Birt-Hogg-Dube Syndrome via the FLCN Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
1204 FLCN$750.00 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
FLCN causative mutations will be detected in approximately 88% of individuals with BHDS by sequencing. Almost half of the individuals with BHDS will have a deletion (c.1285delC) or duplication (c.1285dupC) of a C nucleotide in the polycytosine tract in exon 11 (Toro. GeneReviews. 2008). Gross deletions or duplications that are not normally detected via sequencing will not be detected using this method.

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 FLCN$690.00 81479 Add to Order
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Turnaround Time

The great majority of tests are completed within 28 days.

Clinical Features
Birt-Hogg-Dubé syndrome (BHDS) includes cutaneous manifestations, such as fibrofolliculomas (yellowish dome-shaped papules), trichodiscomas (multiple small papules), and acrochordons (skin tags). Skin features typically appear in the third to fourth decade of life and continually grow in size and number with age. BHDS is also characterized by pulmonary cysts/history of pneumothorax, and various types of renal tumors.  The renal tumors that develop are usually bilateral and multifocal, and slow growing (Toro. GeneReviews. 2008). Tumor types include renal oncocytoma, chromophobe renal cell carcinoma, oncocytic hybrid tumor, and a minority of clear cell renal cell carcinoma. The median diagnosis of renal tumors is 48 years of age (range 31-71 years) (Schmidt et al. Am J Hum Genet 76:1023–33, 2005). Some families have renal tumor and/or autosomal dominant spontaneous pneumothorax without cutaneous manifestations. Early diagnosis is important for intervention and improving patient morbidity, since mutations in the FLCN gene may be associated with other cancers (Palmirotta et al. Anticancer Research 30: 751-758 2010; Toro et al. J Med Genet 45:321–331, 2008).
BHDS is inherited in an autosomal dominant pattern with high penetrance and is caused by mutations in the FLCN gene. The proportion of de novo versus inherited mutations in FLCN is currently unknown. FLCN encodes the folliculin protein, which is highly expressed in skin, type 1 pneumocytes, and distal nephrons of the kidney (Toro. GeneReviews. 2008).  Its exact function is unknown, although it may act downstream of rapamycin (mTOR), adenosine monophosphate-activated protein kinase (AMPK), and have a role in the modulation of energy/nutrient sensing and signaling pathways (Hartnan Oncogene 28(13): 1594-1604, 2009).  It has also been suggested to have a role in tumor suppression from the observation that germline mutations in FLCN cause renal tumors, and the presence of somatic mutations and loss of heterozygosity in tumors tissues. The most frequent causative mutation occurs within a polycytosine C8 tract of exon 11 . This mutation probably occurs due to DNA polymerase slippage resulting in gains or losses of repeat units leading to truncated folliculin. Other causative mutations are located throughout the FLCN gene (Palmirotta et al. Anticancer Research 30: 751-758 2010). These include missense, nonsense, splicing, small and large insertions and deletions (Human Gene Mutation Database).
Testing Strategy
The folliculin protein is encoded by 11 exons (4-14) from the FLCN gene on chromosome 11q21.  Testing is accomplished by amplifying each coding exon and ~10 bp of adjacent noncoding sequence, then determining the nucleotide sequence using standard Sanger dideoxy sequencing methods and a capillary electrophoresis instrument. We will also sequence any single exon (Test #100) in family members of patients with a known mutation or to confirm research results.
Indications for Test
Molecular genetic testing is suggested for individuals known to have or suspected of having BHDS, including individuals with either one major or two minors findings as listed below (Menko et al. Lancet 10:1199, 2009):

Major criteria
• At least five fibrofolliculomas or trichodiscomas (at least one histologically confirmed)

Minor criteria
• Multiple lung cysts: bilateral basally located lung cysts with no other apparent cause, with or without spontaneous primary pneumothorax
• Renal cancer: early onset (<50 years) or multifocal or bilateral renal cancer, or renal cancer of mixed chromophobe and oncocytic histology
• A first-degree relative with BHDS


Official Gene Symbol OMIM ID
FLCN 607273
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Tests

Hereditary Leiomyomatosis and Renal Cell Cancer or Fumarase Deficiency via the FH Gene
Hereditary Papillary Renal Cell Carcinoma via the MET Gene


Genetic Counselors
  • Hartnan et al. 2008. The role of the Birt-Hogg-Dubé protein in mTOR activation and renal tumorigenesis. Oncogene 28(13): 1594-1604. PubMed ID: 19234517
  • Human Gene Mutation Database (Bio-base).
  • Menko et al. (2009) "Birt-Hogg-Dubé syndrome: diagnosis and management."  Lancet 10:1199. PubMed ID: 19959076
  • Palmirotta et al. (2010) "Association between Birt Hogg Dube syndrome and cancer predisposition." Anticancer Research 30: 751-758. PubMed ID: 20392993
  • Schmidt et al. (2005) "Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome." Am J Hum Genet 76:1023–33,. PubMed ID: 15852235
  • Toro et al. (2008) "BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports." J Med Genet 45:321–331. PubMed ID: 18234728
  • Toro JR. 1993. Birt-Hogg-Dubé Syndrome. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, and Stephens K, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle,. PubMed ID: 20301695
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Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (  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 10 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of February 2018, we compared 26.8 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 14 years of our lab operation we have Sanger sequenced roughly 14,300 PCR amplicons. Only one error has been identified, and this was an error in analysis of sequence data.

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 10 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.

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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.
  • 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.


(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.


(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.


(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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