Birt-Hogg-Dube Syndrome via the FLCN Gene

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).

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).

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).

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.