Background:

Fanconi Anemia (FA) is characterized by bone marrow failure, increased risk for cancer, and physical abnormalities. Progressive bone marrow failure is responsible for the most significant morbidity and mortality.  Clinically heterogeneous, FA individuals are at increased risk for acute myelogenous leukemia, myelodysplasia, and solid tumors of the neck, head, oral cavities, and gynecological system. Congenital abnormalities are present in approximately 70% of FA patients and include: café au lait spots or hypopigmentation; short stature; radial ray defects; eye defects such as microphthalmia; malformations of the kidney, genitalia, heart, gastrointestinal tract, ears, and feet.  Currently, 15 genes have been identified that, when mutated, can cause FA.  Fanconi complementation group C gene, or FANCC, is inherited in an autosomal recessive manner.  Mutations (nucleotide changes as well as small deletions/duplications) in FANCC are responsible for approximately 10% of all FA cases.

Reasons for Referral:

  • Confirmation of clinical diagnosis in patients with classical or atypical FANCC.
  • Carrier testing of family members of FANCC patients with known mutations.
  • Prenatal diagnosis.
Note: Prior to submitting a sample for FANCC molecular testing, cytogenetic confirmation of Fanconi anemia, by breakage analysis, is recommended and can be performed in the Knight Diagnostic Laboratories.

For breakage analysis please contact Client Services at (855) 535-1522 to obtain the correct requisition form to accompany the specimen.

Additionally, prior to molecular testing, complementation typing (complementation group assignment) is strongly recommended.  Complementation typing is available at a CLIA certified laboratory at the following URL address:
http://www.cincinnatichildrens.org/service/d/diagnostic-labs/cytogenetics/fanconi-anemia/

Please attach the complementation group assignment documentation to the molecular testing requisition form, if possible.

Methodology:

Sequencing can be performed by either Sanger Sequencing or Next-Generation Sequencing.

Sanger Sequencing: Sequencing of FANCC is carried out by amplification of all exons and intron/exon boundaries followed by bi-directional Sanger sequencing. The sensitivity of full gene sequencing is estimated to be approximately 99% for single nucleotide substitutions and small insertions/deletions. All nucleotide changes are analyzed within the context of current databases and literature to predict pathogenicity.

NGS: Next generation sequencing will analyze the exons or coding regions of FANCC using Illumina NextSeq 500/550 technology. Samples are prepared using hybridization probes to enrich exonic regions. Promoter, intronic, etc. regions are not assessed on our assay, but may contain variants that impact gene function.

Test reporting follows the ACMG Standards & Guidelines for Clinical Genetics Laboratories, Ultra-Rare Disorders Guidelines, and Interpretation of Sequence Variants Guidelines.

Specimen Requirements:

Blood: Lavender tube (EDTA) or yellow (ACD)

    • Adult: 6mL
    • Child: 6mL
    • Infant: 2mL

Saliva:  2 ORAgene Saliva Kits (OGR-500) used according to manufacturer instructions.  Please contact KDL Client Services for a Saliva Collection Kit for patients that cannot provide a blood sample.
Assisted Saliva: 4 ORAgene Assisted Saliva Kits (OGR-575) used according to manufacturer instructions.  Please contact KDL Client Services for an Assisted Saliva Collection Kit for patients that cannot provide a blood sample.
Skin Fibroblast: Punch Biopsy (cell cultures will be prepared at KDL and used for testing), or 2 T-25 confluent flasks
DNA: 5-10µg at a minimum of 60-100ng/µL (DNA must be extracted in a CLIA-certified laboratory or a laboratory meeting equivalent requirements as determined by the CAP and/or CMS).

Prenatal:

  • Direct Amniotic Fluid (10-20mL)
  • Direct CVS
  • Cultured Amniocytes (2 T-25 flasks)
  • Cultured CVS (2 T-25 flasks)
  • Cultured Fetal Tissue: Product of Conception (2 T-25 flasks)
  • Cord Blood (1-2mL)

  • Notice Regarding Molecular Genetic Testing on CVS or Amniotic Fluid Specimens:

    • Maternal cell rule-out testing will be performed on all prenatal specimens received.  Please provide maternal blood in addition to the fetal specimen.  Additional charges apply for the maternal cell rule-out test.
    • All genetic testing performed on Direct CVS or Direct Amniotic Fluid specimens will be confirmed on cell cultures prepared by Knight Diagnostic Laboratories.  Cell cultures will be prepared from the specimen received.  Additional charges apply for confirmatory testing.

    For routine testing of blood and saliva (or DNA extracted from them), KDL does NOT accept samples from patients within two (2) weeks of a packed cell/platelet transfusion or within four (4) weeks of a whole blood transfusion.  For extraordinary circumstances, where testing must be performed outside of the above windows, please contact our lab.

    A REQUISITION FORM MUST ACCOMPANY ALL SAMPLES.  Please include detailed clinical information, including ethnicity, clinical history, and family history.

    Test Performed (Days):

    Weekly

    Turn Around Time:

    14 – 21 Days

    Shipment Sensitivity Requirements:

    • Package and ship specimen to remain cold, but not frozen. 
    • Ship via overnight express, using the FedEx priority overnight label provided. 
    • Contact Client Services for shipping kits and instructions at (855) 535-1522.

    References:

    Additional Info:

    Prior to any genetic testing we recommend genetic counseling.  To receive forms and information about prenatal diagnostic testing, please contact Client Services at (855) 535-1522.

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