Familial primary pulmonary hypoplasia

Summary

Familial primary pulmonary hypoplasia (MONDO:0009936) is a disease with 2 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 5
• Phenotypes (HPO): 26

Clinical features

Signs & symptoms

Clinical features (HPO)

26 HPO clinical features (Orphanet curated; top 26 by frequency):

HPO ID	Term	Frequency
HP:0002089	Pulmonary hypoplasia	Obligate (100%)
HP:0000961	Cyanosis	Frequent (30-79%)
HP:0002091	Restrictive ventilatory defect	Frequent (30-79%)
HP:0002104	Apnea	Frequent (30-79%)
HP:0002643	Neonatal respiratory distress	Frequent (30-79%)
HP:0002789	Tachypnea	Frequent (30-79%)
HP:0012418	Hypoxemia	Frequent (30-79%)
HP:0030829	Abnormal breath sound	Frequent (30-79%)
HP:0000175	Cleft palate	Occasional (5-29%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000286	Epicanthus	Occasional (5-29%)
HP:0000347	Micrognathia	Occasional (5-29%)
HP:0000369	Low-set ears	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0001511	Intrauterine growth retardation	Occasional (5-29%)
HP:0001651	Dextrocardia	Occasional (5-29%)
HP:0001684	Secundum atrial septal defect	Occasional (5-29%)
HP:0002205	Recurrent respiratory infections	Occasional (5-29%)
HP:0002778	Abnormal trachea morphology	Occasional (5-29%)
HP:0003065	Patellar hypoplasia	Occasional (5-29%)
HP:0040045	Abnormal hemidiaphragm morphology	Occasional (5-29%)
HP:0032094	Increased circulating surfactant protein level	Excluded (0%)
HP:0000071	Ureteral stenosis	Very rare (<1-4%)
HP:0002099	Asthma	Very rare (<1-4%)
HP:0002107	Pneumothorax	Very rare (<1-4%)
HP:0030966	Abnormal pulmonary artery morphology	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	familial primary pulmonary hypoplasia
Mondo ID	MONDO:0009936
OMIM	265430
Orphanet	2257
ICD-11	1778475393
SNOMED CT	277656005
UMLS	C0456891
MedGen	141589
GARD	0016591
Is cancer (heuristic)	no

Data availability: 5 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › respiratory system disorder › familial primary pulmonary hypoplasia

Related subtypes (58): lower respiratory tract disorder, respiratory system cancer, respiratory system benign neoplasm, allergic respiratory disease, paranasal sinus disorder, upper respiratory tract disorder, pertussis, severe acute respiratory syndrome, sleep apnea syndrome, diaphragm disorder, pulmonary tuberculosis, altitude sickness, perinatal asphyxia, pulmonary nodular lymphoid hyperplasia, tracheobronchopathia osteochondroplastica, Williams-Campbell syndrome, cystic fibrosis, growth delay-hydrocephaly-lung hypoplasia syndrome, laryngo-onycho-cutaneous syndrome, congenital pulmonary lymphangiectasia, Mounier-Kuhn syndrome, Young syndrome, lung agenesis-heart defect-thumb anomalies syndrome, sudden infant death-dysgenesis of the testes syndrome, alpha 1-antitrypsin deficiency, hereditary sclerosing poikiloderma with tendon and pulmonary involvement, autoimmune interstitial lung disease-arthritis syndrome, mucopolysaccharidosis-plus syndrome, congenital bronchobiliary fistula, bronchogenic cyst, primary ciliary dyskinesia, congenital pulmonary airway malformation, transient hyperammonemia of the newborn, congenital pulmonary sequestration, Siegler-Brewer-Carey syndrome, tracheal agenesis, 16q24.1 microdeletion syndrome, staphylococcal necrotizing pneumonia, pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis, plastic bronchitis, recurrent respiratory papillomatosis, IgG4-related mediastinitis, bronchopulmonary dysplasia, infantile apnea, diffuse alveolar hemorrhage, respiratory or thoracic malformation, pulmonary agenesis, eosinophilic granuloma, disorder of pharynx, respiratory tract neoplasm, pulmonary alveolar proteinosis with hypogammaglobulinemia, respiratory tract infectious disorder, Middle East respiratory syndrome, reactive airway disease, acinar dysplasia, pulmonary hypoplasia, isolated left bronchial isomerism, bronchiectasis and nasal polyposis

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

5 retrieved; paginated sample, class counts are floors:

2 not provided, 1 pathogenic, 1 uncertain significance, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1064421	NC_000005.9:g.44300489_44312646del	FGF10	Pathogenic	criteria provided, single submitter
812880	NM_001321120.2(TBX4):c.1115dup (p.Pro373fs)	TBX4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
800378	NM_001321120.2(TBX4):c.256G>A (p.Glu86Lys)	TBX4	Uncertain significance	no assertion criteria provided
1341433	NM_001321120.2(TBX4):c.524_527del (p.Asn175fs)	TBX4	not provided	no classification provided
1341434	NM_001321120.2(TBX4):c.1201G>A (p.Glu401Lys)	TBX4	not provided	no classification provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 7 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TBX4	Orphanet:1509	Coxopodopatellar syndrome
TBX4	Orphanet:238578	Familial clubfoot due to 17q23.1q23.2 microduplication
TBX4	Orphanet:261279	17q23.1q23.2 microdeletion syndrome
TBX4	Orphanet:275777	Heritable pulmonary arterial hypertension
TBX4	Orphanet:3301	Tetraamelia-multiple malformations syndrome
FGF10	Orphanet:2363	Lacrimoauriculodentodigital syndrome
FGF10	Orphanet:86815	Aplasia of lacrimal and salivary glands

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
TBX4	HGNC:11603	ENSG00000121075	P57082	T-box transcription factor TBX4	clinvar
FGF10	HGNC:3666	ENSG00000070193	O15520	Fibroblast growth factor 10	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TBX4	T-box transcription factor TBX4	Transcriptional regulator that has an essential role in the organogenesis of lungs, pelvis, and hindlimbs.
FGF10	Fibroblast growth factor 10	Plays an important role in the regulation of embryonic development, cell proliferation and cell differentiation.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TBX4	Transcription factor	no		TF_T-box, p53-like_TF_DNA-bd_sf, TF_T-box_CS
FGF10	Other/Unknown	no		Fibroblast_GF_fam, IL1/FGF

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right lung	1
upper lobe of left lung	1
upper lobe of lung	1
buccal mucosa cell	1
endocervix	1
synovial joint	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TBX4	116	tissue_specific	yes	right lung, upper lobe of left lung, upper lobe of lung
FGF10	169	broad	marker	buccal mucosa cell, synovial joint, endocervix

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FGF10	4,233
TBX4	1,054

Intra-cohort edges

A	B	Sources
FGF10	TBX4	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FGF10	O15520	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TBX4	P57082	60.96

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 24. Enrichment computed across 2 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
Regulation of gene expression in early pancreatic precursor cells	1	1427.5×	0.003	FGF10
FGFR1b ligand binding and activation	1	1268.9×	0.003	FGF10
FGFR2b ligand binding and activation	1	1142.0×	0.003	FGF10
FGFRL1 modulation of FGFR1 signaling	1	878.5×	0.003	FGF10
Developmental Lineage of Mammary Stem Cells	1	761.3×	0.003	FGF10
Activated point mutants of FGFR2	1	671.8×	0.003	FGF10
Phospholipase C-mediated cascade: FGFR1	1	671.8×	0.003	FGF10
Phospholipase C-mediated cascade; FGFR2	1	634.4×	0.003	FGF10
Developmental Lineage of Multipotent Pancreatic Progenitor Cells	1	601.0×	0.003	FGF10
Downstream signaling of activated FGFR1	1	543.8×	0.003	FGF10
PI-3K cascade:FGFR1	1	519.1×	0.003	FGF10
SHC-mediated cascade:FGFR1	1	496.5×	0.003	FGF10
PI-3K cascade:FGFR2	1	496.5×	0.003	FGF10
SHC-mediated cascade:FGFR2	1	475.8×	0.003	FGF10
FRS-mediated FGFR1 signaling	1	456.8×	0.003	FGF10
FRS-mediated FGFR2 signaling	1	439.2×	0.003	FGF10
Negative regulation of FGFR1 signaling	1	368.4×	0.004	FGF10
Negative regulation of FGFR2 signaling	1	368.4×	0.004	FGF10
PI3K Cascade	1	271.9×	0.005	FGF10
Signaling by FGFR2 in disease	1	265.6×	0.005	FGF10
Constitutive Signaling by Aberrant PI3K in Cancer	1	126.9×	0.009	FGF10
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	1	96.8×	0.011	FGF10
PIP3 activates AKT signaling	1	66.8×	0.016	FGF10
RAF/MAP kinase cascade	1	61.1×	0.016	FGF10

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
embryonic genitalia morphogenesis	1	8426.0×	0.001	FGF10
regulation of activin receptor signaling pathway	1	8426.0×	0.001	FGF10
urothelial cell proliferation	1	8426.0×	0.001	FGF10
positive regulation of urothelial cell proliferation	1	8426.0×	0.001	FGF10
bronchiole morphogenesis	1	8426.0×	0.001	FGF10
mesenchymal-epithelial cell signaling involved in lung development	1	8426.0×	0.001	FGF10
fibroblast growth factor receptor signaling pathway involved in mammary gland specification	1	8426.0×	0.001	FGF10
submandibular salivary gland formation	1	8426.0×	0.001	FGF10
semicircular canal fusion	1	8426.0×	0.001	FGF10
lung proximal/distal axis specification	1	8426.0×	0.001	FGF10
positive regulation of hair follicle cell proliferation	1	8426.0×	0.001	FGF10
regulation of saliva secretion	1	4213.0×	0.001	FGF10
mammary gland bud formation	1	4213.0×	0.001	FGF10
branch elongation involved in salivary gland morphogenesis	1	4213.0×	0.001	FGF10
mesenchymal cell differentiation involved in lung development	1	4213.0×	0.001	FGF10
positive regulation of white fat cell proliferation	1	4213.0×	0.001	FGF10
fibroblast growth factor receptor apoptotic signaling pathway	1	4213.0×	0.001	FGF10
embryonic lung development	1	4213.0×	0.001	TBX4
angiogenesis	2	62.4×	0.002	TBX4, FGF10
female genitalia morphogenesis	1	2808.7×	0.002	FGF10
bud outgrowth involved in lung branching	1	2808.7×	0.002	FGF10
secretion by lung epithelial cell involved in lung growth	1	2808.7×	0.002	FGF10
metanephros morphogenesis	1	2106.5×	0.002	FGF10
salivary gland development	1	2106.5×	0.002	FGF10
prostatic bud formation	1	2106.5×	0.002	FGF10
tear secretion	1	2106.5×	0.002	FGF10
white fat cell proliferation	1	2106.5×	0.002	FGF10
male genitalia morphogenesis	1	1685.2×	0.002	FGF10
epithelial cell proliferation involved in salivary gland morphogenesis	1	1685.2×	0.002	FGF10
regulation of branching involved in salivary gland morphogenesis by mesenchymal-epithelial signaling	1	1685.2×	0.002	FGF10

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 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
TBX4	0	0
FGF10	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	TBX4, FGF10

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)
TBX4	0	—
FGF10	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.