Birt-Hogg-Dube Syndrome via the FLCN Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
8409 FLCN 81479 81479,81479 $640 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8409FLCN81479 81479 $640 Order Options and Pricing

Pricing Comments

This test is also offered via our exome backbone with CNV detection (click here). The exome-based test may be higher priced, but permits reflex to the entire exome or to any other set of clinically relevant genes.

A 25% additional charge will be applied to STAT orders. View STAT turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

Turnaround Time

18 days on average

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

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. 2014). 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).

Genetics

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. 2014). 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

This test provides full coverage of all coding exons of the FLCN gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Clinical Sensitivity - Sequencing with CNV PG-Select

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. 2014. GeneReviews). Deletions and duplications are reported in 3-5% of individuals with Birt-Hogg-Dubé Syndrome (Toro. 2014. GeneReviews).

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

Gene

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

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Citations

  • 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. 2014. Birt-Hogg-DubĂ© 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

Ordering/Specimens

Ordering Options

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  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

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