Alveolar capillary dysplasia with misalignment of pulmonary veins

disease

On this page

Also known as ACDMPValveolar capillary dysplasiaalveolar capillary dysplasia with misalignment of pulmonary veins and other congenital anomaliesalveolar capillary dysplasia with misalignment of pulmonary vesselsalveolar capillary dysplasia with pulmonary venous misalignmentcongenital alveolar capillary dysplasiafamilial persistent pulmonary hypertension of the newbornfoetal circulationpersistent fetal circulationpersistent foetal circulationpersistent foetal circulation syndromepulmonary hypertension, familial persistent of the newborn

Summary

Alveolar capillary dysplasia with misalignment of pulmonary veins (MONDO:0009934) is a disease caused by FOXF1 (GenCC Definitive), with 8 cohort genes and 2 clinical trials. Top therapeutic interventions include oxygen.

At a glance

Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
Causal gene: FOXF1 (GenCC Definitive)
Cohort genes: 8
ClinVar variants: 84
Phenotypes (HPO): 23
Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		40	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated
Prevalence at birth	1-9 / 100 000	1.2	Canada	Validated

Signs & symptoms

Clinical features (HPO)

23 HPO clinical features (Orphanet curated; top 23 by frequency):

HPO ID	Term	Frequency
HP:0002092	Pulmonary arterial hypertension	Very frequent (80-99%)
HP:0002098	Respiratory distress	Very frequent (80-99%)
HP:0001643	Patent ductus arteriosus	Frequent (30-79%)
HP:0002566	Intestinal malrotation	Frequent (30-79%)
HP:0004383	Hypoplastic left heart	Frequent (30-79%)
HP:0000126	Hydronephrosis	Occasional (5-29%)
HP:0001195	Single umbilical artery	Occasional (5-29%)
HP:0001629	Ventricular septal defect	Occasional (5-29%)
HP:0001631	Atrial septal defect	Occasional (5-29%)
HP:0001636	Tetralogy of Fallot	Occasional (5-29%)
HP:0001647	Bicuspid aortic valve	Occasional (5-29%)
HP:0001650	Aortic valve stenosis	Occasional (5-29%)
HP:0001734	Annular pancreas	Occasional (5-29%)
HP:0001746	Asplenia	Occasional (5-29%)
HP:0002023	Anal atresia	Occasional (5-29%)
HP:0002251	Aganglionic megacolon	Occasional (5-29%)
HP:0002575	Tracheoesophageal fistula	Occasional (5-29%)
HP:0002580	Volvulus	Occasional (5-29%)
HP:0003468	Abnormal vertebral morphology	Occasional (5-29%)
HP:0006695	Atrioventricular canal defect	Occasional (5-29%)
HP:0010882	Pulmonary valve atresia	Occasional (5-29%)
HP:0011467	Absent gallbladder	Occasional (5-29%)
HP:0100867	Duodenal stenosis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	alveolar capillary dysplasia with misalignment of pulmonary veins
Mondo ID	MONDO:0009934
MeSH	C536590
OMIM	265380
Orphanet	210122
DOID	DOID:13042
NCIT	C98809
SNOMED CT	447275002
UMLS	C2960310
MedGen	755478
GARD	0008644
MedDRA	10054726
NORD	759
Is cancer (heuristic)	no

Also known as: ACDMPV · alveolar capillary dysplasia · alveolar capillary dysplasia with misalignment of pulmonary veins · alveolar capillary dysplasia with misalignment of pulmonary veins and other congenital anomalies · alveolar capillary dysplasia with misalignment of pulmonary vessels · alveolar capillary dysplasia with pulmonary venous misalignment · congenital alveolar capillary dysplasia · familial persistent pulmonary hypertension of the newborn · foetal circulation · persistent fetal circulation · persistent foetal circulation · persistent foetal circulation syndrome · pulmonary hypertension, familial persistent of the newborn

Data availability: 84 ClinVar variants · 4 GenCC gene-disease records · 3 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › respiratory system disorder › lower respiratory tract disorder › lung disorder › interstitial lung disease › interstitial lung disease specific to childhood › primary interstitial lung disease specific to childhood › alveolar capillary dysplasia with misalignment of pulmonary veins

Related subtypes (4): congenital chylothorax, lung fibrosis-immunodeficiency-46,XX gonadal dysgenesis syndrome, interstitial lung disease specific to infancy, newborn respiratory distress syndrome

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

84 retrieved; paginated sample, class counts are floors:

45 pathogenic, 15 likely pathogenic, 9 uncertain significance, 4 likely benign, 4 benign, 2 pathogenic/likely pathogenic, 2 conflicting classifications of pathogenicity, 2 benign/likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
267798	46;XY;t(9;16)(p24;q22)dn		Pathogenic	criteria provided, single submitter
813309	GRCh37/hg19 16q24.1-24.2(chr16:84872102-87678641)	FBXO31	Pathogenic	criteria provided, single submitter
973755	NM_001451.3(FOXF1):c.57_60del (p.Gly20fs)	FENDRR	Pathogenic	criteria provided, single submitter
1030400	NM_001451.3(FOXF1):c.668C>A (p.Ser223Ter)	FOXF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1300142	NM_001451.3(FOXF1):c.276G>A (p.Trp92Ter)	FOXF1	Pathogenic	criteria provided, single submitter
1302014	NM_001451.3(FOXF1):c.852_856del (p.Tyr284_Lys286delinsTer)	FOXF1	Pathogenic	criteria provided, single submitter
1322932	NM_001451.3(FOXF1):c.889del (p.Ala297fs)	FOXF1	Pathogenic	criteria provided, single submitter
1695721	NM_001451.3(FOXF1):c.899del (p.Leu300fs)	FOXF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2500699	NM_001451.3(FOXF1):c.21del (p.Lys7fs)	FOXF1	Pathogenic	criteria provided, single submitter
2505284	NM_001451.3(FOXF1):c.1070_1080del (p.His357fs)	FOXF1	Pathogenic	no assertion criteria provided
2584476	NM_001451.3(FOXF1):c.797C>A (p.Ser266Ter)	FOXF1	Pathogenic	criteria provided, single submitter
2584512	NM_001451.3(FOXF1):c.256C>T (p.Arg86Trp)	FOXF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2584540	NM_001451.3(FOXF1):c.185A>C (p.Gln62Pro)	FOXF1	Pathogenic	criteria provided, single submitter
2635136	NM_001451.3(FOXF1):c.310G>T (p.Glu104Ter)	FOXF1	Pathogenic	criteria provided, multiple submitters, no conflicts
2662961	NM_001451.3(FOXF1):c.268C>T (p.Gln90Ter)	FOXF1	Pathogenic	criteria provided, multiple submitters, no conflicts
3235920	NM_001451.3(FOXF1):c.802_805del (p.Ala268fs)	FOXF1	Pathogenic	criteria provided, single submitter
3238755	NM_001451.3(FOXF1):c.1138T>A (p.Ter380Arg)	FOXF1	Pathogenic	criteria provided, single submitter
3256575	NM_001451.3(FOXF1):c.229T>C (p.Phe77Leu)	FOXF1	Pathogenic	criteria provided, single submitter
4279919	NM_001451.3(FOXF1):c.385G>T (p.Glu129Ter)	FOXF1	Pathogenic	criteria provided, single submitter
4531621	NM_001451.3(FOXF1):c.225C>G (p.Tyr75Ter)	FOXF1	Pathogenic	criteria provided, single submitter
4755386	NM_001451.3(FOXF1):c.245_246insA (p.Phe82fs)	FOXF1	Pathogenic	criteria provided, single submitter
692054	NM_001451.3(FOXF1):c.691_698del (p.Ala231fs)	FOXF1	Pathogenic	criteria provided, multiple submitters, no conflicts
800364	NM_001451.3(FOXF1):c.1031_1032del (p.Phe344fs)	FOXF1	Pathogenic	no assertion criteria provided
800365	NM_001451.3(FOXF1):c.145C>T (p.Pro49Ser)	FOXF1	Pathogenic	no assertion criteria provided
800366	NM_001451.3(FOXF1):c.89C>A (p.Ser30Ter)	FOXF1	Pathogenic	no assertion criteria provided
800367	NM_001451.3(FOXF1):c.872_879del (p.Leu290_Ser291insTer)	FOXF1	Pathogenic	no assertion criteria provided
800368	NM_001451.3(FOXF1):c.899_903dup (p.Gly302fs)	FOXF1	Pathogenic	no assertion criteria provided
800369	NM_001451.3(FOXF1):c.191C>A (p.Ser64Ter)	FOXF1	Pathogenic	no assertion criteria provided
800370	NM_001451.3(FOXF1):c.1139G>C (p.Ter380Ser)	FOXF1	Pathogenic	no assertion criteria provided
800371	NM_001451.3(FOXF1):c.221T>A (p.Ile74Asn)	FOXF1	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
FOXF1	Definitive	Autosomal dominant	alveolar capillary dysplasia with misalignment of pulmonary veins	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FOXF1	Orphanet:210122	Congenital alveolar capillary dysplasia
FBXO31	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability
GATA2	Orphanet:228423	GATA2 deficiency spectrum

Cohort genes → proteins

8 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	8

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FOXF1	HGNC:3809	ENSG00000103241	Q12946	Forkhead box protein F1	gencc,clinvar
FBXO5	HGNC:13584	ENSG00000112029	Q9UKT4	F-box only protein 5	clinvar
FBXO31	HGNC:16510	ENSG00000103264	Q5XUX0	F-box only protein 31	clinvar
MTHFSD	HGNC:25778	ENSG00000103248	Q2M296	Methenyltetrahydrofolate synthase domain-containing protein	clinvar
ATP2C2	HGNC:29103	ENSG00000064270	O75185	Calcium-transporting ATPase type 2C member 2	clinvar
GATA2	HGNC:4171	ENSG00000179348	P23769	Endothelial transcription factor GATA-2	clinvar
FENDRR	HGNC:43894	ENSG00000268388		FOXF1 adjacent non-coding developmental regulatory RNA	clinvar
LINC01082	HGNC:49125	ENSG00000269186		long intergenic non-protein coding RNA 1082	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FOXF1	Forkhead box protein F1	Probable transcription activator for a number of lung-specific genes.
FBXO5	F-box only protein 5	Regulator of APC activity during mitotic and meiotic cell cycle.
FBXO31	F-box only protein 31	Substrate-recognition component of the SCF(FBXO31) protein ligase complex, which specifically mediates the ubiquitination of proteins amidated at their C-terminus in response to oxidative stress, leading to their degradation by the proteas…
ATP2C2	Calcium-transporting ATPase type 2C member 2	ATP-driven pump that supplies the Golgi apparatus with Ca(2+) and Mn(2+) ions, both essential cofactors for processing and trafficking of newly synthesized proteins in the secretory pathway.
GATA2	Endothelial transcription factor GATA-2	Transcriptional activator which regulates endothelin-1 gene expression in endothelial cells.

Protein-family classification

Druggable: 0 · Difficult: 3 · Unknown: 5 · 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
Transcription factor	3	3.1×	0.124
Other/Unknown	5	1.1×	0.496

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FOXF1	Transcription factor	no		Fork_head_dom, TF_fork_head_CS_1, TF_fork_head_CS_2
FBXO5	Other/Unknown	no		F-box_dom, ZF_ZBR, FBX5_43
FBXO31	Other/Unknown	no		F-box_dom, F-box-like_dom_sf, FBXO31/39
MTHFSD	Other/Unknown	no		RRM_dom, FTHF_cligase, Nucleotide-bd_a/b_plait_sf
ATP2C2	Transcription factor	no	7.2.2.10	P_typ_ATPase, ATPase_P-typ_cation-transptr_N, ATPase_P-typ_cation-transptr_C
GATA2	Transcription factor	no		Znf_GATA, Znf_NHR/GATA, TF_GATA-2/3
FENDRR	Other/Unknown	no
LINC01082	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

7 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)	8
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right lung	3
muscle layer of sigmoid colon	2
mucosa of transverse colon	2
mucosa of stomach	1
ganglionic eminence	1
secondary oocyte	1
ventricular zone	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
buccal mucosa cell	1
minor salivary gland	1
right uterine tube	1
mucosa of sigmoid colon	1
rectum	1
left uterine tube	1
seminal vesicle	1
lower esophagus muscularis layer	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FOXF1	202	broad	marker	muscle layer of sigmoid colon, mucosa of stomach, right lung
FBXO5	225	ubiquitous	marker	ventricular zone, ganglionic eminence, secondary oocyte
FBXO31	261	ubiquitous	marker	cerebellar hemisphere, cerebellar cortex, right hemisphere of cerebellum
MTHFSD	207	ubiquitous	marker	buccal mucosa cell, right uterine tube, minor salivary gland
ATP2C2	210	broad	marker	rectum, mucosa of transverse colon, mucosa of sigmoid colon
GATA2	273	ubiquitous	marker	seminal vesicle, right lung, left uterine tube
FENDRR	188	broad	marker	right lung, muscle layer of sigmoid colon, lower esophagus muscularis layer
LINC01082	115	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, mucosa of transverse colon, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GATA2	4,979
FBXO5	2,844
ATP2C2	1,801
MTHFSD	1,716
FOXF1	1,694
FBXO31	634
FENDRR	0
LINC01082	0

Intra-cohort edges

A	B	Sources
FBXO31	FBXO5	string_interaction
FOXF1	MTHFSD	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 2 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FBXO5	Q9UKT4	3
FBXO31	Q5XUX0	2
GATA2	P23769	2
MTHFSD	Q2M296	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ATP2C2	O75185	81.13
FOXF1	Q12946	59.41

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. Enrichment computed across 8 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Mitotic Metaphase/Anaphase Transition	1	761.3×	0.016	FBXO5
Formation of lateral plate mesoderm	1	456.8×	0.016	FOXF1
Phosphorylation of Emi1	1	285.5×	0.017	FBXO5
Regulation of CDH11 gene transcription	1	207.6×	0.018	FOXF1
G1/S-Specific Transcription	1	71.4×	0.040	FBXO5
Regulation of APC/C activators between G1/S and early anaphase	1	61.7×	0.040	FBXO5
SCF-beta-TrCP mediated degradation of Emi1	1	47.6×	0.045	FBXO5
Ion transport by P-type ATPases	1	41.5×	0.045	ATP2C2
Transcriptional regulation of granulopoiesis	1	25.1×	0.065	GATA2
Ion channel transport	1	19.2×	0.070	ATP2C2
RUNX1 regulates transcription of genes involved in differentiation of HSCs	1	19.0×	0.070	GATA2
Factors involved in megakaryocyte development and platelet production	1	13.3×	0.091	GATA2
Neddylation	1	9.5×	0.117	FBXO31
Antigen processing: Ubiquitination & Proteasome degradation	1	7.4×	0.136	FBXO31
Transport of small molecules	1	5.0×	0.184	ATP2C2

GO biological processes by enrichment

GO term	Cohort genes	Fold	FDR	Sample cohort genes
detection of wounding	1	3370.4×	0.008	FOXF1
embryonic ectodermal digestive tract morphogenesis	1	3370.4×	0.008	FOXF1
right lung morphogenesis	1	3370.4×	0.008	FOXF1
semicircular canal development	1	3370.4×	0.008	GATA2
regulation of forebrain neuron differentiation	1	3370.4×	0.008	GATA2
regulation of primitive erythrocyte differentiation	1	1685.2×	0.008	GATA2
negative regulation of DNA endoreduplication	1	1685.2×	0.008	FBXO5
eosinophil fate commitment	1	1685.2×	0.008	GATA2
lateral mesodermal cell differentiation	1	1685.2×	0.008	FOXF1
ventral spinal cord interneuron differentiation	1	1123.5×	0.008	GATA2
cell differentiation in hindbrain	1	1123.5×	0.008	GATA2
trachea development	1	1123.5×	0.008	FOXF1
negative regulation of mitotic metaphase/anaphase transition	1	842.6×	0.008	FBXO5
negative regulation of ubiquitin-protein transferase activity	1	842.6×	0.008	FBXO5
epithelial cell differentiation involved in mammary gland alveolus development	1	842.6×	0.008	FOXF1
negative regulation of hematopoietic progenitor cell differentiation	1	842.6×	0.008	GATA2
positive regulation of mesenchymal stem cell migration	1	842.6×	0.008	FBXO5
spindle assembly involved in female meiosis I	1	674.1×	0.008	FBXO5
respiratory tube development	1	674.1×	0.008	FOXF1
venous blood vessel development	1	674.1×	0.008	FOXF1
mesenchyme migration	1	674.1×	0.008	FOXF1
ductus arteriosus closure	1	674.1×	0.008	FOXF1
GABAergic neuron differentiation	1	674.1×	0.008	GATA2
negative regulation of ubiquitin protein ligase activity	1	674.1×	0.008	FBXO5
commitment of neuronal cell to specific neuron type in forebrain	1	561.7×	0.008	GATA2
negative regulation of mast cell degranulation	1	561.7×	0.008	FOXF1
thyroid-stimulating hormone-secreting cell differentiation	1	561.7×	0.008	GATA2
positive regulation of biomineral tissue development	1	561.7×	0.008	FBXO5
ureter development	1	561.7×	0.008	FOXF1
negative regulation of brown fat cell differentiation	1	561.7×	0.008	GATA2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 8

Druggability breadth: 1 of 8 evidence-associated genes (12%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FOXF1	0	0
FBXO5	0	0
FBXO31	0	0
MTHFSD	0	0
ATP2C2	0	0
GATA2	0	0
FENDRR	0	0
LINC01082	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
GATA2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ATP2C2	7.2.2.10	P-type Ca2+ transporter

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; 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	8	FOXF1, FBXO5, FBXO31, MTHFSD, ATP2C2, GATA2, FENDRR, LINC01082

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
FOXF1	0	—
FBXO5	0	—
FBXO31	0	—
MTHFSD	0	—
ATP2C2	0	—
GATA2	1	—
FENDRR	0	—
LINC01082	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE4	1
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00732537	PHASE4	COMPLETED	Inhaled Nitric Oxide by Oxygen Hood in Neonates
NCT04328636	PHASE1/PHASE2	COMPLETED	Nebulized MgSO4 in Persistent Pulmonary Hypertension of Newborn

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
OXYGEN	4	1

Cohort genes: FOXF1, FBXO5, FBXO31, MTHFSD, ATP2C2, GATA2, FENDRR, LINC01082
Drugs: Oxygen