Birt-Hogg-Dubé Syndrome — a hereditary syndrome where spontaneous pneumothorax, skin fibrofolliculomas, and renal cell carcinoma occur together, frequently misattributed to separate unrelated conditions for years.
Whole genome sequencing identifies all FLCN pathogenic variants, establishing the diagnosis that transforms three seemingly unrelated conditions — lung cysts, skin tumors, and kidney cancer — into a single manageable hereditary syndrome.
Birt-Hogg-Dubé Syndrome
Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant hereditary tumor syndrome caused by germline pathogenic variants in FLCN (folliculin) on chromosome 17p11.2. FLCN encodes folliculin, a tumor suppressor that regulates the mTOR signaling pathway. BHD is characterized by three cardinal features: multiple skin fibrofolliculomas (benign hair follicle hamartomas, appearing as small white papules on the face, neck, and upper trunk), pulmonary cysts with risk of spontaneous pneumothorax, and renal cell carcinoma — most commonly a distinctive hybrid oncocytic/chromophobe histologic hybrid unique to BHD, though clear cell and other subtypes also occur.
Renal cell carcinoma develops in approximately 27-34% of FLCN pathogenic variant carriers, with a median onset age of 48 years — substantially younger than sporadic RCC. The distinctive histological features of BHD-associated RCC — chromophobe, oncocytoma, and hybrid variants — differ from most common sporadic clear cell RCC and may prompt the pathologist to raise BHD consideration after nephrectomy. Spontaneous pneumothorax occurs in approximately 24% of BHD carriers, approximately 7-fold more frequently than in the general population, and recurrence rates are high. Pulmonary cysts are present on chest CT in the vast majority of FLCN carriers even without symptomatic pneumothorax.
The diagnostic challenge of BHD lies in the presentation pattern. Patients presenting with spontaneous pneumothorax — particularly those under 40, with recurrent episodes, or with a family history of pneumothorax — may have BHD evaluated only as 'idiopathic spontaneous pneumothorax' without genomic testing. These patients then receive no renal surveillance and develop RCC without preventive monitoring. Similarly, patients with characteristic fibrofolliculomas who do not have a dermatologist familiar with BHD may receive biopsies with a generic fibromatosis or angiofibromatosis diagnosis. FLCN pathogenic variants include mononucleotide C-insert deletions in exon 11 (a hotspot accounting for approximately 50% of pathogenic variants), missense variants, nonsense variants, and large genomic deletions.
Large FLCN genomic deletions are missed by standard sequencing panels. The exon 11 hotspot accounts for 50% of variants, leaving the other 50% requiring complete gene analysis to detect.
Large FLCN deletions explain a significant fraction of BHD — and require copy number analysis to detect
Approximately 10-15% of FLCN pathogenic variants are large genomic deletions spanning one or more exons. These are not detected by standard Sanger or next-generation sequencing panel approaches that do not include dedicated copy number variant analysis. In the BHD context, a missed large FLCN deletion in a patient with recurrent pneumothorax means they never receive the renal surveillance that would detect RCC at a surgically curable stage. Whole genome sequencing simultaneously sequences all FLCN exons, detects copy number variants across the FLCN locus, and resolves the complete variant landscape — providing the definitive molecular diagnosis in a single test.
Confirming BHD converts three alarming diagnoses into one manageable hereditary syndrome
A BHD patient without a diagnosis may be followed by a pulmonologist for 'recurrent idiopathic pneumothorax,' a dermatologist for 'fibrofolliculomas of uncertain significance,' and a urologist for 'incidentally discovered renal mass' — three separate clinical pathways with no coordination. After FLCN molecular confirmation, these three findings are unified into one hereditary syndrome with a single coordinated surveillance protocol: annual renal ultrasound or alternating MRI/CT every 3 years (NCCN recommendation), dermatological review, pulmonary evaluation, and cascade family testing. This integration of care is only possible after the molecular diagnosis is established.
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A patient had spent decades in the UK healthcare system without a diagnosis. Dante data, accepted by NHS clinical teams at Queen Elizabeth University Hospital Glasgow, identified Noonan Syndrome and a RUNX1 leukemia-associated variant that had gone undetected. After 40 years, they finally had an answer.
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A patient came to Dante to investigate periodic paralysis. Reading the complete genome identified a concurrent hereditary cardiac finding — Brugada syndrome — that their doctor confirmed with an ECG. The result also explained a family member's unresolved cardiac history. One test. Every answer in it.
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Common questions about whole genome sequencing.
What is the difference between whole genome sequencing and a targeted genetic test?
Targeted genetic tests — including standard hereditary cancer panels — read a pre-defined list of known variants in a specific set of genes. They are designed to find what they already know to look for. Whole genome sequencing reads your entire genome: all 6 billion base pairs, every gene, every region between genes. A Mayo Clinic study published in JAMA Oncology found that standard testing guidelines missed more than half of patients with inherited cancer mutations. Genome Test does not have a fixed list.
What will I receive when my results are ready?
Your Dante Genome delivers 200+ physician-ready reports organized by clinical category — hereditary cancer, cardiac conditions, rare diseases, pharmacogenomics, carrier status, and more. Reports are delivered to your secure Genome Manager and are formatted for direct clinical use. Your genome data is permanently retained and re-analyzed automatically as science advances.
What happens if a clinically significant variant is found?
If a pathogenic or likely-pathogenic variant is identified, it will be clearly flagged in your physician-ready report with clinical context, published evidence, and recommended next steps. We recommend sharing any clinically significant finding with your physician or a genetic counselor, who can guide decisions about surveillance, risk reduction, or cascade testing for family members.
How is this different from a consumer DNA test like 23andMe or AncestryDNA?
Consumer DNA tests use genotyping chips that read less than 0.1% of your genome — a tiny pre-selected set of common variants. They are optimized for ancestry and population-level traits, not clinical genetic findings. The Dante Genome Test sequences 100% of your genome at 30X coverage, the same standard used in clinical diagnostic settings. The two tests are not comparable in scope, methodology, or clinical utility.
How long does it take to get results, and how are they delivered?
Your collection kit ships within 48 hours of ordering. Once your sample arrives at our CLIA-certified laboratory, sequencing and analysis takes 6–8 weeks. Results are delivered securely to your Genome Manager, where you can access your reports, share them with your physician, and receive automatic updates as new findings are validated against your genome.
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