Familial spontaneous pneumothorax

Summary

Familial spontaneous pneumothorax (MONDO:0008259) is a disease caused by FLCN (GenCC Strong), with 1 cohort gene and 19 clinical trials. Top therapeutic interventions include tetracycline.

At a glance

• Prevalence: 1-5 / 10 000 (Finland) [Orphanet-validated]
• Causal gene: FLCN (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 287
• Phenotypes (HPO): 3
• Clinical trials: 19

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000	54.64	Finland	Validated

Signs & symptoms

Clinical features (HPO)

3 HPO clinical features (Orphanet curated; top 3 by frequency):

HPO ID	Term	Frequency
HP:0002086	Abnormality of the respiratory system	Very frequent (80-99%)
HP:0002103	Abnormality of the pleura	Very frequent (80-99%)
HP:0002107	Pneumothorax	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	familial spontaneous pneumothorax
Mondo ID	MONDO:0008259
MeSH	C566795
OMIM	173600
Orphanet	2903
DOID	DOID:0080218
ICD-11	319022944
SNOMED CT	715219001
UMLS	C1868193
MedGen	357445
GARD	0004997
Is cancer (heuristic)	no

Also known as: primary spontaneous pneumothorax · spontaneous pneumothorax

Data availability: 287 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › respiratory system disorder › lower respiratory tract disorder › pleural disorder › pneumothorax › familial spontaneous pneumothorax

Related subtypes (4): spontaneous tension pneumothorax, tuberculous pneumothorax, hemopneumothorax, catamenial pneumothorax

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

287 retrieved; paginated sample, class counts are floors:

97 conflicting classifications of pathogenicity, 96 uncertain significance, 35 benign/likely benign, 20 pathogenic, 20 benign, 12 pathogenic/likely pathogenic, 7 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
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
161246	NM_144997.7(FLCN):c.779G>A (p.Trp260Ter)	FLCN	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
231274	NM_144997.7(FLCN):c.779+1G>T	FLCN	Pathogenic/Likely 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
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
253259	NM_144997.7(FLCN):c.1579_1580insA (p.Arg527fs)	FLCN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265154	NM_144997.7(FLCN):c.1062+2T>G	FLCN	Pathogenic	criteria provided, multiple submitters, no conflicts
265155	NM_144997.7(FLCN):c.1601del (p.Lys534fs)	FLCN	Pathogenic	criteria provided, multiple submitters, no conflicts
3363	NM_144997.7(FLCN):c.1285dup (p.His429fs)	FLCN	Pathogenic	criteria provided, multiple submitters, no conflicts
3364	NM_144997.7(FLCN):c.1285del (p.His429fs)	FLCN	Pathogenic	criteria provided, multiple submitters, no conflicts
3367	NM_144997.7(FLCN):c.1389C>G (p.Tyr463Ter)	FLCN	Pathogenic	criteria provided, multiple submitters, no conflicts
3371	NM_144997.7(FLCN):c.235_238del (p.Ser79fs)	FLCN	Pathogenic	criteria provided, multiple submitters, no conflicts
3372	NM_144997.7(FLCN):c.1533_1536del (p.Glu510_Trp511insTer)	FLCN	Pathogenic	criteria provided, multiple submitters, no conflicts
3373	NM_144997.7(FLCN):c.404del (p.Pro135fs)	FLCN	Pathogenic	criteria provided, single submitter
3375	NM_144997.7(FLCN):c.1156_1175del (p.Ser386fs)	FLCN	Pathogenic	criteria provided, single submitter
3379	NM_144997.7(FLCN):c.(871+1_872-1)(*1?)del	FLCN	Pathogenic	no assertion criteria provided
3382013	NM_144997.7(FLCN):c.636del (p.Gln212fs)	FLCN	Pathogenic	criteria provided, single submitter
3581694	NM_144997.7(FLCN):c.1372dup (p.Gln458fs)	FLCN	Pathogenic	criteria provided, single submitter
428647	NM_144997.7(FLCN):c.1657T>C (p.Trp553Arg)	FLCN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
428649	NM_144997.7(FLCN):c.1426dup (p.Asp476fs)	FLCN	Pathogenic	criteria provided, multiple submitters, no conflicts
428656	NM_144997.7(FLCN):c.44dup (p.Arg17fs)	FLCN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
428658	NM_144997.7(FLCN):c.1357_1363del (p.Gly453fs)	FLCN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
633219	NM_144997.7(FLCN):c.1432+2T>C	FLCN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
96473	NM_144997.7(FLCN):c.1203dup (p.Ile402fs)	FLCN	Pathogenic	criteria provided, multiple submitters, no conflicts
96478	NM_144997.7(FLCN):c.1533G>A (p.Trp511Ter)	FLCN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
96481	NM_144997.7(FLCN):c.250-2A>G	FLCN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 3 · 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	Strong	Autosomal dominant	familial spontaneous pneumothorax	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

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FLCN	HGNC:27310	ENSG00000154803	Q8NFG4	Folliculin	gencc,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.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FLCN	Other/Unknown	no		Folliculin, Folliculin_DENN, Folliculin/SMCR8_longin

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
cerebellar hemisphere	1
right hemisphere of cerebellum	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

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FLCN	1,317

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FLCN	Q8NFG4	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Amino acids regulate mTORC1	1	200.3×	0.005	FLCN

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 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	16852.0×	0.002	FLCN
cell proliferation involved in kidney development	1	5617.3×	0.002	FLCN
negative regulation of post-translational protein modification	1	4213.0×	0.002	FLCN
negative regulation of lysosome organization	1	4213.0×	0.002	FLCN
regulation of pro-B cell differentiation	1	3370.4×	0.002	FLCN
negative regulation of brown fat cell differentiation	1	2808.7×	0.002	FLCN
regulation of Ras protein signal transduction	1	1872.4×	0.003	FLCN
negative regulation of glycolytic process	1	1053.2×	0.004	FLCN
regulation of TOR signaling	1	936.2×	0.004	FLCN
TOR signaling	1	766.0×	0.004	FLCN
negative regulation of Rho protein signal transduction	1	766.0×	0.004	FLCN
negative regulation of TOR signaling	1	561.7×	0.005	FLCN
positive regulation of transforming growth factor beta receptor signaling pathway	1	526.6×	0.005	FLCN
lysosome localization	1	526.6×	0.005	FLCN
positive regulation of TOR signaling	1	495.6×	0.005	FLCN
positive regulation of intrinsic apoptotic signaling pathway	1	481.5×	0.005	FLCN
cell-cell junction assembly	1	443.5×	0.005	FLCN
intrinsic apoptotic signaling pathway	1	358.6×	0.005	FLCN
negative regulation of cold-induced thermogenesis	1	343.9×	0.005	FLCN
cellular response to amino acid starvation	1	318.0×	0.005	FLCN
ERK1 and ERK2 cascade	1	318.0×	0.005	FLCN
epithelial cell proliferation	1	312.1×	0.005	FLCN
positive regulation of TORC1 signaling	1	295.6×	0.005	FLCN
negative regulation of epithelial cell proliferation	1	290.6×	0.005	FLCN
energy homeostasis	1	271.8×	0.005	FLCN
hemopoiesis	1	267.5×	0.005	FLCN
negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	263.3×	0.005	FLCN
negative regulation of ERK1 and ERK2 cascade	1	216.1×	0.006	FLCN
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	210.7×	0.006	FLCN
positive regulation of autophagy	1	208.1×	0.006	FLCN

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) 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

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	FLCN

Undrugged target profiles

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

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

Clinical trials & evidence

Clinical trials

Clinical trials: 19.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	14
PHASE3	1
PHASE2/PHASE3	1
PHASE2	1
EARLY_PHASE1	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00615849	PHASE3	COMPLETED	Efficacy of the Additional Mechanical Pleurodesis for Surgical Management of Primary Spontaneous Pneumothorax
NCT01848860	PHASE2/PHASE3	UNKNOWN	Absorbable Mesh Pleurodesis in Thoracoscopic Treatment of Spontaneous Pneumothorax
NCT02030795	PHASE2	COMPLETED	Techniques for Lung Deflation With Arndt® Blocker
NCT02916992	PHASE1	UNKNOWN	Prevalence of Spontaneous Pneumothorax in BHD
NCT02866305	EARLY_PHASE1	UNKNOWN	Study Designed to Optimize the Treatment of Primary Pneumothorax
NCT06411431	Not specified	RECRUITING	Early Chest Tube Removal After Surgery for Primary Spontaneous Pneumothorax: A Randomized Controlled Trial
NCT06413966	Not specified	RECRUITING	Study Compares Pneumothorax Recurrence: Absorbable Mesh vs. Pleurectomy in Primary Spontaneous Pneumothorax.
NCT06471608	Not specified	NOT_YET_RECRUITING	Impact of Ambulatory Management for Primary Spontaneous Pneumothorax in the Emergency Department on Quality of Life
NCT06644820	Not specified	RECRUITING	Clinical Characteristics and Outcome of Patients Xith Spontaneous Pneumothorax
NCT07331805	Not specified	NOT_YET_RECRUITING	Conservative Management in Primary Spontaneous Pneumothorax: a Multicenter Randomized Non-inferiority Study
NCT00430664	Not specified	UNKNOWN	A Comparative Study of the Safety and Efficacy of Face Talc Slurry and Iodopovidone for Pleurodesis
NCT02109510	Not specified	COMPLETED	Comparative Study of Nonintubated Anesthesia Versus Intubated General Anesthesia in Single Port Thoracoscopic Bullectomy
NCT02573285	Not specified	COMPLETED	Spontaneous Pneumothorax in Children
NCT03557320	Not specified	COMPLETED	Environmental Factor and Onset of Spontaneous Pneumothorax
NCT03634605	Not specified	COMPLETED	Effect of Tetracycline Pleurodesis on Prevention of Primary Spontaneous Pneumothorax Recurrence
NCT04758143	Not specified	UNKNOWN	Most Preventable Surgical Option to Reduce Primary Spontaneous Pneumothorax Patients’ Postoperative Recurrence: A Prospective Cohort Study
NCT04831554	Not specified	UNKNOWN	Which is Better Between Single Chest Tube and Multiple Tubes Drainage in Primary Spontaneous Pneumothorax
NCT06088901	Not specified	WITHDRAWN	Autologous Blood Patch for Primary Spontaneous Pneumothorax
NCT06734442	Not specified	COMPLETED	Thoracoscopy for Idiopathic Pneumothorax in Children

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
TETRACYCLINE	4	1