Birt-Hogg-Dubé Syndrome (BHDS)

Birt-Hogg-Dubé syndrome (BHDS) is characterized by an increased risk of unique benign skin tumors, pulmonary cysts, spontaneous pneumothorax, and various types of renal tumors and renal cell carcinoma (RCC).

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Quick Reference
Test Code: 5921 Test Name: FLCN seq and del/dup TAT 14-21 days Gene: 1
Test Code: 5922 Test Name: FLCN specific site analysis TAT 7-14 days Gene: 1

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Why Is This Important?

  1. Option to modify age, frequency, and type of cancer screening, as needed
  2. Identify at-risk family members

When To Consider Testing

Testing is indicated for those with any of the following findings:1

  • Five or more facial or truncal papules with at least one histologically confirmed fibrofolliculoma, with or without a family history of BHDS
  • Facial papules histologically confirmed to be angiofibroma in someone that does not fit the clinical criteria of tuberous sclerosis complex (TSC) or multiple endocrine neoplasia type 1 (MEN1)
  • Multiple and bilateral chromophobe, oncocytic, and/or hybrid renal tumors
  • A single oncocytic, chromophobe, or oncocytic hybrid renal tumor and a family history of renal cancer with any of the above renal cell tumor types
  • A family history of autosomal dominant primary spontaneous pneumothorax (PSP) without a history of smoking or chronic obstructive pulmonary disease (COPD).
  • Family members with a known FLCN mutation

Mutation Detection Rate

Ambry's FLCN analysis can detect >99.9% of described mutations in the gene, when present (analytic sensitivity).

Test Description

FLCN coding exons 1-11 and well into the 5’ and 3’ ends of all the introns and untranslated regions are analyzed by sequencing. Gross deletion/duplication analysis determines gene copy number for coding exons 1-11. Clinically significant intronic findings beyond 5 base pairs are always reported. Intronic variants of unknown or unlikely clinical significance are not reported beyond 5 base pairs from the splice junction. Genomic deoxyribonucleic acid (gDNA) is isolated from the patient’s specimen using standardized methodology and quantified. Sequence enrichment of the targeted coding exons and adjacent intronic nucleotides is carried out by a bait-capture methodology, using long biotinylated oligonucleotide probes followed by polymerase chain reaction (PCR) and next generation sequencing (NGS). Sanger sequencing is performed for any regions missing or with insufficient read depth coverage for reliable heterozygous variant detection. Reportable small insertions and deletions, potentially homozygous variants, variants in regions complicated by pseudogene interference, and single nucleotide variant calls not satisfying 100x depth of coverage and 40% het ratio thresholds are verified by Sanger sequencing. Gross deletion/duplication analysis of FLCN using read-depth from NGS data is also performed. Any copy number changes detected by NGS are confirmed by targeted chromosomal microarray and/or multiplex ligation-dependent probe amplification (MLPA).

 

1. JR T. Birt-Hogg-Dubé syndrome. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

2. Mu W, et al. Sanger confirmation is required to achieve optimal sensitivity and specificity in next-generation sequencing panel testing. J Mol Diagn. 2016. 18(6):923-932.

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