FLCN (folliculin) genetic testing

Heritable FLCN testing should be considered in individuals:

• with a suspected diagnosis of Birt-Hogg-Dubé syndrome (BHD)
• where a known pathogenic variant is identified in a relative.

Genetic testing is important for good clinical care of individuals who are suspected of having a heritable pathogenic variant in this gene.

The results of the following investigations may significantly influence the likelihood of detecting a heritable pathogenic variant in the FLCN gene:

• excision and histological confirmation of suspicious skin lesions
• chest CT
• renal imaging - preferably MRI with contrast.

There is no data on the frequency of FLCN heritable (germline) pathogenic variants in unselected, population-based series of cancer of the kidney, however the incidence is low. Data are only available from studies where patients have been ascertained on the basis of presenting with manifestations clinically suggestive of BHD (probands) and then cascade testing of at risk relatives (carriers). The frequency of heritable pathogenic variants in FLCN is dependent on kidney cancer pathology (hybrid oncocytic tumours, oncocytomas and chromophobe renal cancers in particular) and the presence of pulmonary and dermatologic features of BHD.

* sequencing only
** A number of large deletions in folliculin have been identified in families who had been clinically diagnosed with BHD but had not been shown to have a pathogenic variant using DNA sequencing techniques^r

Predictive testing should never be ordered when only a variant of uncertain significance or a benign/likely benign variant has been identified in a family.

A range of testing methodologies are needed to identify pathogenic changes in the FLCN gene including:

• sequencing 
• copy number analysis (e.g. MLPA)

Information about DNA tests and testing laboratories is available from: 

• RCPA catalogue of genetic tests and laboratories 
• GeneReviews^®
• European Directory of DNA Diagnostic Laboratories 
• Genetic Testing Registry 
• UK Genetic Testing Network 

If a decision is made to test this gene(s) as part of a cancer gene panel, care should be taken to select a panel where the individual genes tested have both clinical validity and clinical utility. 

If this gene is tested using genomic sequencing (“next generation sequencing” or NGS), and testing is uninformative, the value of testing using another methodology (e.g. MLPA, Sanger sequencing) should be considered.

If a pathogenic variant is identified refer to a clinical genetics service or familial cancer centre for review, family risk notification and predictive testing. 

If a mosaic pathogenic variant is identified refer to a clinical genetics service or familial cancer centre for review and guidance about the penetrance of phenotypic features (including cancer risk).

Pre test counselling information.

BHD Foundation

The European Molecular Genetic Quality Network (EMQN)

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Bibliography

Schmidt, L. S. and W. M. Linehan. 2015. "Molecular genetics and clinical features of Birt-Hogg-Dube syndrome." Nat Rev Urol 12(10):558-569.

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Birt-Hogg-Dube (BHD) syndrome is an inherited renal cancer syndrome in which affected individuals are at risk of developing benign cutaneous fibrofolliculomas, bilateral pulmonary cysts and spontaneous pneumothoraces, and kidney tumours. Bilateral multifocal renal tumours that develop in BHD syndrome are most frequently hybrid oncocytic tumours and chromophobe renal carcinoma, but can present with other histologies. Germline mutations in the FLCN gene on chromosome 17 are responsible for BHD syndrome--BHD-associated renal tumours display inactivation of the wild-type FLCN allele by somatic mutation or chromosomal loss, confirming that FLCN is a tumour suppressor gene that fits the classic two-hit model. FLCN interacts with two novel proteins, FNIP1 and FNIP2, and with AMPK, a negative regulator of mTOR. Studies with FLCN-deficient cell and animal models support a role for FLCN in modulating the AKT-mTOR pathway. Emerging evidence links FLCN with a number of other molecular pathways and cellular processes important for cell homeostasis that are frequently deregulated in cancer, including regulation of TFE3 and/or TFEB transcriptional activity, amino-acid-dependent mTOR activation through Rag GTPases, TGFbeta signalling, PGC1alpha-driven mitochondrial biogenesis, and autophagy. Currently, surgical intervention is the only therapy available for BHD-associated renal tumours, but improved understanding of the FLCN pathway will hopefully lead to the development of effective forms of targeted systemic therapy for this disease.

Dow, E. and I. Winship. 2016. "Renal angiomyolipoma in Birt-Hogg-Dube syndrome: A case study supporting overlap with tuberous sclerosis complex." Am J Med Genet A 170(12):3323-3326.

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Birt-Hogg-Dube syndrome (BHD) is an autosomal dominant disease characterised by benign cutaneous lesions, pulmonary cysts, and an increased risk of renal tumors. This rare condition is due to a mutation in the folliculin (FLCN) gene on chromosome 17q11.2, which has a role in the mechanistic/mammalian target of rapamycin (mTOR) signaling pathway of tumorigenesis. This case illustrates a patient with BHD and a renal angiomyolipoma, a neoplastic lesion not usually associated with BHD but common in Tuberous Sclerosis Complex (TSC). There is both clinical and molecular overlap between BHD and TSC, which may arise from similarities in function of the TSC and FLCN proteins in the mTOR pathway; this case further demonstrates this potential correlation. (c) 2016 Wiley Periodicals, Inc.

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