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Fanconi Anemia via the FANCC Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
Order Kits
TEST METHODS

Sequencing

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
722 FANCC$860.00 81479 Add to Order
Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 18 days.

Clinical Sensitivity

FA via FANCC accounts for ~ 16% of all FA cases.

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 FANCC$690.00 81479 Add to Order
Pricing Comment

# of Genes Ordered

Total Price

1

$690

2

$730

3

$770

4-10

$840

11-30

$1,290

31-100

$1,670

Over 100

Call for quote

Turnaround Time

The great majority of tests are completed within 28 days.

Clinical Features

Fanconi Anemia (FA) is considered a blood disorder, however the clinical features of FA expand well beyond hematologic disorders alone.  FA is characterized by a range of physical abnormalities, bone marrow failure (aplastic anemia), pancytopenia, and predisposition to cancers - particularly acute myelogenous leukemia (AML), gynecologic and GI tract cancers, and cancers of the head and neck  (Auerbach. Mutat Res 668:4-10, 2009). FA patients are up to 800 fold more susceptible to AML than the general population with a median age of onset of 13 years (Rosenberg et al. Blood 101:822, 2003). Physical abnormalities include radial ray defects (absent thumb or radius), skin pigmentation defects, short stature, microphthalmia, renal and urinary tract defects, genital defects (males in particular), gastrointestinal malformations (atresia), congenital heart disease, hearing and central nervous system defects, and general developmental delay (Tischkowitz and Hodgson. J Med Genet 40:1-10, 2003; Dokal. Baillieres Best Pract Res Clin Haematol 13:407-425, 2000). About one-third of FA patients have no obvious physical abnormalities and are diagnosed only after a family member is diagnosed, or after developing hematologic anomalies such as thromobocytopenia, leukopenia, and anemia (Giampietro et al. Am J Med Genet 68:58-61, 1997). A hallmark of FA is hypersensitivity of chromosomes to interstrand cross linking agents such as diepoxybutane (DEB) or mitomycin C (MMC) (Sasaki and Tonomura. Cancer Res 33:1829-1836, 1973). Exposure of primary cell cultures from FA patients to DEB or MMC results in chromosomal aberrations (breaks, radials, rearrangements) due to damaged DNA repair mechanisms that require functional products of the Fanconi anemia genes. For example, the FANCA, -B, -C, -E, -F, -G, -L, and -M proteins are part of a nuclear core complex that regulates monoubiquitination of the FANCD2 and FANCI proteins (ID complex) during S-phase and after exposure to DNA crosslinking agents (Moldovan and D'Andrea. Annu Rev Genet 43:223, 2009). In unaffected individuals, ubiquitination helps localize the ID complex to sites of DNA damage and facilitate repair (Grompe, and van de Vrugt. Developmental Cell 12:661, 2007; Smogorzewska et al. Cell 129:289, 2007), but in FA patients, this mechanism is impaired.

Genetics

FA is a genetically heterogeneous autosomal recessive disorder. To date, 16 FA or FA-like genes have been discovered. Approximately  86% of all cases are attributed to mutations in three genes: FANCA (OMIM 607139) (~ 60%), FANCC (OMIM 227645) (~ 16%), and FANCG (OMIM 602956) (~ 10%) (Auerbach. Mutat Res 668:4-10, 2009). Nearly 95% of all cases are attributed to mutations in the eight genes, FANCA, -B, -C, -E, -F, -G, -L, and -M, that encode components of a nuclear core complex required for ID complex ubiquitination and facilitation of DNA repair (Grompe, and van de Vrugt. Developmental Cell 12:661, 2007). In the United States, the carrier frequency for FA is estimated at 1 in 181 and the incidence rate of FA is estimated at 1 in 131,000 (see http://www.fanconi.org/; Rosenberg et al. Am J Med Genet A 155:1877, 2011). With the exception of FANCD1 and FANCN patients who seem to have more severe clinical symptoms, obvious genotype-phenotype correlations are generally lacking, and related individuals who harbor a common mutation(s) may have drastically different phenotypes. Other notable exceptions are the c.456+4A>T (IVS4+4A>T) mutation in FANCC, and the R548X and L554P mutations in exon 14 of FANCC which all correlate with a severe form of FA marked by a high frequency of birth defects and early onset of hematologic disease and leukemia (Gillio et al. Blood 90:105-110, 1997). The IVS4+4 mutation is a founder mutation in the Ashkenazi Jewish population with a carrier frequency estimated at ~ 1 in 90 (Verlander. Blood 86:4034-4038, 1995; Whitney et al. Nat Genet 4:202-205, 1993). While the IVS4+4 mutation results in a severe phenotype in the Ashkenazi Jewish population, it does not correlate with a severe phenotype in the Japanese population (Futaki et al. Blood 95:1493, 2000). Other causative mutations in FANCC are spread throughout the gene and include primarily missense/nonsense mutations, splice-site mutations, and small insertions or deletions. Large multi-exon deletions have also been reported in the FANCC gene. Three mutations, c.67delG (a.k.a. 322delG), IVS4+4T>C, and c.1642C>T (a.k.a.1897C>T) are more common than other FANCC mutations.

Testing Strategy

This test involves bidirectional DNA sequencing of the FANCC gene plus ~20 bp of flanking non-coding DNA on either side of each exon. We will also sequence any single exon (Test #100) or pair of exons (Test #200) in family members of patients with known mutations or to confirm research results.

Indications for Test

Patients with clinical features of FA, individuals with a family history of FA, and patients that develop aplastic anemia at any age even if they present no other physical abnormalities.

Gene

Official Gene Symbol OMIM ID
FANCC 613899
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Fanconi Anemia, Complementation Group C 227645

CONTACTS

Genetic Counselors
Geneticist
Citations
  • Auerbach AD. 2009. Fanconi anemia and its diagnosis. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 668: 4–10. PubMed ID: 19622403
  • Dokal I. 2000. The genetics of Fanconi’s anaemia. Baillieres Best Pract. Res. Clin. Haematol. 13: 407–425. PubMed ID: 11030042
  • Fanconi Anemia Research Fund, Inc.
  • Futaki, M., et al. (2000). "The IVS4 + 4 A to T mutation of the fanconi anemia gene FANCC is not associated with a severe phenotype in Japanese patients". Blood 95(4):1493-8.
    PubMed ID: 10666230
  • Giampietro PF, Verlander PC, Davis JG, Auerbach AD. 1997. Diagnosis of Fanconi anemia in patients without congenital malformations: an international Fanconi Anemia Registry Study. Am. J. Med. Genet. 68: 58–61. PubMed ID: 8986277
  • Gillio, A. P., et.al. (1997). "Phenotypic consequences of mutations in the Fanconi anemia FAC gene: an International Fanconi Anemia Registry study." Blood 90(1): 105-10. PubMed ID: 9207444
  • Grompe M, and Van de Vrugt, H. 2007. The Fanconi Family Adds a Fraternal Twin. Developmental Cell 12: 661–662. PubMed ID: 17488615
  • Moldovan G-L, D’Andrea AD. 2009. How the Fanconi Anemia Pathway Guards the Genome. Annual Review of Genetics 43: 223–249. PubMed ID: 19686080
  • Rosenberg PS, Greene MH, Alter BP. 2003. Cancer incidence in persons with Fanconi anemia. Blood 101: 822–826. PubMed ID: 12393424
  • Sasaki MS, Tonomura A. 1973. A high susceptibility of Fanconi’s anemia to chromosome breakage by DNA cross-linking agents. Cancer Research 33: 1829–1836. PubMed ID: 4352739
  • Smogorzewska A, Matsuoka S, Vinciguerra P, McDonald ER, Hurov KE, Luo J, Ballif BA, Gygi SP, Hofmann K, D’Andrea AD, Elledge SJ. 2007. Identification of the FANCI Protein, a Monoubiquitinated FANCD2 Paralog Required for DNA Repair. Cell 129: 289–301. PubMed ID: 17412408
  • The Rockefeller University Fanconi Anemia Mutation Database
  • Tischkowitz MD, Hodgson SV. 2003. Fanconi anaemia. Journal of medical genetics 40: 1–10. PubMed ID: 12525534
  • Verlander, P. C., et.al. (1995). "Carrier frequency of the IVS4 + 4 A-->T mutation of the Fanconi anemia gene FAC in the Ashkenazi Jewish population." Blood 86(11): 4034-8. PubMed ID: 7492758
  • Whitney, M. A., et.al. (1993). "A common mutation in the FACC gene causes Fanconi anaemia in Ashkenazi Jews." Nat Genet 4(2): 202-5. PubMed ID: 8348157
Order Kits
TEST METHODS

Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (http://www.hgvs.org).  As required, DNA is extracted from the patient specimen.  PCR is used to amplify the indicated exons plus additional flanking non-coding sequence.  After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions.  In nearly all cases, the full coding region of each exon as well as 20 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of March 2016, we compared 17.37 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 12 years of our lab operation we have Sanger sequenced roughly 8,800 PCR amplicons. Only one error has been identified, and this was due to sequence analysis error.

Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).

Analytical Limitations

In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.

Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.

In most cases, only the indicated exons and roughly 20 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.

In nearly all cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants, due for example to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR and cycle sequencing.

Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.

Deletion/Duplication Testing Via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

Order Kits

Ordering Options


myPrevent - Online Ordering
  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
REQUISITION FORM
  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

SPECIMEN TYPES
WHOLE BLOOD

(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.

DNA

(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.

CELL CULTURE

(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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