Birt-Hogg-Dube syndrome 1

Summary

Birt-Hogg-Dube syndrome 1 (MONDO:0800445) is a disease caused by FLCN (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe)
• Causal gene: FLCN (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 639
• Phenotypes (HPO): 21

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.5	Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

21 HPO clinical features (Orphanet curated; top 21 by frequency):

HPO ID	Term	Frequency
HP:0010609	Skin tags	Very frequent (80-99%)
HP:0030436	Fibrofolliculoma	Very frequent (80-99%)
HP:0002108	Spontaneous pneumothorax	Frequent (30-79%)
HP:0005948	Multiple pulmonary cysts	Frequent (30-79%)
HP:0006522	Repeated pneumothoraces	Frequent (30-79%)
HP:0000107	Renal cyst	Occasional (5-29%)
HP:0001012	Multiple lipomas	Occasional (5-29%)
HP:0002107	Pneumothorax	Occasional (5-29%)
HP:0002664	Neoplasm	Occasional (5-29%)
HP:0002865	Medullary thyroid carcinoma	Occasional (5-29%)
HP:0002897	Parathyroid adenoma	Occasional (5-29%)
HP:0005584	Renal cell carcinoma	Occasional (5-29%)
HP:0010615	Angiofibromas	Occasional (5-29%)
HP:0012056	Cutaneous melanoma	Occasional (5-29%)
HP:0025388	Thyroid nodule	Occasional (5-29%)
HP:0031523	Salivary gland oncocytoma	Occasional (5-29%)
HP:0032228	Trichodiscoma	Occasional (5-29%)
HP:0200040	Epidermoid cyst	Occasional (5-29%)
HP:6000022	Collagenoma	Occasional (5-29%)
HP:6000853	Thyroid cyst	Occasional (5-29%)
HP:6000957	Oral mucosal papule	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Birt-Hogg-Dube syndrome 1
Mondo ID	MONDO:0800445
MeSH	D058249
OMIM	135150
Orphanet	122
DOID	DOID:0050676
NCIT	C28244
SNOMED CT	110985001
GARD	0002322
MedDRA	10067736
Is cancer (heuristic)	no

Also known as: fibrofolliculomas with trichodiscomas and acrochordons · Hornstein-Knickenberg syndrome

Data availability: 639 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › Birt-Hogg-Dube syndrome › Birt-Hogg-Dube syndrome 1

Related subtypes (1): Birt-Hogg-Dube syndrome 2

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

246 benign/likely benign, 125 conflicting classifications of pathogenicity, 86 likely benign, 66 uncertain significance, 36 pathogenic, 25 benign, 13 pathogenic/likely pathogenic, 3 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1068469	NM_144997.7(FLCN):c.57_58del (p.Phe20fs)	FLCN	Pathogenic	criteria provided, multiple submitters, no conflicts
1073198	NM_144997.7(FLCN):c.1347_1353dup (p.Val452fs)	FLCN	Pathogenic	criteria provided, multiple submitters, no conflicts
1381774	NM_144997.7(FLCN):c.970C>T (p.Gln324Ter)	FLCN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
141865	NM_144997.7(FLCN):c.499C>T (p.Gln167Ter)	FLCN	Pathogenic	criteria provided, multiple submitters, no conflicts
1457134	NM_144997.7(FLCN):c.1222C>T (p.Gln408Ter)	FLCN	Pathogenic	criteria provided, multiple submitters, no conflicts
161246	NM_144997.7(FLCN):c.779G>A (p.Trp260Ter)	FLCN	Pathogenic	criteria provided, multiple submitters, no conflicts
1752068	NM_144997.7(FLCN):c.618+1G>A	FLCN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1769406	NM_144997.7(FLCN):c.1300G>C (p.Glu434Gln)	FLCN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
186785	NM_144997.7(FLCN):c.466TTC[1] (p.Phe157del)	FLCN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2024236	NM_144997.7(FLCN):c.1395del (p.Phe465fs)	FLCN	Pathogenic	criteria provided, multiple submitters, no conflicts
233744	NM_144997.7(FLCN):c.189del (p.Ala64fs)	FLCN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
241922	NM_144997.7(FLCN):c.347dup (p.Leu117fs)	FLCN	Pathogenic	criteria provided, multiple submitters, no conflicts
241927	NM_144997.7(FLCN):c.584del (p.Gly195fs)	FLCN	Pathogenic	criteria provided, multiple submitters, no conflicts
242379	NM_144997.7(FLCN):c.1323delinsGA (p.His442fs)	FLCN	Pathogenic	criteria provided, multiple submitters, no conflicts
253230	NM_144997.7(FLCN):c.453del (p.Phe152fs)	FLCN	Pathogenic	criteria provided, multiple submitters, no conflicts
253234	NM_144997.7(FLCN):c.735_738del (p.Ser246fs)	FLCN	Pathogenic	criteria provided, multiple submitters, no conflicts
253239	NM_144997.7(FLCN):c.853C>T (p.Gln285Ter)	FLCN	Pathogenic	criteria provided, multiple submitters, no conflicts
253244	NM_144997.7(FLCN):c.1098G>A (p.Trp366Ter)	FLCN	Pathogenic	criteria provided, multiple submitters, no conflicts
253249	NM_144997.7(FLCN):c.1318_1334dup (p.Leu449fs)	FLCN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
253251	NM_144997.7(FLCN):c.1429C>T (p.Arg477Ter)	FLCN	Pathogenic	criteria provided, multiple submitters, no conflicts
253252	NM_144997.7(FLCN):c.1432+1G>A	FLCN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
253254	NM_144997.7(FLCN):c.1487_1490dup (p.Asp498fs)	FLCN	Pathogenic	criteria provided, multiple submitters, no conflicts
253258	NM_144997.7(FLCN):c.1579C>T (p.Arg527Ter)	FLCN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
253259	NM_144997.7(FLCN):c.1579_1580insA (p.Arg527fs)	FLCN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2578485	NM_144997.7(FLCN):c.318C>G (p.Tyr106Ter)	FLCN	Pathogenic	criteria provided, single submitter
265155	NM_144997.7(FLCN):c.1601del (p.Lys534fs)	FLCN	Pathogenic	criteria provided, multiple submitters, no conflicts
2683678	NM_144997.7(FLCN):c.1150_1160del (p.Val384fs)	FLCN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3148672	NM_144997.7(FLCN):c.1014G>A (p.Trp338Ter)	FLCN	Pathogenic	criteria provided, single submitter
3254412	NM_144997.7(FLCN):c.340_349del (p.His114fs)	FLCN	Pathogenic	criteria provided, single submitter
3363	NM_144997.7(FLCN):c.1285dup (p.His429fs)	FLCN	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
FLCN	Definitive	Autosomal dominant	Birt-Hogg-Dube syndrome 1	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FLCN	Orphanet:122	Birt-Hogg-Dubé syndrome
FLCN	Orphanet:2903	Familial spontaneous pneumothorax
FLCN	Orphanet:422526	Hereditary clear cell renal cell carcinoma
FN1	Orphanet:84090	Fibronectin glomerulopathy
FN1	Orphanet:93315	Spondylometaphyseal dysplasia, ‘corner fracture’ type

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FLCN	HGNC:27310	ENSG00000154803	Q8NFG4	Folliculin	gencc,clinvar
FN1	HGNC:3778	ENSG00000115414	P02751	Fibronectin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FLCN	Folliculin	Multi-functional protein, involved in both the cellular response to amino acid availability and in the regulation of glycolysis.
FN1	Fibronectin	Fibronectins bind cell surfaces and various compounds including collagen, fibrin, heparin, DNA, and actin.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Antibody/Immunoglobulin	1	14.6×	0.135
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FLCN	Other/Unknown	no		Folliculin, Folliculin_DENN, Folliculin/SMCR8_longin
FN1	Antibody/Immunoglobulin	yes		Fibronectin_type1, FN_type2_dom, FN3_dom

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
decidua	1
right coronary artery	1
synovial joint	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FLCN	261	ubiquitous	marker	buccal mucosa cell, right hemisphere of cerebellum, cerebellar hemisphere
FN1	292	ubiquitous	marker	synovial joint, right coronary artery, decidua

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FN1	8,860
FLCN	1,317

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FN1	P02751	65
FLCN	Q8NFG4	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 30. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
ALK mutants bind TKIs	1	475.8×	0.014	FN1
p130Cas linkage to MAPK signaling for integrins	1	380.7×	0.014	FN1
GRB2:SOS provides linkage to MAPK signaling for Integrins	1	356.9×	0.014	FN1
Fibronectin matrix formation	1	285.5×	0.014	FN1
Attachment of bacteria to epithelial cells	1	248.3×	0.014	FN1
Syndecan interactions	1	211.5×	0.014	FN1
Integrin signaling	1	211.5×	0.014	FN1
MET activates PTK2 signaling	1	190.3×	0.014	FN1
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells	1	178.4×	0.014	FN1
Signaling by high-kinase activity BRAF mutants	1	158.6×	0.014	FN1
Molecules associated with elastic fibres	1	154.3×	0.014	FN1
MAP2K and MAPK activation	1	142.8×	0.014	FN1
Signaling by RAF1 mutants	1	139.3×	0.014	FN1
Signaling by moderate kinase activity BRAF mutants	1	126.9×	0.014	FN1
Paradoxical activation of RAF signaling by kinase inactive BRAF	1	126.9×	0.014	FN1
Signaling downstream of RAS mutants	1	126.9×	0.014	FN1
GPER1 signaling	1	124.1×	0.014	FN1
Developmental Lineage of Pancreatic Ductal Cells	1	114.2×	0.015	FN1
Amino acids regulate mTORC1	1	100.2×	0.016	FLCN
Signaling by BRAF and RAF1 fusions	1	85.2×	0.017	FN1
Non-integrin membrane-ECM interactions	1	77.2×	0.017	FN1
ECM proteoglycans	1	75.1×	0.017	FN1
Signaling by ALK fusions and activated point mutants	1	75.1×	0.017	FN1
Integrin cell surface interactions	1	67.2×	0.019	FN1
Degradation of the extracellular matrix	1	58.9×	0.020	FN1
Interleukin-4 and Interleukin-13 signaling	1	51.4×	0.022	FN1
Post-translational protein phosphorylation	1	50.1×	0.022	FN1
Cell surface interactions at the vascular wall	1	47.6×	0.022	FN1
Platelet degranulation	1	43.9×	0.023	FN1
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	43.3×	0.023	FN1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of cell proliferation involved in kidney development	1	8426.0×	0.004	FLCN
cell proliferation involved in kidney development	1	2808.7×	0.004	FLCN
negative regulation of monocyte activation	1	2808.7×	0.004	FN1
calcium-independent cell-matrix adhesion	1	2106.5×	0.004	FN1
negative regulation of post-translational protein modification	1	2106.5×	0.004	FLCN
positive regulation of substrate-dependent cell migration, cell attachment to substrate	1	2106.5×	0.004	FN1
negative regulation of lysosome organization	1	2106.5×	0.004	FLCN
negative regulation of transforming growth factor beta production	1	1685.2×	0.004	FN1
regulation of pro-B cell differentiation	1	1685.2×	0.004	FLCN
cell-substrate junction assembly	1	1404.3×	0.004	FN1
biological process involved in interaction with symbiont	1	1404.3×	0.004	FN1
negative regulation of brown fat cell differentiation	1	1404.3×	0.004	FLCN
regulation of Ras protein signal transduction	1	936.2×	0.005	FLCN
neural crest cell migration involved in autonomic nervous system development	1	936.2×	0.005	FN1
blood coagulation, fibrin clot formation	1	842.6×	0.005	FN1
integrin activation	1	702.2×	0.006	FN1
regulation of protein phosphorylation	1	561.7×	0.007	FN1
negative regulation of glycolytic process	1	526.6×	0.007	FLCN
enteric nervous system development	1	495.6×	0.007	FN1
regulation of TOR signaling	1	468.1×	0.007	FLCN
TOR signaling	1	383.0×	0.008	FLCN
negative regulation of Rho protein signal transduction	1	383.0×	0.008	FLCN
response to muscle activity	1	290.6×	0.009	FN1
regulation of ERK1 and ERK2 cascade	1	290.6×	0.009	FN1
negative regulation of TOR signaling	1	280.9×	0.009	FLCN
positive regulation of transforming growth factor beta receptor signaling pathway	1	263.3×	0.009	FLCN
lysosome localization	1	263.3×	0.009	FLCN
positive regulation of axon extension	1	255.3×	0.009	FN1
positive regulation of TOR signaling	1	247.8×	0.009	FLCN
endodermal cell differentiation	1	247.8×	0.009	FN1

Therapeutics

Drugs indicated for this disease

0 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Sirolimus	Phase 3 (in late-stage trials)

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FLCN	0	0
FN1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
FN1	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	FN1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	FLCN

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
FLCN	0	—
FN1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.