Publications about genetic testing for metabolic disorders
  1. NGS panel - Genetic testing for Fanconi anemia

Fanconi anemia

March 18, 2018

Disease summary

Fanconi Anemia (FA) is a rare inherited chromosome breakage syndrome characterized by physical abnormalities, bone marrow failure, and increased risk for development of various malignancies. FA is the most common genetic cause of aplastic anemia and one of the most common genetic causes of hematologic malignancy. Many different genes, mostly involved in DNA repair, are underlying FA and they account for different phenotypic complementation groups, including FANCA, FANCB, FANCC, FANCD1 (BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (BRIP1), FANCL, FANCM and FANCN (PALB2) genes (Table 1).

FA-associated proteins (namely: FANCA, FANCB, FANCE, FANCF, FANCG, and FANCL) are assembled in a nuclear “FA core” complex, a multi-subunit ubiquitin ligase complex (see Figure 1). Additional FA proteins (FANCD2 and FANCI) are associated with the FA core complex, and after ubiquitination by ubiquitin ligase FANCL they are translocated to nuclear foci that include the “DNA repair” proteins BRCA2, RAD51, NBS1, and others (Figure 1). The latest proteins actively participate in DNA repair and therefore, when they carry a pathogenic variant, the DNA repair function is missing and as a result the DNA is no longer stable and tumors can develop.


Autosomal recessive, autosomal dominant (RAD51), X-linked (FANCB)

1/100,000 1; carrier frequency is 1/100 in Ashkenazi Jewish, Spanish Gypsy, and black South African 1, 2

Clinical symptoms:

Fanconi anemia is suspected in individuals with the following clinical features 1, 4, 10, 15:

  • Abnormal skin pigmentation with café au lait spots is present in about 40% of all FA-affected cases, commonly associated with generalized hypopigmentation1
  • Malformations of the skeletal system are commonly present (in ~35% of cases1) in form of absent thumbs, absent or hypoplastic radii followed by weak pulse, congenital hip dislocation and syndactyly (in about 5% of FA-cases)1
  • Short stature, pre-  or postnatal accompanied with low birth weight in majority of affected
  • Microcephaly or CNS-anomalies in 20% of FA-cases1
  • Ocular anomalies (in 20% affected) including cataract, microphthalmia, strabismus, astigmatism, ptosis and others.
  • Gastrointestinal and urinary system anomalies, including renal anomalies, hypospadias and cryptorchidism in man and small ovaries in females.
  • Progressive bone marrow failure manifested as thrombocytopenia, leukopenia, anemia, macrocytosis and/or increased fetal hemoglobin levels.
  • Increased risk of malignancy, including the following:

              o    Adult-onset aplastic anemia.

              o    Myelodysplastic syndrome (MDS).

              o    Acute myelogenous leukemia (AML): the relative risk for AML is ~500 times higher than in   non-affected people 3, 4

              o    Solid tumors (early-onset) that may be the first manifestation of disease, including squamous cell carcinomas of the head and neck (most common form. With the incidence >700 times higher compared to normal population 1, 5), esophagus, and vulva; cervical cancer and liver tumors.

Diagnostic criteria for Fanconi anemia 1, 4, 10, 15:

  • 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).
  • Biallelic pathogenic variants in one of the dozen genes known to cause autosomal recessive FA (BRCA2, BRIP1, ERCC4, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, PALB2, RAD51C, SLX4, UBE2T, XRCC2).
  • A heterozygous pathogenic variant in RAD51, known to cause autosomal dominant FA
  • A hemizygous pathogenic variant in FANCB, known to cause X-linked FA.

Treatment options:

  • Allogeneic hematopoietic stem cell transplant is the only curative treatment for patients with Fanconi anemia 1, 20.
  • Alternative treatments are beneficial and include administration of oral androgens (improvement of blood counts in 50% of FA-patients), administration of G-CSF (granulocyte-colony stimulating factor) and others 1, 20.
  • Chromosome breakage syndromes, such as Bloom syndrome or ataxia-telangiectasia
  • Nijmegen breakage syndrome (NBS)
  • Seckel syndrome
  • Neurofibromatosis 1 (NF1)
  • TAR syndrome (thrombocytopenia with absent radii)
  • VACTERL association

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for Fanconi anemia using NGS Panel Genomic:

Step 1: Whole genome sequencing from a single filter card (drop of blood), covering the entire genic region (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Fanconi anemia panel. Copy Number Variants analysis derived from NGS data is also included.

Step 2: If no pathogenic variant is identified in Step1, continue with bioinformatics analysis covering genes that are either implicated or associated with overlapping phenotype or similar pathways.   

  • Individuals with a positive family history of Fanconi anemia.
  • Individuals with most common symptoms of Fanconi anemia (regardless of family history).

Confirmation of a clinical diagnosis through genetic testing of Fanconi anemia can allow for genetic counseling and may direct medical management.

Figure 1:
Schematic presentation of the Fanconi anemia DNA repair pathway: DNA damage activates Fanconi anemia complex which includes the Fanconi anemia-associated proteins FANCA, FANCB, FANCE, FANCF, FANCG and subsequently FANCL. FANCL is a ubiquitin ligase and it ubiquitinate FANCD2 and FANCI. This FANCD2/FANCI ubiquitinated/activated complex further activates “DNA repair proteins” associated with Fanconi anemia: BRCA2, RAD51, BRCA1, NBS1 and PCNA, subsequently leading to DNA repair.

Overview of genes included in Fanconi anemia panel

Gene OMIM (Gene) Associated diseases (OMIM) Inheritance CentoMD® exclusive variant numbers (++)
BRCA2 600185 Breast cancer, male, susceptibility to; Medulloblastoma; Prostate cancer; Wilms tumor; Fanconi anemia, complementation group D1; Breast-ovarian cancer, familial, 2; Glioblastoma 3; Pancreatic cancer 2 AD, AR, Somatic mutation 227
BRIP1 605882 Breast cancer, early-onset; Fanconi anemia, complementation group J AD 15
ERCC4 133520 Xeroderma pigmentosum, group F; Xeroderma pigmentosum, type F/Cockayne syndrome; ?XFE progeroid syndrome; Fanconi anemia, complementation group Q AR 0
FANCA 607139 Fanconi anemia, complementation group A AR 62
FANCB 300515 Fanconi anemia, complementation group B 6
FANCC 613899 Fanconi anemia, complementation group C AR 10
FANCD2 613984 Fanconi anemia, complementation group D2 AR 22
FANCE 613976 Fanconi anemia, complementation group E AR 8
FANCF 613897 Fanconi anemia, complementation group F 4
FANCG 602956 Fanconi anemia, complementation group G 13
FANCI 611360 Fanconi anemia, complementation group I AR 34
FANCL 608111 Fanconi anemia, complementation group L AR 15
FANCM 609644 16
PALB2 610355 Breast cancer, susceptibility to; Fanconi anemia, complementation group N; Pancreatic cancer, susceptibility to, 3 AD 11
RAD51C 602774 Fanconi anemia, complementation group O; Breast-ovarian cancer, familial, susceptibility to, 3 AR 3
SLX4 613278 Fanconi anemia, complementation group P AR 11
UBE2T 610538 Fanconi anemia, complementation group T AR 0
XRCC2 600375 ?Fanconi anemia, complementation group U AR 7

Allogeneic hematopoietic stem cell transplant is the only curative treatment for patients with Fanconi anemia20. However, alternative treatments are beneficial and include administration of oral androgens (improvement of blood counts in 50% of FA-patients), administration of G-CSF (granulocyte-colony stimulating factor), and others20.

CENTOGENE offers the Fanconi anemia panel, including sequencing (genes: BRCA2, BRIP1, ERCC4, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, PALB2, RAD51C, SLX4, UBE2T, XRCC2) and deletion/duplication analysis of selected genes (FANCD2, BRIP1, FANCB, PALB2, BRCA2, FANCA, RAD51C). In addition, any of the genes in the Fanconi anemia panel can also be ordered individually, for sequencing and deletion/duplication analysis.