Pulmonary hypoplasia

Summary

Pulmonary hypoplasia (MONDO:0800133) is a disease with 4 cohort genes and 11 clinical trials. Top therapeutic interventions include milrinone.

At a glance

• Cohort genes: 4
• ClinVar variants: 7
• Clinical trials: 11

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	pulmonary hypoplasia
Mondo ID	MONDO:0800133
NCIT	C99035
UMLS	C0265783
MedGen	78574
GARD	0026450
Is cancer (heuristic)	no

Data availability: 7 ClinVar variants.

Disease family

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

7 retrieved; paginated sample, class counts are floors:

3 uncertain significance, 2 pathogenic, 1 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
143044	NM_020745.4(AARS2):c.647dup (p.Cys218fs)	AARS2	Pathogenic	criteria provided, multiple submitters, no conflicts
30940	NM_020745.4(AARS2):c.1774C>T (p.Arg592Trp)	AARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
638159	NM_001321120.2(TBX4):c.402G>A (p.Trp134Ter)	TBX4	Pathogenic	criteria provided, single submitter
374171	NM_133433.4(NIPBL):c.1811_1812del (p.Lys603_Ser604insTer)	NIPBL	Likely pathogenic	criteria provided, single submitter
267803	46;X;t(X;10)(p11.2;q24.3)		Uncertain significance	criteria provided, single submitter
267914	46;XY;t(9;14)(p21;q12)dn		Uncertain significance	criteria provided, single submitter
4070917	NM_176096.3(CDK5RAP3):c.334+243G>A	CDK5RAP3	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 10 · 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
AARS2	Orphanet:313808	Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia
AARS2	Orphanet:319504	Combined oxidative phosphorylation defect type 8
AARS2	Orphanet:99853	Ovarioleukodystrophy
NIPBL	Orphanet:199	Cornelia de Lange syndrome
NIPBL	Orphanet:329802	5p13 microduplication syndrome

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TBX4	HGNC:11603	ENSG00000121075	P57082	T-box transcription factor TBX4	clinvar
CDK5RAP3	HGNC:18673	ENSG00000108465	Q96JB5	CDK5 regulatory subunit-associated protein 3	clinvar
AARS2	HGNC:21022	ENSG00000124608	Q5JTZ9	Alanine–tRNA ligase, mitochondrial	clinvar
NIPBL	HGNC:28862	ENSG00000164190	Q6KC79	Nipped-B-like protein	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.
CDK5RAP3	CDK5 regulatory subunit-associated protein 3	Substrate adapter of E3 ligase complexes mediating ufmylation, the covalent attachment of the ubiquitin-like modifier UFM1 to substrate proteins, and which is involved in various processes, such as ribosome recycling and reticulophagy (als…
AARS2	Alanine–tRNA ligase, mitochondrial	Catalyzes the attachment of alanine to tRNA(Ala) in a two-step reaction: alanine is first activated by ATP to form Ala-AMP and then transferred to the acceptor end of tRNA(Ala).
NIPBL	Nipped-B-like protein	Plays an important role in the loading of the cohesin complex on to DNA.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.25

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
Enzyme (other)	1	3.0×	0.605
Transcription factor	1	2.1×	0.605
Other/Unknown	2	0.9×	0.769

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
CDK5RAP3	Other/Unknown	no		CDK5RAP3
AARS2	Enzyme (other)	yes	6.1.1.7	Ala-tRNA-lgiase_IIc, Transl_B-barrel_sf, tRNA_SAD
NIPBL	Other/Unknown	no		ARM-like, ARM-type_fold, Nipped-B_C

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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right lung	1
upper lobe of left lung	1
upper lobe of lung	1
adenohypophysis	1
pituitary gland	1
right uterine tube	1
cardiac muscle of right atrium	1
left ventricle myocardium	1
tendon of biceps brachii	1
calcaneal tendon	1
colonic epithelium	1
male germ line stem cell (sensu Vertebrata) in testis	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
CDK5RAP3	134	ubiquitous	marker	pituitary gland, right uterine tube, adenohypophysis
AARS2	246	ubiquitous	yes	cardiac muscle of right atrium, tendon of biceps brachii, left ventricle myocardium
NIPBL	288	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, calcaneal tendon, colonic epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AARS2	3,695
NIPBL	3,278
CDK5RAP3	1,150
TBX4	1,054

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CDK5RAP3	Q96JB5	5
AARS2	Q5JTZ9	3
NIPBL	Q6KC79	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TBX4	P57082	60.96

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 4 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
Cohesin Loading onto Chromatin	1	571.0×	0.009	NIPBL
Mitochondrial tRNA aminoacylation	1	259.6×	0.010	AARS2
tRNA Aminoacylation	1	142.8×	0.012	AARS2
Translation	1	31.0×	0.040	AARS2
Metabolism of proteins	1	6.2×	0.155	AARS2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
external genitalia morphogenesis	1	4213.0×	0.006	NIPBL
mitochondrial alanyl-tRNA aminoacylation	1	4213.0×	0.006	AARS2
regulation of phosphatase activity	1	2106.5×	0.006	CDK5RAP3
regulation of developmental growth	1	2106.5×	0.006	NIPBL
gallbladder development	1	2106.5×	0.006	NIPBL
embryonic lung development	1	2106.5×	0.006	TBX4
definitive erythrocyte differentiation	1	1404.3×	0.006	CDK5RAP3
negative regulation of protein serine/threonine kinase activity	1	1404.3×	0.006	CDK5RAP3
positive regulation of reticulophagy	1	1404.3×	0.006	CDK5RAP3
maintenance of mitotic sister chromatid cohesion	1	1053.2×	0.006	NIPBL
ear morphogenesis	1	1053.2×	0.006	NIPBL
eye morphogenesis	1	1053.2×	0.006	NIPBL
brain development	2	39.8×	0.006	CDK5RAP3, NIPBL
negative regulation of protein kinase activity by regulation of protein phosphorylation	1	842.6×	0.006	CDK5RAP3
apoptotic nuclear changes	1	702.2×	0.006	CDK5RAP3
uterus morphogenesis	1	702.2×	0.006	NIPBL
replication-born double-strand break repair via sister chromatid exchange	1	702.2×	0.006	NIPBL
establishment of mitotic sister chromatid cohesion	1	601.9×	0.006	NIPBL
regulation of hair cycle	1	601.9×	0.006	NIPBL
protein ufmylation	1	601.9×	0.006	CDK5RAP3
forelimb morphogenesis	1	526.6×	0.007	NIPBL
establishment of protein localization to chromatin	1	468.1×	0.007	NIPBL
embryonic viscerocranium morphogenesis	1	421.3×	0.008	NIPBL
cellular response to X-ray	1	421.3×	0.008	NIPBL
negative regulation of MAP kinase activity	1	351.1×	0.009	CDK5RAP3
chromatin looping	1	300.9×	0.009	NIPBL
positive regulation of signal transduction by p53 class mediator	1	300.9×	0.009	CDK5RAP3
mitotic sister chromatid cohesion	1	280.9×	0.010	NIPBL
limb morphogenesis	1	263.3×	0.010	TBX4
negative regulation of cGAS/STING signaling pathway	1	263.3×	0.010	AARS2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 4 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
CDK5RAP3	0	0
AARS2	0	0
NIPBL	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
AARS2	6.1.1.7	alanine-tRNA ligase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	AARS2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	TBX4, CDK5RAP3, NIPBL

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TBX4	0	—
CDK5RAP3	0	—
AARS2	0	—
NIPBL	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 11.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	6
PHASE2	2
PHASE2/PHASE3	1
PHASE3	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07187206	PHASE3	RECRUITING	Safety and Efficacy of FETO in CDH Phase III
NCT01240057	PHASE2/PHASE3	COMPLETED	Tracheal Occlusion To Accelerate Lung Growth (TOTAL) Trial for Severe Pulmonary Hypoplasia
NCT02875860	PHASE2	COMPLETED	‘TOTAL’ (Tracheal Occlusion To Accelerate Lung Growth) Trial
NCT02951130	PHASE2	COMPLETED	Milrinone in Congenital Diaphragmatic Hernia
NCT03101891	PHASE1	ACTIVE_NOT_RECRUITING	Renal Anhydramnios Fetal Therapy
NCT02549820	Not specified	ACTIVE_NOT_RECRUITING	Fetoscopic Endoluminal Tracheal Occlusion in Severe Left Congenital Diaphragmatic Hernia
NCT02986087	Not specified	RECRUITING	Feto-Endoscopic Tracheal Occlusion (FETO) for Severe Congenital Diaphragmatic Hernia
NCT03138863	Not specified	RECRUITING	Fetal Endoscopic Tracheal Occlusion for Congenital Diaphragmatic Hernia (FETO)
NCT06728228	Not specified	RECRUITING	Amnioinfusion for Fetal Renal Failure
NCT06884423	Not specified	RECRUITING	Safety and Efficacy of FETO in CDH: A Phase III Trial
NCT00763737	Not specified	COMPLETED	Fetal Surgery for Moderate Left Sided Congenital Diaphragmatic Hernia.

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
MILRINONE	4	1