Birt-Hogg-Dube Syndrome: FLCN Gene Sequencing

Condition Description

Birt-Hogg-Dube syndrome (BHDS) is an autosomaldominant condition, the symptoms of which include hair follicle hamartomas,kidney tumors, and spontaneous pneumothorax. Individuals with BHDS usuallypresent with multiple, small, skin-colored, dome-shaped papules distributedover the face, neck, and upper trunk. These cutaneous manifestations includefibrofolliculomas, trichodiscomas/angiofibromas, perifollicular fibromas, andacrochordons; only fibrofolliculomas, however, are specific for BHDS. Skinlesions typically first appear in early adulthood and increase in size andnumber with age. Renal tumors are typically bilateral, multifocal, and usuallyslow growing; median age of tumor diagnosis is 48 years. The most common renaltumors are renal hybrids of oncocytoma and chromophobe histologic cell types.Lung cysts are mostly bilateral and multifocal; most individuals areasymptomatic but have a high risk for spontaneous pneumothorax. Some familieshave renal tumor and/or autosomal dominant spontaneous pneumothorax withoutcutaneous manifestations. Disease severity can vary significantly even withinthe same family.

The FLCN gene(17p11.2) (also known as BHD) is the only gene known to be associatedwith BHDS. Sequence analysis detects mutations in FLCN in 88% ofaffected individuals; therefore, some affected individuals who fulfill clinicaldiagnostic criteria do not have an identifiable mutation. Molecular genetictesting is indicated in all individuals known to have or suspected of havingBHDS, including individuals with one of the following:

o        Five ormore facial or truncal papules with at least one histologically confirmedfibrofolliculoma, with or without a family history of BHDS

o        Facialpapules histologically confirmed to be angiofibroma in an individual who doesnot fit the clinical criteria of tuberous sclerosiscomplex (TSC) or multiple endocrineneoplasia type 1 (MEN1)

o        Multipleand bilateral chromophobe, oncocytic, and/or hybrid renal tumors

o        Asingle oncocytic, chromophobe, or oncocytic hybrid renal tumor and a familyhistory of renal cancer with any of the above renal cell tumor types

o        Afamily history of autosomal dominant primary spontaneous pneumothorax without ahistory of smoking or COPD

Theproportion of cases caused by de novo mutations is unknown because asufficient number of parents have not been evaluated for subtle manifestation,nor are there sufficient data on clinically unaffected parents who have beenevaluated by molecular genetic testing. Although some individuals diagnosedwith BHDS have an affected parent, the family history may appear to be negativebecause of failure to recognize the disorder in family members, early death ofthe parent before the onset of symptoms, or late onset of the disease in theaffected parent.

For patients with suspected BHDS, sequence analysis is recommended as the first step in mutation identification. For patients in whom mutations are not identified by full gene sequencing, deletion/duplication analysis is appropriate.

Click here for the GeneTests summary on this condition.

Genes (1)


This test is indicated for:

  • Confirmation of a clinical diagnosis of Birt-Hogg-Dube syndrome
  • Individuals at-risk for Birt-Hogg-Dube syndrome due to family history


PCR amplification of 14 exons contained in the FLCN gene is performed on the patient's genomic DNA. Direct sequencing of amplification products is performed in both forward and reverse directions, using automated fluorescence dideoxy sequencing methods. The patient's gene sequences are then compared to a normal reference sequence. Sequence variations are classified as mutations, benign variants unrelated to disease, or variations of unknown clinical significance. Variants of unknown clinical significance may require further studies of the patient and/or family members. This assay does not interrogate the promoter region, deep intronic regions, or other regulatory elements, and does not detect large deletions.


Clinical Sensitivity: 88%. Mutations in the promoter region, some mutations in the introns and other regulatory element mutations cannot be detected by this analysis. Large deletions will not be detected by this analysis. Results of molecular analysis should be interpreted in the context of the patient's biochemical phenotype.

Analytical Sensitivity: ~99%

Specimen Requirements

Listed below are EGL's preferred sample criteria. For any questions, please call 470.378.2200 and ask to speak with client services (
Submit only 1 of the following specimen types
Whole Blood (EDTA)

EDTA (Purple Top)
Infants and Young Children (<2 years of age): 2-3 ml
Children > 2 years of age to 10 years old: 3-5 ml
Older Children & Adults: 5-10 ml
Autopsy: 2-3 ml unclotted cord or cardiac blood
Collection and Shipping
Ship sample at room temperature for receipt at EGL within 72 hours of collection. Do not freeze.
DNA, Isolated

Isolation using the Perkin Elmer™Chemagen™ Chemagen™ Automated Extraction method or Qiagen™ Puregene kit for DNA extraction is recommended.
Collection and Shipping
Refrigerate until time of shipment in 100 ng/µL in TE buffer. Ship sample at room temperature with overnight delivery.

Oragene™ Saliva Collection Kit
Orangene™ Saliva Collection Kit used according to manufacturer instructions. Please contact EGL for a Saliva Collection Kit for patients that cannot provide a blood sample.
Collection and Shipping
Please do not refrigerate or freeze saliva sample. Please store and ship at room temperature.

Special Instructions

Submit copies of diagnostic biochemical test results with the sample, if appropriate. Contact the laboratory if further information is needed.

Sequence analysis is required before deletion/duplication analysis by targeted CGH array. If sequencing is performed outside of EGL Genetics, please submit a copy of the sequencing report with the test requisition.

  • Deletion/duplication analysis of the FLCN gene by CGH array is available for those individuals in whom sequence analysis is negative (VK).
  • Custom diagnostic mutation analysis (KM) is available to family members if mutations are identified by targeted mutation testing or sequencing analysis.
  • Prenatal testing is available to individuals who are confirmed carriers of mutations. Please contact the laboratory genetic counselor to discuss appropriate testing prior to collecting a prenatal specimen.

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