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Birt-Hogg-Dubé syndrome (BHDS), caused by heterozygous germline pathogenic variants in the FLCN gene, is commonly characterized by cutaneous manifestations, pulmonary cysts (typically with history of pneumothorax), and various renal tumors.
Disease Overview
Common Features
Clinical Criteria
BHDS should be suspected in individuals with any of the following major or minor criteria. The diagnosis of BHDS is established in an individual with one major or two minor criteria.
- Major criteria
- Five or more fibrofolliculomas/trichodiscomas with at least one confirmed histologically
- A single pathogenic FLCN germline variant
- Minor criteria
- Multiple lung cysts, with or without spontaneous primary pneumothoraxes
- Early-onset renal cancer (<50 years of age)
- Multifocal or bilateral renal cancer
- Renal cancer of mixed chromophobe and oncocytic histology
- First-degree relative with BHDS
Genetics
Gene
FLCN (NM_144997)
Etiology
Approximately two individuals per million in the general population are estimated to have BHDS. Over 400 families affected by BHDS have been reported.
Inheritance
Autosomal dominant
Penetrance
High; approximately 90-95% of individuals with a single pathogenic FLCN variant will develop at least one feature of BHDS.
Recurrent Variants
Twenty to 24% of families with BHDS were found to have either the pathogenic variant c.1285delC or c.1285dupC, located in the polycytosine mutational hotspot in exon 11.
Test Interpretation
Contraindications for Ordering
- Should not be ordered to detect somatic variants associated with malignancy because sensitivity for mosaic variants is low with methodology used for germline assays
- Individuals with hematologic malignancy and/or a previous allogeneic bone marrow transplantation should not undergo molecular genetic testing on a peripheral blood specimen.
- Testing of cultured fibroblasts is required for accurate interpretation of test results.
- When a relative has a previously identified pathogenic variant, targeted sequencing for that variant may be appropriate; refer to the Laboratory Test Directory for additional information.
This test is performed using the following sequence of steps:
- Selected genomic regions, primarily coding exons and exon-intron boundaries, from the targeted genes are isolated from extracted genomic DNA using a probe-based hybrid capture enrichment workflow.
- Enriched DNA is sequenced by massively parallel sequencing (MPS; also known as next generation sequencing [NGS]) followed by paired-end read alignment and variant calling using a custom bioinformatics pipeline. The pipeline includes an algorithm for detection of large (single exon-level or larger) deletions and duplications.
- Sanger sequencing is performed as necessary to fill in regions of low coverage and in certain situations, to confirm variant calls.
- Large deletion/duplication calls made using MPS are confirmed by an orthogonal exon-level microarray when sample quality and technical conditions allow.
Sensitivity and Specificity
Clinical Sensitivity
Analytic Sensitivity and Specificity
| Variant Class | Analytic Sensitivity (PPA) Estimatea (%) and 95% Credibility Region | Analytic Specificity (NPA) Estimate (%) |
|---|---|---|
|
SNVs |
>99 (96.9-99.4) |
>99.9 |
|
Deletions 1-10 bpb |
93.8 (84.3-98.2) |
>99.9 |
|
Insertions 1-10 bpb |
94.8 (86.8-98.5) |
>99.9 |
|
Exon-levelc deletions |
97.8 (90.3-99.8) [2 exons or larger] 62.5 (38.3-82.6) [single exon] |
>99.9 |
|
Exon-levelc duplications |
83.3 (56.4-96.4) [3 exons or larger] |
>99.9 |
|
aPPA values are derived from larger methods-based MPS and/or Sanger validations. These values do not apply to testing performed by multiplex ligation-dependent probe amplification (MLPA) unless otherwise indicated. bVariants greater than 10 bp may be detected, but the analytic sensitivity may be reduced. cIn most cases, a single exon deletion or duplication is less than 450 bp and 3 exons span a genomic region larger than 700 bp. bp, base pairs; NPA, negative percent agreement; PPA, positive percent agreement; SNVs, single nucleotide variants |
||
Results
| Result | Variant(s) Detected | Clinical Significance |
|---|---|---|
|
Positive |
One FLCN pathogenic variant detected |
Consistent with a diagnosis of Birt-Hogg-Dubé syndrome |
|
Negative |
No pathogenic variants detected |
Diagnosis of Birt-Hogg-Dubé syndrome is unlikely but not excluded |
|
Uncertain |
FLCN variant(s) of uncertain clinical significance detected |
Uncertain; it is unknown whether variant is benign or pathogenic |
Limitations
- A negative result does not exclude a diagnosis of BHDS or FLCN-associated tumors.
- Diagnostic errors can occur due to rare sequence variations.
- Interpretation of this test result may be impacted if this patient has had an allogeneic stem cell transplantation.
- The following will not be evaluated:
- Variants outside the coding regions and intron-exon boundaries of the FLCN gene
- Regulatory region variants and deep intronic variants
- Breakpoints of large deletions/duplications
- The following may not be detected:
- Deletions/duplications/insertions of any size by MPS
- Large duplications less than 3 exons in size
- Noncoding transcripts
- Low-level somatic variants
- Certain other variants due to technical limitations in the presence of pseudogenes and/or repetitive or homologous regions
References
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18234728
Toro JR, Wei MH, Glenn GM, et al. 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. 2008;45(6):321-331.
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20413710
Kunogi M, Kurihara M, Ikegami TS, et al. Clinical and genetic spectrum of Birt-Hogg-Dube syndrome patients in whom pneumothorax and/or multiple lung cysts are the presenting feature. J Med Genet. 2010;47(4):281-2877.
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26334087
Schmidt LS, Linehan WM. Molecular genetics and clinical features of Birt-Hogg-Dubé syndrome. Nat Rev Urol. 2015;12(10):558-569.
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Houweling AC, Gijezen LM, Jonker MA, et al. Renal cancer and pneumothorax risk in Birt-Hogg-Dubé syndrome; an analysis of 115 FLCN mutation carriers from 35 BHD families. Br J Cancer. 2011;105(12):1912-1919.
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11927500
Zbar B, Alvord WG, Glenn G, et al. Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dubé syndrome. Cancer Epidemiol Biomarkers Prev. 2002;11(4):393-400.
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30586397
Sattler EC, Reithmair M, Steinlein OK. Kidney cancer characteristics and genotype-phenotype-correlations in Birt-Hogg-Dubé syndrome. PLoS One. 20186;13(12):e0209504.
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30845233
Johannesma PC, van de Beek I, van der Wel TJWT, et al. Renal imaging in 199 Dutch patients with Birt-Hogg-Dubé syndrome: Screening compliance and outcome. PLoS One. 2019;14(3):e0212952.
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GeneReviews - Birt-Hogg-Dubé Syndrome
Sattler EC, Steinlein OK. Birt-Hogg-Dubé syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, ed. GeneReviews. University of Washington, Seattle. Last update Jan 2020; accessed Aug 2022.
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33987191
Muller ME, Daccord C, Taffé P, et al. Prevalence of Birt-Hogg-Dubé syndrome determined through epidemiological data on spontaneous pneumothorax and Bayes theorem. Front Med (Lausanne). 2021;8:631168.
Recommended test to confirm a clinical diagnosis or family history of BHDS
If a familial sequence variant has been previously identified, targeted sequencing for that variant may be appropriate; refer to the Laboratory Test Directory for additional information.