. 2010;362:1909–19. [PMC free article: PMC3069698] [PubMed: 20484397]
  43. 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]
  44. 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]
  45. 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]
  46. Deans AJ, West SC. FANCM connects the genome instability disorders Bloom's Syndrome and Fanconi Anemia. Mol Cell. 2009;36:943–53. [PubMed: 20064461]
  47. Deans AJ, West SC. DNA interstrand crosslink repair and cancer. Nat Rev Cancer. 2011;11:467–80. [PMC free article: PMC3560328] [PubMed: 21701511]
  48. 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]
  49. Du W, Erden O, Wilson A, Sipple JM, Schick J, Mehta P, Myers KC, Steinbrecher KA, Davies SM, Pang Q. Deletion of Fanca or Fancd2 dysregulates Treg in mice. Blood. 2014;123:1938–47. [PMC free article: PMC3962166] [PubMed: 24501220]
  50. 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]
  51. 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]
  52. 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]
  53. 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]
  54. Fanconi Anaemia/Breast Cancer Consortium. Positional cloning of the Fanconi anaemia group A gene. Nat Genet. 1996;14:324–8. [PubMed: 8896564]
  55. 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]
  56. Frohnmayer D, Frohnmayer L, Guinan E, Kennedy T, Larsen K, eds. Fanconi Anemia: Guidelines for Diagnosis and Management. 4 ed. Eugene, OR: Fanconi Anemia Research Fund, Inc. Available online. 2014. Accessed 9-13-16.
  57. 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]
  58. Garbati MR, Hays LE, Keeble W, Yates JE, Rathbun RK, Bagby GC. FANCA and FANCC modulate TLR and p38 MAPK-dependent expression of IL-1β in macrophages. Blood. 2013;122:3197–205. [PMC free article: PMC3814736] [PubMed: 24046015]
  59. 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]
  60. 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]
  61. Giulino L, Guinan EC, Gillio AP, Drachtman RA, Teruya-Feldstein J, Boulad F. Sweet syndrome in patients with Fanconi anaemia: association with extracutaneous manifestations and progression of haematological disease. Br J Haematol. 2011;154:278–81. [PubMed: 21501135]
  62. Guardiola P, Socié G, Li X, Ribaud P, Devergie A, Espérou H, Richard P, Traineau R, Janin A, Gluckman E. Acute graft-versus-host disease in patients with Fanconi anemia or acquired aplastic anemia undergoing bone marrow transplantation from HLA-identical sibling donors: risk factors and influence on outcome. Blood. 2004;103:73–7. [PubMed: 12946993]
  63. Guo M, Vidhyasagar V, Ding H, Wu Y. Insight into the roles of helicase motif Ia by characterizing Fanconi anemia group J protein (FANCJ) patient mutations. J Biol Chem. 2014;289:10551–65. [PMC free article: PMC4036176] [PubMed: 24573678]
  64. Haitjema A, Mol BM, Kooi IE, Massink MP, Jørgensen JA, Rockx DA, Rooimans MA, de Winter JP, Meijers-Heijboer H, Joenje H, Dorsman JC. Coregulation of FANCA and BRCA1 in human cells. Springerplus. 2014;3:381. [PMC free article: PMC4143540] [PubMed: 25161863]
  65. Hira A, Yoshida K, Sato K, Okuno Y, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Shimamoto A, Tahara H, Ito E, Kojima S, Kurumizaka H, Ogawa S, Takata M, Yabe H, Yabe M. Mutations in the gene encoding the E2 conjugating enzyme UBE2T cause Fanconi anemia. Am J Hum Genet. 2015;96:1001–7. [PMC free article: PMC4457949] [PubMed: 26046368]
  66. 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]
  67. 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]
  68. Ho TV, Schärer OD. Translesion DNA synthesis polymerases in DNA interstrand crosslink repair. Environ Mol Mutagen. 2010;51:552–66. [PubMed: 20658647]
  69. Hosoya Y, Lefor A, Hirashima Y, Nokubi M, Yamaguti T, Jinbu Y, Muroi K, Nakazawa M, Yasuda Y. Successful treatment of esophageal squamous cell carcinoma in a patient with Fanconi anemia. Jpn J Clin Oncol. 2010;40:805–10. [PubMed: 20410055]
  70. 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]
  71. 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]
  72. Howlett NG, Harney JA, Rego MA, Kolling FW 4th, 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]
  73. 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]
  74. 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]
  75. Huang Y, Leung JW, Lowery M, Matsushita N, Wang Y, Shen X, Huong D, Takata M, Chen J, Li L. Modularized functions of the Fanconi anemia core complex. Cell Rep. 2014;7:1849–57. [PMC free article: PMC4157997] [PubMed: 24910428]
  76. 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]
  77. 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]
  78. Jones S, Hruban RH, Kamiyama M, Borges M, Zhang X, Parsons DW, Lin JC, Palmisano E, Brune K, Jaffee EM, Iacobuzio-Donahue CA, Maitra A, Parmigiani G, Kern SE, Velculescu VE, Kinzler KW, Vogelstein B, Eshleman JR, Goggins M, Klein AP. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science. 2009;324:217. [PMC free article: PMC2684332] [PubMed: 19264984]
  79. Joo W, Xu G, Persky NS, Smogorzewska A, Rudge DG, Buzovetsky O, Elledge SJ, Pavletich NP. Structure of the FANCI-FANCD2 complex: insights into the Fanconi anemia DNA repair pathway. Science. 2011;333:312–6. [PMC free article: PMC3310437] [PubMed: 21764741]
  80. Kahraman S, Beyazyurek C, Yesilipek MA, Ozturk G, Ertem M, Anak S, Kansoy S, Aksoylar S, Kuşkonmaz B, Oniz H, Slavin S, Karakas Z, Tac HA, Gulum N, Ekmekci GC. Successful haematopoietic stem cell transplantation in 44 children from healthy siblings conceived after preimplantation HLA matching. Reprod Biomed Online. 2014;29:340–51. [PubMed: 25066893]
  81. Kee Y, D'Andrea AD. Molecular pathogenesis and clinical management of Fanconi anemia. J Clin Invest. 2012;122:3799–806. [PMC free article: PMC3484428] [PubMed: 23114602]
  82. Kim H, D'Andrea AD. Regulation of DNA cross-link repair by the Fanconi anemia/BRCA pathway. Genes Dev. 2012;26:1393–408. [PMC free article: PMC3403008] [PubMed: 22751496]
  83. 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]
  84. 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]
  85. 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]
  86. Kratz K, Schöpf B, Kaden S, Sendoel A, Eberhard R, Lademann C, Cannavó E, Sartori AA, Hengartner MO, Jiricny J. Deficiency of FANCD2-associated nuclease KIAA1018/FAN1 sensitizes cells to interstrand crosslinking agents. Cell. 2010;142:77–88. [PubMed: 20603016]
  87. 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]
  88. Leung JW, Wang Y, Fong KW, Huen MS, Li L, Chen J. Fanconi anemia (FA) binding protein FAAP20 stabilizes FA complementation group A (FANCA) and participates in interstrand cross-link repair. Proc Natl Acad Sci U S A. 2012;109:4491–6. [PMC free article: PMC3311328] [PubMed: 22396592]
  89. Léveillé F, Blom E, Medhurst AL, Bier P. Laghmani el H, Johnson M, Rooimans MA, Sobeck A, Waisfisz Q, Arwert F, Patel KJ, Hoatlin ME, Joenje H, de Winter JP. The Fanconi anemia gene product FANCF is a flexible adaptor protein. J Biol Chem. 2004;279:39421–30. [PubMed: 15262960]
  90. Léveillé F, Ferrer M, Medhurst AL. Laghmani el H, Rooimans MA, Bier P, Steltenpool J, Titus TA, Postlethwait JH, Hoatlin ME, Joenje H, de Winter JP. The nuclear accumulation of the Fanconi anemia protein FANCE depends on FANCC. DNA Repair (Amst) 2006;5:556–65. [PubMed: 16513431]
  91. 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]
  92. 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]
  93. 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]
  94. Liang CC, Zhan B, Yoshikawa Y, Haas W, Gygi SP, Cohn MA. UHRF1 is a sensor for DNA interstrand crosslinks and recruits FANCD2 to initiate the Fanconi anemia pathway. Cell Rep. 2015;10:1947–56. [PMC free article: PMC4386029] [PubMed: 25801034]
  95. 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]
  96. 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]
  97. 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]
  98. Lossaint G, Larroque M, Ribeyre C, Bec N, Larroque C, Décaillet C, Gari K, Constantinou A. FANCD2 binds MCM proteins and controls replisome function upon activation of s phase checkpoint signaling. Mol Cell. 2013;51:678–90. [PubMed: 23993743]
  99. MacKay C, Déclais AC, Lundin C, Agostinho A, Deans AJ, MacArtney TJ, Hofmann K, Gartner A, West SC, Helleday T, Lilley DM, Rouse J. Identification of KIAA1018/FAN1, a DNA repair nuclease recruited to DNA damage by monoubiquitinated FANCD2. Cell. 2010;142:65–76. [PMC free article: PMC3710700] [PubMed: 20603015]
  100. MacMillan ML, DeFor TE, Young JA, Dusenbery KE, Blazar BR, Slungaard A, Zierhut H, Weisdorf DJ, Wagner JE. Alternative donor hematopoietic cell transplantation for Fanconi anemia. Blood. 2015;125:3798–804. [PMC free article: PMC4463740] [PubMed: 25824692]
  101. MacMillan ML, Wagner JE. Haematopoeitic cell transplantation for Fanconi anaemia - when and how? Br J Haematol. 2010;149:14–21. [PubMed: 20136826]
  102. 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]
  103. Magron A, Elowe S, Carreau M. The Fanconi Anemia C Protein Binds to and Regulates Stathmin-1 Phosphorylation. PLoS One. 2015;10:e0140612. [PMC free article: PMC4605623] [PubMed: 26466335]
  104. 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]
  105. Masserot C, Peffault de Latour R, Rocha V, Leblanc T, Rigolet A, Pascal F, Janin A, Soulier J, Gluckman E, Socié G. Head and neck squamous cell carcinoma in 13 patients with Fanconi anemia after hematopoietic stem cell transplantation. Cancer. 2008;113:3315–22. [PubMed: 18831513]
  106. 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]
  107. McCauley J, Masand N, McGowan R, Rajagopalan S, Hunter A, Michaud JL, Gibson K, Robertson J, Vaz F, Abbs S, Holden ST. X-linked VACTERL with hydrocephalus syndrome: further delineation of the phenotype caused by FANCB mutations. Am J Med Genet A. 2011;155A:2370–80. [PubMed: 21910217]
  108. 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]
  109. 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]
  110. 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]
  111. 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]
  112. Mehta PA, Davies SM, Myers K, Leemhuis T, Williams D, Lehmann L, Guinan E, Margolis D, Baker S, Lane A, Klein E, Boulad F. Chemotherapy-only preparative regimen for alternative donor hematopoietic cell transplantation for patients with Fanconi anemia (FA): results of a multi-institutional study. Biol Blood Marrow Transplant. 2015;21:S104a.
  113. Mehta PA, Harris RE, Davies SM, Kim MO, Mueller R, Lampkin B, Mo J, Myers K, Smolarek TA. Numerical chromosomal changes and risk of development of myelodysplastic syndrome—acute myeloid leukemia in patients with Fanconi anemia. Cancer Genet Cytogenet. 2010;203:180–6. [PubMed: 21156231]
  114. Mehta PA, Ileri T, Harris RE, Williams DA, Mo J, Smolarek T, Auerbach AD, Kelly P, Davies SM. Chemotherapy for Myeloid Malignancy in Children with Fanconi Anemia. Pediatr Blood Cancer. 2007;48:668–72. [PubMed: 16609946]
  115. 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]
  116. 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]
  117. 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]
  118. 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]
  119. Morris LG, Sikora AG, Patel SG, Hayes RB, Ganly I. Second primary cancers after an index head and neck cancer: subsite-specific trends in the era of human papillomavirus-associated oropharyngeal cancer. J Clin Oncol. 2011;29:739–46. [PMC free article: PMC3056657] [PubMed: 21189382]
  120. Moynahan ME, Pierce AJ, Jasin M. BRCA2 is required for homology-directed repair of chromosomal breaks. Mol Cell. 2001;7:263–72. [PubMed: 11239455]
  121. Myers K, Davies SM, Harris RE, Spunt SL, Smolarek T, Zimmerman S, McMasters R, Wagner L, Mueller R, Auerbach AD, Mehta PA. The clinical phenotype of children with Fanconi anemia caused by biallelic FANCD1/BRCA2 mutations. Pediatr Blood Cancer. 2012;58:462–5. [PubMed: 21548014]
  122. Nabhan SK, Bitencourt MA, Duval M, Abecasis M, Dufour C, Boudjedir K, Rocha V, Socié G, Passweg J, Goi K, Sanders J, Snowden J, Yabe H, Pasquini R, Gluckman E., Aplastic Anaemia Working Party, EBMT. Fertility recovery and pregnancy after allogeneic hematopoietic stem cell transplantation in Fanconi anemia patients. Haematologica. 2010;95:1783–7. [PMC free article: PMC2948106] [PubMed: 20494929]
  123. Nakanishi K, Cavallo F, Perrouault L, Giovannangeli C, Moynahan ME, Barchi M, Brunet E, Jasin M. Homology-directed Fanconi anemia pathway cross-link repair is dependent on DNA replication. Nat Struct Mol Biol. 2011;18:500–3. [PMC free article: PMC3273992] [PubMed: 21423196]
  124. 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]
  125. 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]
  126. Neitzel H, Kühl JS, Gerlach A, Ebell W, Tönnies H. Clonal chromosomal aberrations in bone marrow cells of Fanconi anemia patients: results and implications. In: Schindler D, Hoehn H, eds. Fanconi Anemia. a Paradigmatic Disease for the Understanding of Cancer and Aging. Monographs in Human Genetics. Vol 15. Basel: Karger. 2007:79-94.
  127. Neveling K, Endt D, Hoehn H, Schindler D. Genotype–phenotype correlations in Fanconi anemia. Mutat Res. 2009;668:73–91. [PubMed: 19464302]
  128. Nicchia E, Benedicenti F, De Rocco D, Greco C, Bottega R, Inzana F, Faleschini M, Bonin S, Cappelli E, Mogni M, Stanzial F, Svahn J, Dufour C, Savoia A. Clinical aspects of Fanconi anemia individuals with the same mutation of FANCF identified by next generation sequencing. Birth Defects Res A Clin Mol Teratol. 2015;103:1003–10. [PubMed: 26033879]
  129. 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]
  130. 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]
  131. 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]
  132. 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]
  133. Olopade OI, Wei M. FANCF methylation contributes to chemoselectivity in ovarian cancer. Cancer Cell. 2003;3:417–20. [PubMed: 12781358]
  134. Osorio A, Bogliolo M, Fernández V, Barroso A, de la Hoya M, Caldés T, Lasa A, Ramón y Cajal T, Santamariña M, Vega A, Quiles F, Lázaro C, Díez O, Fernández D, González-Sarmiento R, Durán M, Piqueras JF, Marín M, Pujol R, Surrallés J, Benítez J. Evaluation of rare variants in the new fanconi anemia gene ERCC4 (FANCQ) as familial breast/ovarian cancer susceptibility alleles. Hum Mutat. 2013;34:1615–8. [PubMed: 24027083]
  135. 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]
  136. 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]
  137. Parmar K, Kim J, Sykes SM, Shimamura A, Stuckert P, Zhu K, Hamilton A, Deloach MK, Kutok JL, Akashi K, Gilliland DG, D'andrea A. Hematopoietic stem cell defects in mice with deficiency of Fancd2 or Usp1. Stem Cells. 2010;28:1186–95. [PMC free article: PMC2910804] [PubMed: 20506303]
  138. 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]
  139. Polito D, Cukras S, Wang X, Spence P, Moreau L, D'Andrea AD, Kee Y. The carboxyl terminus of FANCE recruits FANCD2 to the Fanconi anemia (FA) E3 ligase complex to promote the FA DNA repair pathway. J Biol Chem. 2014;289:7003–10. [PMC free article: PMC3945361] [PubMed: 24451376]
  140. 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]
  141. Rafnar T, Gudbjartsson DF, Sulem P, Jonasdottir A, Sigurdsson A, Jonasdottir A, Besenbacher S, Lundin P, Stacey SN, Gudmundsson J, Magnusson OT, le Roux L, Orlygsdottir G, Helgadottir HT, Johannsdottir H, Gylfason A, Tryggvadottir L, Jonasson JG, de Juan A, Ortega E, Ramon-Cajal JM, García-Prats MD, Mayordomo C, Panadero A, Rivera F, Aben KK, van Altena AM, Massuger LF, Aavikko M, Kujala PM, Staff S, Aaltonen LA, Olafsdottir K, Bjornsson J, Kong A, Salvarsdottir A, Saemundsson H, Olafsson K, Benediktsdottir KR, Gulcher J, Masson G, Kiemeney LA, Mayordomo JI, Thorsteinsdottir U, Stefansson K. Mutations in BRIP1 confer high risk of ovarian cancer. Nat Genet. 2011;43:1104–7. [PubMed: 21964575]
  142. 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. Breast Cancer Susceptibility Collaboration (UK), Easton DF, Stratton MR. 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]
  143. Rajendra E, Oestergaard VH, Langevin F, Wang M, Dornan GL, Patel KJ, Passmore LA. The genetic and biochemical basis of FANCD2 monoubiquitination. Mol Cell. 2014;54:858–69. [PMC free article: PMC4051986] [PubMed: 24905007]
  144. 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]
  145. Rickman KA, Lach FP, Abhyankar A, Donovan FX, Sanborn EM, Kennedy JA, Sougnez C, Gabriel SB, Elemento O, Chandrasekharappa SC, Schindler D, Auerbach AD, Smogorzewska A. Deficiency of UBE2T, the E2 ubiquitin ligase necessary for FANCD2 and FANCI ubiquitination, causes FA-T subtype of Fanconi anemia. Cell Rep. 2015;12:35–41. [PMC free article: PMC4497947] [PubMed: 26119737]
  146. Rose SR, Kim MO, Korbee L, Wilson KA, Douglas Ris M, Eyal O, Sherafat-Kazemzadeh R, Bollepalli S, Harris R, Jeng MR, Williams DA, Smith FO. Oxandrolone for the treatment of bone marrow failure in Fanconi anemia. Pediatr Blood Cancer. 2014;61:11–9. [PubMed: 24019220]
  147. 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]
  148. 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]
  149. Rosenberg PS, Tamary H, Alter BP. How high are carrier frequencies of rare recessive syndromes? Contemporary estimates for Fanconi Anemia in the United States and Israel. Am J Med Genet A. 2011;155A:1877–83. [PMC free article: PMC3140593] [PubMed: 21739583]
  150. Sarkies P, Murat P, Phillips LG, Patel KJ, Balasubramanian S, Sale JE. FANCJ coordinates two pathways that maintain epigenetic stability at G-quadruplex DNA. Nucleic Acids Res. 2012;40:1485–98. [PMC free article: PMC3287192] [PubMed: 22021381]
  151. Sato K, Toda K, Ishiai M, Takata M, Kurumizaka H. DNA robustly stimulates FANCD2 monoubiquitylation in the complex with FANCI. Nucleic Acids Res. 2012;40:4553–61. [PMC free article: PMC3378891] [PubMed: 22287633]
  152. Sawyer SL, Tian L, Kähkönen M, Schwartzentruber J, Kircher M., University of Washington Centre for Mendelian Genomics. FORGE Canada Consortium, Majewski J, Dyment DA, Innes AM, Boycott KM, Moreau LA, Moilanen JS, Greenberg RA. Biallelic mutations in BRCA1 cause a new Fanconi anemia subtype. Cancer Discov. 2015;5:135–42. [PMC free article: PMC4320660] [PubMed: 25472942]
  153. Scheckenbach K, Morgan M, Filger-Brillinger J, Sandmann M, Strimling B, Scheurlen W, Schindler D, Gobel U, Hanenberg H. Treatment of the bone marrow failure in Fanconi anemia patients with danazol. Blood Cells Mol Dis. 2012;48:128–131. [PubMed: 22178060]
  154. 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. Breast Cancer Susceptibility Collaboration (UK), Easton DF, Stratton MR, Rahman N. Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat Genet. 2006;38:1239–41. [PubMed: 17033622]
  155. 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]
  156. 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]
  157. Smogorzewska A, Desetty R, Saito TT, Schlabach M, Lach FP, Sowa ME, Clark AB, Kunkel TA, Harper JW, Colaiácovo MP, Elledge SJ. A genetic screen identifies FAN1, a Fanconi anemia-associated nuclease necessary for DNA interstrand crosslink repair. Mol Cell. 2010;39:36–47. [PMC free article: PMC2919743] [PubMed: 20603073]
  158. Smogorzewska A, Matsuoka S, Vinciguerra P, McDonald ER 3rd, 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]
  159. Sommers JA, Banerjee T, Hinds T, Wan B, Wold MS, Lei M, Brosh RM Jr. Novel function of the Fanconi anemia group J or RECQ1 helicase to disrupt protein-DNA complexes in a replication protein A-stimulated manner. J Biol Chem. 2014;289:19928–41. [PMC free article: PMC4106313] [PubMed: 24895130]
  160. 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]
  161. Spanier G, Pohl F, Giese T, Meier JK, Koelbl O, Reichert TE. Fatal course of tonsillar squamous cell carcinoma associated with Fanconi anaemia: a mini review. J Craniomaxillofac Surg. 2012;40:510–5. [PubMed: 21925890]
  162. 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]
  163. Talbot A, Peffault de Latour R, Raffoux E, Buchbinder N, Vigouroux S, Milpied N, Leblanc T, Soulier J, Michallet M, Socié G. Sequential treatment for allogeneic hematopoietic stem cell transplantation in Fanconi anemia with acute myeloid leukemia. Haematologica. 2014;99:e199–200. [PMC free article: PMC4181270] [PubMed: 25085358]
  164. 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]
  165. Tan IB, Cutcutache I, Zang ZJ, Iqbal J, Yap SF, Hwang W, Lim WT, Teh BT, Rozen S, Tan EH, Tan P. Fanconi's anemia in adulthood: chemoradiation-induced bone marrow failure and a novel FANCA mutation identified by targeted deep sequencing. J Clin Oncol. 2011;29:e591–4. [PubMed: 21519011]
  166. Taniguchi T, D'Andrea AD. Molecular pathogenesis of Fanconi anemia: recent progress. Blood. 2006;107:4223–33. [PubMed: 16493006]
  167. 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]
  168. 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]
  169. 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]
  170. 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]
  171. Tolar J, Adair JE, Antoniou M, Bartholomae CC, Becker PS, Blazar BR, Bueren J, Carroll T, Cavazzana-Calvo M, Clapp DW, Dalgleish R, Galy A, Gaspar HB, Hanenberg H, Von Kalle C, Kiem HP, Lindeman D, Naldini L, Navarro S, Renella R, Rio P, Sevilla J, Schmidt M, Verhoeyen E, Wagner JE, Williams DA, Thrasher AJ. Stem cell gene therapy for fanconi anemia: report from the 1st international Fanconi anemia gene therapy working group meeting. Mol Ther. 2011;19:1193–8. [PMC free article: PMC3129570] [PubMed: 21540837]
  172. Turner N, Tutt A, Ashworth A. Hallmarks of 'BRCAness' in sporadic cancers. Nat Rev Cancer. 2004;4:814–9. [PubMed: 15510162]
  173. Umaña LA, Magoulas P, Bi W, Bacino CA. A male newborn with VACTERL association and Fanconi anemia with a FANCB deletion detected by array comparative genomic hybridization (aCGH). Am J Med Genet A. 2011;155A:3071–4. [PubMed: 22052692]
  174. 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]
  175. 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]
  176. 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]
  177. Vetro A, Iascone M, Limongelli I, Ameziane N, Gana S, Della Mina E, Giussani U, Ciccone R, Forlino A, Pezzoli L, Rooimans MA, van Essen AJ, Messa J, Rizzuti T, Bianchi P, Dorsman J, de Winter JP, Lalatta F, Zuffardi O. Loss-of-Function FANCL Mutations Associate with Severe Fanconi Anemia Overlapping the VACTERL Association. Hum Mutat. 2015;36:562–8. [PubMed: 25754594]
  178. Virts EL, Jankowska A, Mackay C, Glaas MF, Wiek C, Kelich SL, Lottmann N, Kennedy FM, Marchal C, Lehnert E, Scharf RE, Dufour C, Lanciotti M, Farruggia P, Santoro A, Savasan S, Scheckenbach K, Schipper J, Wagenmann M, Lewis T, Leffak M, Farlow JL, Foroud TM, Honisch E, Niederacher D, Chakraborty SC, Vance GH, Pruss D, Timms KM, Lanchbury JS, Alpi AF, Hanenberg H. AluY-mediated germline deletion, duplication and somatic stem cell reversion in UBE2T defines a new subtype of Fanconi anemia. Hum Mol Genet. 2015;24:5093–108. [PMC free article: PMC4550815] [PubMed: 26085575]
  179. 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]
  180. Wang AT, Smogorzewska A. SnapShot: Fanconi anemia and associated proteins. Cell. 2015;160:354–354.e1. [PubMed: 25594185]
  181. 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]
  182. 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]
  183. 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]
  184. Wang AT, Kim T, Wagner JE, Conti BA, Lach FP, Huang AL, Molina H, Sanborn EM, Zierhut H, Cornes BK, Abhyankar A, Sougnez C, Gabriel SB, Auerbach AD, Kowalczykowski SC, Smogorzewska A. A Dominant Mutation in Human RAD51 Reveals Its Function in DNA Interstrand Crosslink Repair Independent of Homologous Recombination. Mol Cell. 2015;59:478–90. [PMC free article: PMC4529964] [PubMed: 26253028]
  185. 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]
  186. 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]
  187. Williams SA, Longerich S, Sung P, Vaziri C, Kupfer GM. The E3 ubiquitin ligase RAD18 regulates ubiquitylation and chromatin loading of FANCD2 and FANCI. Blood. 2011a;117:5078–87. [PMC free article: PMC3109534] [PubMed: 21355096]
  188. Williams SA, Wilson JB, Clark AP, Mitson-Salazar A, Tomashevski A, Ananth S, Glazer PM, Semmes OJ, Bale AE, Jones NJ, Kupfer GM. Functional and physical interaction between the mismatch repair and FA-BRCA pathways. Hum Mol Genet. 2011b;20:4395–410. [PMC free article: PMC3196888] [PubMed: 21865299]
  189. 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]
  190. 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]
  191. Wu Y, Brosh RM Jr. 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]
  192. Wu Y, Sommers JA, Loiland JA, Kitao H, Kuper J, Kisker C, Brosh RM Jr. The Q motif of Fanconi anemia group J protein (FANCJ) DNA helicase regulates its dimerization, DNA binding, and DNA repair function. J Biol Chem. 2012;287:21699–716. [PMC free article: PMC3381133] [PubMed: 22582397]
  193. 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]
  194. 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]
  195. Xie J, Peng M, Guillemette S, Quan S, Maniatis S, Wu Y, Venkatesh A, Shaffer SA, Brosh RM Jr, Cantor SB. FANCJ/BACH1 acetylation at lysine 1249 regulates the DNA damage response. PLoS Genet. 2012;8:e1002786. [PMC free article: PMC3390368] [PubMed: 22792074]
  196. 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]
  197. 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]
  198. Yoshikiyo K, Kratz K, Hirota K, Nishihara K, Takata M, Kurumizaka H, Horimoto S, Takeda S, Jiricny J. KIAA1018/FAN1 nuclease protects cells against genomic instability induced by interstrand cross-linking agents. Proc Natl Acad Sci U S A. 2010;107:21553–7. [PMC free article: PMC3003052] [PubMed: 21115814]
  199. 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. [PMC free article: PMC4928586] [PubMed: 20676667]
  200. 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]
  201. Zhu B, Yan K, Li L, Lin M, Zhang S, He Q, Zheng D, Yang H, Shao G. K63-linked ubiquitination of FANCG is required for its association with the Rap80-BRCA1 complex to modulate homologous recombination repair of DNA interstand crosslinks. Oncogene. 2015a;34:2867–78. [PubMed: 25132264]
  202. Zhu J, Su F, Mukherjee S, Mori E, Hu B, Asaithamby A. FANCD2 influences replication fork processes and genome stability in response to clustered DSBs. Cell Cycle. 2015b;14:1809–22. [PMC free article: PMC4613663] [PubMed: 26083937]
  203. Zou J, Tian F, Li J, Pickner W, Long M, Rezvani K, Wang H, Zhang D. FancJ regulates interstrand crosslinker induced centrosome amplification through the activation of polo-like kinase 1. Biol Open. 2013;2:1022–31. [PMC free article: PMC3798185] [PubMed: 24167712]
  204. Zou J, Zhang D, Qin G, Chen X, Wang H, Zhang D. BRCA1 and FancJ cooperatively promote interstrand crosslinker induced centrosome amplification through the activation of polo-like kinase 1. Cell Cycle. 2014;13:3685–97. [PMC free article: PMC4612125] [PubMed: 25483079]

Suggested Reading

  1. Auerbach AD, Buchwald M, Joenje H. Fanconi anemia. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 31. Available online.
  2. Huret JL. Fanconi anaemia. Atlas of Genetics and Cytogenetics Oncology and Haematology. Available online. 2002. Accessed 9-13-16.

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, FAAP; National Cancer Institute (2011-2016)
Alan D'Andrea, MD; Dana Farber Cancer Institute (2002-2007)
Gary Kupfer, MD; Yale University School of Medicine (2011-2016)
Parinda A Mehta, MD (2016-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)
Jakub Tolar, MD, PhD (2016-present)

Revision History

  • 22 September 2016 (sw) Comprehensive update posted live
  • 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
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