Congenital diaphragmatic hernia

Summary

Congenital diaphragmatic hernia (MONDO:0005711) is a disease (an umbrella term covering 5 Mondo subtypes) with 21 cohort genes and 85 clinical trials. Top therapeutic interventions include milrinone, sildenafil, and autologous cord blood.

At a glance

• Prevalence: 1-5 / 10 000 (Worldwide) [Orphanet-validated]
• Umbrella term: 5 Mondo subtypes
• Cohort genes: 21
• ClinVar variants: 34
• Phenotypes (HPO): 8
• Clinical trials: 85

Clinical features

Epidemiology

Prevalence records

21 prevalence record(s), Orphanet, top 20 (validated / broadest geography first):

Type	Class	Value	Geography	Validation
Prevalence at birth	1-5 / 10 000	30	Worldwide	Validated
Prevalence at birth	1-5 / 10 000	21.2	Europe	Validated
Prevalence at birth	1-5 / 10 000	39.3	Austria	Validated
Prevalence at birth	1-5 / 10 000	14.6	Belgium	Validated
Prevalence at birth	1-5 / 10 000	11.4	Croatia	Validated
Prevalence at birth	1-5 / 10 000	19.8	Denmark	Validated
Prevalence at birth	1-5 / 10 000	23.6	France	Validated
Prevalence at birth	1-9 / 100 000	5.9	Germany	Validated
Prevalence at birth	1-5 / 10 000	23.2	Hungary	Validated
Prevalence at birth	1-5 / 10 000	21.7	Ireland	Validated
Prevalence at birth	1-5 / 10 000	22.6	Italy	Validated
Prevalence at birth	1-5 / 10 000	49.8	Malta	Validated
Prevalence at birth	1-5 / 10 000	29.2	Netherlands	Validated
Prevalence at birth	1-5 / 10 000	22.9	Norway	Validated
Prevalence at birth	1-9 / 100 000	8.2	Poland	Validated
Prevalence at birth	1-5 / 10 000	18.9	Portugal	Validated
Prevalence at birth	1-9 / 100 000	9.4	Spain	Validated
Prevalence at birth	1-5 / 10 000	38.9	Switzerland	Validated
Prevalence at birth	1-5 / 10 000	19.7	United Kingdom	Validated
Prevalence at birth	1-5 / 10 000	22.3	Ukraine	Validated

Signs & symptoms

Clinical features (HPO)

8 HPO clinical features (Orphanet curated; top 8 by frequency):

HPO ID	Term	Frequency
HP:0000776	Congenital diaphragmatic hernia	Very frequent (80-99%)
HP:0000884	Prominent sternum	Frequent (30-79%)
HP:0002089	Pulmonary hypoplasia	Frequent (30-79%)
HP:0002098	Respiratory distress	Frequent (30-79%)
HP:0002566	Intestinal malrotation	Frequent (30-79%)
HP:0010315	Aplasia/Hypoplasia of the diaphragm	Frequent (30-79%)
HP:0012418	Hypoxemia	Frequent (30-79%)
HP:0030680	Abnormal cardiovascular system morphology	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital diaphragmatic hernia
Mondo ID	MONDO:0005711
EFO	EFO:0007216
MeSH	D065630
OMIM	142340
Orphanet	2140
DOID	DOID:3827
ICD-10-CM	Q79.0
ICD-11	1414428936
NCIT	C98893
UMLS	C0235833
MedGen	68625
GARD	0001481
MedDRA	10010439
Is cancer (heuristic)	no

Also known as: agenesis of hemidiaphragm · CDH · congenital diaphragmatic defect · congenital diaphragmatic hernia · diaphragmatic hernia · unilateral agenesis of diaphragm

Data availability: 34 ClinVar variants · 4 GenCC gene-disease records · 6 cell lines.

Disease family

An umbrella term covering 5 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › respiratory system disorder › diaphragm disorder › congenital diaphragmatic hernia

Related subtypes (4): diaphragmatic eventration, diaphragmitis, respiratory paralysis, diaphragmatic malformation

Subtypes (5): diaphragmatic hernia 1, diaphragmatic hernia 2, hernia, anterior diaphragmatic, diaphragmatic hernia 3, diaphragmatic hernia 4, with cardiovascular defects

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

34 retrieved; paginated sample, class counts are floors:

10 uncertain significance, 8 likely pathogenic, 5 pathogenic, 5 conflicting classifications of pathogenicity, 2 benign/likely benign, 2 risk factor, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
267841	46;XX;t(7;13)(p13;q34)dn		Pathogenic	criteria provided, single submitter
631491	NM_001260.3(CDK8):c.185C>A (p.Ser62Ter)	CDK8	Pathogenic	criteria provided, single submitter
156010	NM_005257.6(GATA6):c.712G>T (p.Gly238Ter)	GATA6	Pathogenic	criteria provided, single submitter
156011	NM_005257.6(GATA6):c.1072del (p.Val358fs)	GATA6	Pathogenic	criteria provided, single submitter
30213	NM_005257.6(GATA6):c.1366C>T (p.Arg456Cys)	GATA6	Pathogenic	criteria provided, multiple submitters, no conflicts
816896	NM_006767.4(LZTR1):c.955del (p.Gln319fs)	LZTR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
619228	NM_001127392.3(MYRF):c.1303G>A (p.Gly435Arg)	MYRF	Pathogenic/Likely pathogenic	no assertion criteria provided
427835	NM_207361.5(FREM2):c.[4031G>A];[4558C>T]		Likely pathogenic	no assertion criteria provided
218938	NM_000138.5(FBN1):c.4970_4971insA (p.Cys1658fs)	FBN1	Likely pathogenic	criteria provided, single submitter
369974	NM_207361.6(FREM2):c.5940_5942del (p.Leu1981del)	FREM2	Likely pathogenic	no assertion criteria provided
996605	NM_001127392.3(MYRF):c.1904-1G>A	MYRF	Likely pathogenic	no assertion criteria provided
996607	NM_001127392.3(MYRF):c.1209G>C (p.Gln403His)	MYRF	Likely pathogenic	no assertion criteria provided
996740	NM_001127392.3(MYRF):c.239dup (p.Gly81fs)	MYRF	Likely pathogenic	no assertion criteria provided
374171	NM_133433.4(NIPBL):c.1811_1812del (p.Lys603_Ser604insTer)	NIPBL	Likely pathogenic	criteria provided, single submitter
1195979	NM_005032.7(PLS3):c.617C>T (p.Ala206Val)	PLS3	Likely pathogenic	criteria provided, single submitter
369976	NM_000168.6(GLI3):c.2726C>G (p.Ala909Gly)	GLI3	risk factor	no assertion criteria provided
369979	NM_019055.6(ROBO4):c.569G>C (p.Gly190Ala)	ROBO4	risk factor	no assertion criteria provided
44265	NM_001927.4(DES):c.638C>T (p.Ala213Val)	DES	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
218939	NM_001379081.2(FREM1):c.1394G>C (p.Gly465Ala)	FREM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
41624	NM_000245.4(MET):c.2975C>T (p.Thr992Ile)	MET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
996604	NM_001127392.3(MYRF):c.2036T>C (p.Val679Ala)	MYRF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
218940	NM_181458.4(PAX3):c.944C>A (p.Thr315Lys)	PAX3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
267803	46;X;t(X;10)(p11.2;q24.3)		Uncertain significance	criteria provided, single submitter
267953	46;XY;t(1;6)(p22;q15)dn		Uncertain significance	criteria provided, single submitter
992572	NM_001004356.3(FGFRL1):c.886A>G (p.Ile296Val)	FGFRL1	Uncertain significance	criteria provided, multiple submitters, no conflicts
992573	NM_001004356.3(FGFRL1):c.1328G>C (p.Gly443Ala)	FGFRL1	Uncertain significance	criteria provided, multiple submitters, no conflicts
369975	NM_025074.7(FRAS1):c.2389G>A (p.Glu797Lys)	FRAS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
369978	NM_025074.7(FRAS1):c.6323A>T (p.Asp2108Val)	FRAS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
369977	NM_207361.6(FREM2):c.4994C>T (p.Ser1665Phe)	FREM2	Uncertain significance	criteria provided, single submitter
816905	NM_002430.3(MN1):c.3839del (p.Cys1280fs)	MN1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 21 · Orphanet: 65 · 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
SLIT1	Moderate	Autosomal recessive	congenital diaphragmatic hernia
SLIT3	Moderate	Autosomal dominant	congenital anomaly of kidney and urinary tract	2
LONP1	Limited	Autosomal dominant	congenital diaphragmatic hernia	10
SIN3A	Limited	Autosomal dominant	congenital diaphragmatic hernia	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SIN3A	Orphanet:500166	SIN3-related intellectual disability syndrome due to a point mutation
SIN3A	Orphanet:94065	15q24 microdeletion syndrome
LONP1	Orphanet:1458	CODAS syndrome
LONP1	Orphanet:2140	Congenital diaphragmatic hernia
LONP1	Orphanet:79243	Pyruvate dehydrogenase E1-alpha deficiency
MYRF	Orphanet:647811	Cardiac-urogenital syndrome
CDK8	Orphanet:528084	Non-specific syndromic intellectual disability
ROBO4	Orphanet:402075	Familial bicuspid aortic valve
FRAS1	Orphanet:2052	Fraser syndrome
FRAS1	Orphanet:93100	Renal agenesis, unilateral
FREM1	Orphanet:217266	BNAR syndrome
FREM1	Orphanet:2717	Oculotrichoanal syndrome
FREM1	Orphanet:3366	Non-syndromic metopic craniosynostosis
FREM1	Orphanet:93100	Renal agenesis, unilateral
FREM2	Orphanet:2052	Fraser syndrome
FREM2	Orphanet:93100	Renal agenesis, unilateral
FREM2	Orphanet:98949	Complete cryptophthalmia
DES	Orphanet:154	Familial isolated dilated cardiomyopathy
DES	Orphanet:85146	Neurogenic scapuloperoneal syndrome, Kaeser type
DES	Orphanet:98909	Desminopathy
NIPBL	Orphanet:199	Cornelia de Lange syndrome
NIPBL	Orphanet:329802	5p13 microduplication syndrome
FBN1	Orphanet:1885	Isolated ectopia lentis
FBN1	Orphanet:2084	Glaucoma-ectopia lentis-microspherophakia-stiff joints-short stature syndrome
FBN1	Orphanet:2462	Shprintzen-Goldberg syndrome
FBN1	Orphanet:2623	Geleophysic dysplasia
FBN1	Orphanet:2833	Stiff skin syndrome
FBN1	Orphanet:284963	Marfan syndrome type 1
FBN1	Orphanet:284979	Neonatal Marfan syndrome
FBN1	Orphanet:300382	Progeroid and marfanoid aspect-lipodystrophy syndrome
FBN1	Orphanet:3449	Weill-Marchesani syndrome
FBN1	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
FBN1	Orphanet:969	Acromicric dysplasia
GATA6	Orphanet:2140	Congenital diaphragmatic hernia
GATA6	Orphanet:2255	Pancreatic hypoplasia-diabetes-congenital heart disease syndrome
GATA6	Orphanet:3303	Tetralogy of Fallot
GATA6	Orphanet:334	Hereditary atrial fibrillation
GATA6	Orphanet:665044	Common arterial trunk with aortic dominance
GATA6	Orphanet:665058	Common arterial trunk with pulmonary dominance and interrupted aortic arch
GATA6	Orphanet:99067	Complete atrioventricular septal defect with ventricular hypoplasia
GATA6	Orphanet:99103	Atrial septal defect, ostium secundum type
GLI3	Orphanet:36	Acrocallosal syndrome
GLI3	Orphanet:380	Greig cephalopolysyndactyly syndrome
GLI3	Orphanet:672	Pallister-Hall syndrome
GLI3	Orphanet:93322	Isolated tibial hemimelia
GLI3	Orphanet:93334	Postaxial polydactyly type A
GLI3	Orphanet:93335	Postaxial polydactyly type B
GLI3	Orphanet:93338	Polysyndactyly
LZTR1	Orphanet:251576	Gliosarcoma
LZTR1	Orphanet:251579	Giant cell glioblastoma

Cohort genes → proteins

21 cohort genes, 21 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	21

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLIT1	HGNC:11085	ENSG00000187122	O75093	Slit homolog 1 protein	gencc
SLIT3	HGNC:11087	ENSG00000184347	O75094	Slit homolog 3 protein	gencc
SIN3A	HGNC:19353	ENSG00000169375	Q96ST3	Paired amphipathic helix protein Sin3a	gencc
LONP1	HGNC:9479	ENSG00000196365	P36776	Lon protease homolog, mitochondrial	gencc
MYRF	HGNC:1181	ENSG00000124920	Q9Y2G1	Myelin regulatory factor	clinvar
CDK8	HGNC:1779	ENSG00000132964	P49336	Cyclin-dependent kinase 8	clinvar
ROBO4	HGNC:17985	ENSG00000154133	Q8WZ75	Roundabout homolog 4	clinvar
FRAS1	HGNC:19185	ENSG00000138759	Q86XX4	Extracellular matrix organizing protein FRAS1	clinvar
FREM1	HGNC:23399	ENSG00000164946	Q5H8C1	FRAS1-related extracellular matrix protein 1	clinvar
FREM2	HGNC:25396	ENSG00000150893	Q5SZK8	FRAS1-related extracellular matrix protein 2	clinvar
DES	HGNC:2770	ENSG00000175084	P17661	Desmin	clinvar
NIPBL	HGNC:28862	ENSG00000164190	Q6KC79	Nipped-B-like protein	clinvar
FBN1	HGNC:3603	ENSG00000166147	P35555	Fibrillin-1	clinvar
FGFRL1	HGNC:3693	ENSG00000127418	Q8N441	Fibroblast growth factor receptor-like 1	clinvar
GATA6	HGNC:4174	ENSG00000141448	Q92908	Transcription factor GATA-6	clinvar
GLI3	HGNC:4319	ENSG00000106571	P10071	Transcriptional activator GLI3	clinvar
LZTR1	HGNC:6742	ENSG00000099949	Q8N653	Leucine-zipper-like transcriptional regulator 1	clinvar
MET	HGNC:7029	ENSG00000105976	P08581	Hepatocyte growth factor receptor	clinvar
MN1	HGNC:7180	ENSG00000169184	Q10571	Transcriptional activator MN1	clinvar
PAX3	HGNC:8617	ENSG00000135903	P23760	Paired box protein Pax-3	clinvar
PLS3	HGNC:9091	ENSG00000102024	P13797	Plastin-3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLIT1	Slit homolog 1 protein	Thought to act as molecular guidance cue in cellular migration, and function appears to be mediated by interaction with roundabout homolog receptors.
SLIT3	Slit homolog 3 protein	May act as molecular guidance cue in cellular migration, and function may be mediated by interaction with roundabout homolog receptors.
SIN3A	Paired amphipathic helix protein Sin3a	Acts as a transcriptional repressor.
LONP1	Lon protease homolog, mitochondrial	ATP-dependent serine protease that mediates the selective degradation of misfolded, unassembled or oxidatively damaged polypeptides as well as certain short-lived regulatory proteins in the mitochondrial matrix.
MYRF	Myelin regulatory factor	Constitutes a precursor of the transcription factor.
CDK8	Cyclin-dependent kinase 8	Component of the Mediator complex, a coactivator involved in regulated gene transcription of nearly all RNA polymerase II-dependent genes.
ROBO4	Roundabout homolog 4	Receptor for Slit proteins, at least for SLIT2, and seems to be involved in angiogenesis and vascular patterning.
FRAS1	Extracellular matrix organizing protein FRAS1	Involved in extracellular matrix organization.
FREM1	FRAS1-related extracellular matrix protein 1	Extracellular matrix protein that plays a role in epidermal differentiation and is required for epidermal adhesion during embryonic development.
FREM2	FRAS1-related extracellular matrix protein 2	Extracellular matrix protein required for maintenance of the integrity of the skin epithelium and for maintenance of renal epithelia.
DES	Desmin	Muscle-specific type III intermediate filament essential for proper muscular structure and function.
NIPBL	Nipped-B-like protein	Plays an important role in the loading of the cohesin complex on to DNA.
FBN1	Fibrillin-1	Structural component of the 10-12 nm diameter microfibrils of the extracellular matrix, which conveys both structural and regulatory properties to load-bearing connective tissues.
FGFRL1	Fibroblast growth factor receptor-like 1	Has a negative effect on cell proliferation.
GATA6	Transcription factor GATA-6	Transcriptional activator.
GLI3	Transcriptional activator GLI3	Has a dual function as a transcriptional activator and a repressor of the sonic hedgehog (Shh) pathway, and plays a role in limb development.
LZTR1	Leucine-zipper-like transcriptional regulator 1	Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex that mediates ubiquitination of Ras (K-Ras/KRAS, N-Ras/NRAS and H-Ras/HRAS).
MET	Hepatocyte growth factor receptor	Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to hepatocyte growth factor/HGF ligand.
MN1	Transcriptional activator MN1	Transcriptional activator which specifically regulates expression of TBX22 in the posterior region of the developing palate.
PAX3	Paired box protein Pax-3	Transcription factor that may regulate cell proliferation, migration and apoptosis.
PLS3	Plastin-3	Actin-bundling protein.

Protein-family classification

Druggable: 5 · Difficult: 4 · Unknown: 12 · Druggable fraction: 0.24

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	2	2.8×	0.408
Kinase	2	2.6×	0.408
Transcription factor	4	1.6×	0.408
Protease	1	1.7×	0.542
Other/Unknown	12	1.0×	0.542

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLIT1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, LRRNT, Cys-rich_flank_reg_C
SLIT3	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, LRRNT, Cys-rich_flank_reg_C
SIN3A	Other/Unknown	no		PAH, HDAC_interact_dom, Sin3_C
LONP1	Protease	yes	3.4.21.53	Lon_prtase_N, AAA+_ATPase, ATPase_AAA_core
MYRF	Transcription factor	no		p53-like_TF_DNA-bd_sf, NDT80_DNA-bd_dom, MYRF_C2
CDK8	Kinase	yes	2.7.11.22	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
ROBO4	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom
FRAS1	Other/Unknown	no		EGF, VWF_dom, Calx_beta
FREM1	Other/Unknown	no		C-type_lectin-like, Calx_beta, C-type_lectin-like/link_sf
FREM2	Other/Unknown	no		Calx_beta, CalX-like_sf, CSPG_rpt
DES	Other/Unknown	no		Intermed_filament_DNA-bd, IF_conserved, IF_rod_dom
NIPBL	Other/Unknown	no		ARM-like, ARM-type_fold, Nipped-B_C
FBN1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom
FGFRL1	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, Ig-like_dom
GATA6	Transcription factor	no		Znf_GATA, GATA_N, Znf_NHR/GATA
GLI3	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, GLI-like
LZTR1	Other/Unknown	no		BTB/POZ_dom, Kelch_1, SKP1/BTB/POZ_sf
MET	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Semap_dom
MN1	Other/Unknown	no		MN1
PAX3	Transcription factor	no		HD, Paired_dom, Homeodomain-like_sf
PLS3	Other/Unknown	no		Actinin_actin-bd_CS, CH_dom, EF_hand_dom

Expression context

Cohort genes with no expression data: 0.

20 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)	21
unknown	0

Top tissues across cohort

Tissue	Cohort genes
germinal epithelium of ovary	3
secondary oocyte	2
ventricular zone	2
adrenal tissue	2
apex of heart	2
parietal pleura	2
renal medulla	2
kidney epithelium	2
calcaneal tendon	2
male germ line stem cell (sensu Vertebrata) in testis	2
cortical plate	1
middle temporal gyrus	1
orbitofrontal cortex	1
popliteal artery	1
right coronary artery	1
tibial artery	1
oocyte	1
left adrenal gland	1
right adrenal gland	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLIT1	186	broad	marker	cortical plate, middle temporal gyrus, orbitofrontal cortex
SLIT3	254	ubiquitous	marker	right coronary artery, popliteal artery, tibial artery
SIN3A	245	ubiquitous	marker	secondary oocyte, oocyte, ventricular zone
LONP1	275	ubiquitous	marker	right adrenal gland, right adrenal gland cortex, left adrenal gland
MYRF	223	ubiquitous	marker	middle frontal gyrus, C1 segment of cervical spinal cord, inferior vagus X ganglion
CDK8	289	ubiquitous	yes	adrenal tissue, buccal mucosa cell, secondary oocyte
ROBO4	254	broad	marker	lower lobe of lung, apex of heart, omental fat pad
FRAS1	212	ubiquitous	marker	germinal epithelium of ovary, parietal pleura, renal medulla
FREM1	171	broad	marker	kidney epithelium, smooth muscle tissue, metanephros
FREM2	160	broad	marker	adrenal tissue, kidney epithelium, renal medulla
DES	280	broad	marker	apex of heart, saphenous vein, gastrocnemius
NIPBL	288	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, calcaneal tendon, colonic epithelium
FBN1	275	ubiquitous	marker	synovial joint, skin of hip, decidua
FGFRL1	182	ubiquitous	marker	right uterine tube, left lobe of thyroid gland, right lobe of thyroid gland
GATA6	204	ubiquitous	marker	germinal epithelium of ovary, parietal pleura, jejunal mucosa
GLI3	263	ubiquitous	marker	ventricular zone, olfactory bulb, tendon of biceps brachii
LZTR1	134	ubiquitous	marker	sural nerve, pituitary gland, adenohypophysis
MET	270	ubiquitous	marker	pigmented layer of retina, germinal epithelium of ovary, cartilage tissue
MN1	252	ubiquitous	marker	ganglionic eminence, vastus lateralis, skeletal muscle tissue of biceps brachii
PAX3	116	broad	marker	olfactory segment of nasal mucosa, male germ line stem cell (sensu Vertebrata) in testis, nasal cavity mucosa
PLS3	297	ubiquitous	marker	blood vessel layer, calcaneal tendon, visceral pleura

Protein interactions among cohort

Intra-cohort edges: 5.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MET	5,823
SIN3A	4,666
LONP1	4,030
FBN1	3,640
NIPBL	3,278
SLIT3	3,245
PAX3	2,960
CDK8	2,827
GLI3	2,825
FRAS1	2,552

Intra-cohort edges

A	B	Sources
FRAS1	FREM1	string_interaction
FRAS1	FREM2	string_interaction
FREM1	FREM2	intact, string_interaction
ROBO4	SLIT1	string_interaction
ROBO4	SLIT3	string_interaction

Structural data

PDB: 10 · AlphaFold-only: 11 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MET	P08581	130
CDK8	P49336	36
LONP1	P36776	29
FBN1	P35555	11
PLS3	P13797	6
NIPBL	Q6KC79	3
LZTR1	Q8N653	3
MYRF	Q9Y2G1	2
GLI3	P10071	1
PAX3	P23760	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLIT3	O75094	80.48
SLIT1	O75093	80.28
DES	P17661	77.73
FREM1	Q5H8C1	75.75
FGFRL1	Q8N441	72.04
SIN3A	Q96ST3	69.67
ROBO4	Q8WZ75	57.67
GATA6	Q92908	53.48
MN1	Q10571	42.47
FRAS1	Q86XX4
FREM2	Q5SZK8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 127. Enrichment computed across 21 evidence-associated genes (13 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 13 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Regulation of commissural axon pathfinding by SLIT and ROBO	2	146.4×	0.010	SLIT1, SLIT3
MECP2 regulates neuronal receptors and channels	2	92.5×	0.010	SIN3A, MET
Regulation of MITF-M-dependent genes involved in cell cycle and proliferation	2	87.8×	0.010	SIN3A, MET
Netrin-1 signaling	2	67.6×	0.012	SLIT1, SLIT3
Transcriptional Regulation by MECP2	2	48.8×	0.019	SIN3A, MET
Developmental Biology	5	5.6×	0.027	SLIT1, SLIT3, CDK8, SIN3A, MET
Drug-mediated inhibition of MET activation	1	439.2×	0.036	MET
MITF-M-dependent gene expression	2	27.9×	0.036	SIN3A, MET
Axon guidance	3	10.4×	0.037	SLIT1, SLIT3, MET
Nervous system development	3	9.9×	0.038	SLIT1, SLIT3, MET
MET activates STAT3	1	292.8×	0.039	MET
Regulation of lipid metabolism by PPARalpha	2	21.7×	0.039	CDK8, SIN3A
Loss of MECP2 binding ability to 5mC-DNA	1	219.6×	0.040	SIN3A
MET activates PTPN11	1	175.7×	0.040	MET
MET interacts with TNS proteins	1	175.7×	0.040	MET
Regulation of cortical dendrite branching	1	175.7×	0.040	SLIT1
Signaling by ROBO receptors	2	19.1×	0.040	SLIT1, SLIT3
MITF-M-regulated melanocyte development	2	17.6×	0.040	SIN3A, MET
MET Receptor Activation	1	146.4×	0.043	MET
MET activates PI3K/AKT signaling	1	146.4×	0.043	MET
GLI proteins bind promoters of Hh responsive genes to promote transcription	1	125.5×	0.043	GLI3
Sema4D mediated inhibition of cell attachment and migration	1	109.8×	0.043	MET
Loss of function of MECP2 in Rett syndrome	1	109.8×	0.043	SIN3A
Pervasive developmental disorders	1	109.8×	0.043	SIN3A
MECP2 regulates transcription of neuronal ligands	1	109.8×	0.043	SIN3A
Disorders of Developmental Biology	1	109.8×	0.043	SIN3A
Disorders of Nervous System Development	1	109.8×	0.043	SIN3A
Cohesin Loading onto Chromatin	1	87.8×	0.047	NIPBL
POU5F1 (OCT4), SOX2, NANOG repress genes related to differentiation	1	87.8×	0.047	GATA6
MET receptor recycling	1	87.8×	0.047	MET

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 21 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cell communication	3	120.4×	5e-04	FRAS1, FREM1, FREM2
metanephros development	3	73.0×	0.001	NIPBL, FBN1, GLI3
axon extension involved in axon guidance	2	145.9×	0.006	SLIT1, SLIT3
axon guidance	4	17.3×	0.006	SLIT1, SLIT3, ROBO4, GLI3
embryonic digestive tract morphogenesis	2	89.2×	0.013	NIPBL, GLI3
lateral ganglionic eminence cell proliferation	1	802.5×	0.016	GLI3
negative regulation of transforming growth factor beta2 production	1	802.5×	0.016	GATA6
tube morphogenesis	1	802.5×	0.016	GATA6
external genitalia morphogenesis	1	802.5×	0.016	NIPBL
response to methylglyoxal	1	802.5×	0.016	SIN3A
lambdoid suture morphogenesis	1	802.5×	0.016	GLI3
sagittal suture morphogenesis	1	802.5×	0.016	GLI3
mammary gland specification	1	802.5×	0.016	GLI3
anterior semicircular canal development	1	802.5×	0.016	GLI3
lateral semicircular canal development	1	802.5×	0.016	GLI3
cellular response to tert-butyl hydroperoxide	1	802.5×	0.016	SIN3A
negative regulation of sebum secreting cell proliferation	1	802.5×	0.016	GATA6
developmental growth	2	69.8×	0.016	NIPBL, GLI3
negative chemotaxis	2	61.7×	0.016	SLIT1, SLIT3
ventricular septum morphogenesis	2	41.1×	0.016	SLIT3, FGFRL1
oligodendrocyte differentiation	2	40.1×	0.016	MYRF, GLI3
anatomical structure morphogenesis	3	19.9×	0.016	FRAS1, FREM1, FREM2
morphogenesis of an epithelium	2	32.8×	0.021	FRAS1, FREM2
regulation of antimicrobial humoral response	1	401.2×	0.021	GATA6
endodermal cell fate determination	1	401.2×	0.021	GATA6
smoothened signaling pathway involved in ventral spinal cord interneuron specification	1	401.2×	0.021	GLI3
smoothened signaling pathway involved in spinal cord motor neuron cell fate specification	1	401.2×	0.021	GLI3
regulation of developmental growth	1	401.2×	0.021	NIPBL
gallbladder development	1	401.2×	0.021	NIPBL
oxidation-dependent protein catabolic process	1	401.2×	0.021	LONP1

Therapeutics

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 3 · Phased (≥1): 4 · Undrugged: 17

Druggability breadth: 5 of 21 evidence-associated genes (24%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
LONP1	BORTEZOMIB
CDK8	SORAFENIB
MET	AFATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MET	95	4
CDK8	23	4
SIN3A	1	2
LONP1	1	4
SLIT1	0	0
SLIT3	0	0
MYRF	0	0
ROBO4	0	0
FRAS1	0	0
FREM1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BORTEZOMIB	4	LONP1
SORAFENIB	4	CDK8, MET
PONATINIB	4	CDK8
QUIZARTINIB	4	CDK8
AFATINIB	4	MET
FEDRATINIB	4	MET
TIVOZANIB	4	MET
AXITINIB	4	MET
NERATINIB	4	MET
INFIGRATINIB PHOSPHATE	4	MET
INFIGRATINIB	4	MET
PALBOCICLIB	4	MET
ENTRECTINIB	4	MET
DABRAFENIB	4	MET
CABOZANTINIB S-MALATE	4	MET
AFATINIB DIMALEATE	4	MET
CABOZANTINIB	4	MET
CERITINIB	4	MET
VANDETANIB	4	MET
BOSUTINIB	4	MET
CAPMATINIB	4	MET
TEPOTINIB	4	MET
BRIGATINIB	4	MET
ENSARTINIB	4	MET
PAZOPANIB	4	MET
NINTEDANIB	4	MET
SUNITINIB	4	MET
ERLOTINIB	4	MET
CRIZOTINIB	4	MET
MIDOSTAURIN	4	MET

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
MET	2,015	Binding:2005, Functional:6, ADMET:4
CDK8	509	Binding:499, Functional:10
SIN3A	19	Binding:19
PAX3	17	Binding:17
LONP1	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
LONP1	3.4.21.53	Endopeptidase La
CDK8	2.7.11.22, 2.7.11.23	cyclin-dependent kinase, [RNA-polymerase]-subunit kinase
MET	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
CDK8	509
MET	2,015

Pharmacogenomics

Cohort genes with a PharmGKB record: 21; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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.

Compound	Max phase	Cohort target (bioactivity)
BORTEZOMIB	4	LONP1
SORAFENIB	4	CDK8, MET
PONATINIB	4	CDK8
QUIZARTINIB	4	CDK8
AFATINIB	4	MET
FEDRATINIB	4	MET
TIVOZANIB	4	MET
AXITINIB	4	MET
NERATINIB	4	MET
INFIGRATINIB PHOSPHATE	4	MET
INFIGRATINIB	4	MET
PALBOCICLIB	4	MET
ENTRECTINIB	4	MET
DABRAFENIB	4	MET
CABOZANTINIB S-MALATE	4	MET
AFATINIB DIMALEATE	4	MET
CABOZANTINIB	4	MET
CERITINIB	4	MET
VANDETANIB	4	MET
BOSUTINIB	4	MET
CAPMATINIB	4	MET
TEPOTINIB	4	MET
BRIGATINIB	4	MET
ENSARTINIB	4	MET
PAZOPANIB	4	MET
NINTEDANIB	4	MET
SUNITINIB	4	MET
ERLOTINIB	4	MET
CRIZOTINIB	4	MET
MIDOSTAURIN	4	MET

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	LONP1, CDK8, MET
B	Phased (≥1) drug, not yet approved	1	SIN3A
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	2	ROBO4, FGFRL1
E	Difficult family or no structure, no drug	15	SLIT1, SLIT3, MYRF, FRAS1, FREM1, FREM2, DES, NIPBL, FBN1, GATA6 (+5 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SLIT1	0	—
SLIT3	0	—
MYRF	0	—
ROBO4	0	—
FRAS1	0	—
FREM1	0	—
FREM2	0	—
DES	0	—
NIPBL	0	—
FBN1	0	—
FGFRL1	0	—
GATA6	0	—
GLI3	0	—
LZTR1	0	—
MN1	0	—
PAX3	17	—
PLS3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 85.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	70
PHASE2	7
PHASE3	4
PHASE4	2
PHASE2/PHASE3	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05213676	PHASE4	RECRUITING	De-implementing Inhaled Nitric Oxide for Congenital Diaphragmatic Hernia
NCT07247240	PHASE4	NOT_YET_RECRUITING	Efficacy of Inhaled Nitric Oxide in Congenital Diaphragmatic Hernia
NCT06946576	PHASE3	NOT_YET_RECRUITING	Safety and Efficacy of Fetoscopic Endoluminal Tracheal Occlusion in Congenital Diaphragmatic Hernia
NCT07187206	PHASE3	RECRUITING	Safety and Efficacy of FETO in CDH Phase III
NCT00257946	PHASE3	TERMINATED	Type of Material in Repair of Congenital Diaphragmatic Hernia
NCT01240057	PHASE2/PHASE3	COMPLETED	Tracheal Occlusion To Accelerate Lung Growth (TOTAL) Trial for Severe Pulmonary Hypoplasia
NCT03861182	PHASE3	TERMINATED	Contribution of PRF in CDH in Children With Prothetic Patch Closure
NCT05201144	PHASE2	RECRUITING	A Trial of Phosphodiesterase-5 Inhibitor in Neonatal Congenital Diaphragmatic Hernia (TOP-CDH)
NCT00373438	PHASE2	UNKNOWN	Fetoscopic Tracheal Balloon Occlusion in Left Diaphragmatic Hernia
NCT00966823	PHASE2	TERMINATED	Fetal Tracheal Balloon Study in Diaphragmatic Hernia
NCT01302977	PHASE2	UNKNOWN	Fetal Tracheal Occlusion in Severe Diaphragmatic Hernia: a Randomized Trial
NCT01731509	PHASE2	UNKNOWN	Early FETO for Severe Congenital Diaphragmatic Hernia
NCT02875860	PHASE2	COMPLETED	‘TOTAL’ (Tracheal Occlusion To Accelerate Lung Growth) Trial
NCT02951130	PHASE2	COMPLETED	Milrinone in Congenital Diaphragmatic Hernia
NCT03526588	PHASE1	TERMINATED	Umbilical Cord Blood Mononuclear Cells for Hypoxic Neurologic Injury in Infants With Congenital Diaphragmatic Hernia (CDH)
NCT00950118	Not specified	RECRUITING	Diaphragmatic Hernia Research & Exploration, Advancing Molecular Science
NCT02530073	Not specified	RECRUITING	Trial of Fetoscopic Endoluminal Tracheal Occlusion (FETO) for CDH
NCT02549820	Not specified	ACTIVE_NOT_RECRUITING	Fetoscopic Endoluminal Tracheal Occlusion in Severe Left Congenital Diaphragmatic Hernia
NCT02596802	Not specified	ACTIVE_NOT_RECRUITING	Fetoscopic Endoluminal Tracheal Occlusion (FETO) for Congenital Diaphragm Hernia
NCT02710968	Not specified	ACTIVE_NOT_RECRUITING	Fetoscopic Endoluminal Tracheal Occlusion (FETO) for Severe Left Diaphragmatic Hernia (CDH)
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)
NCT03674372	Not specified	RECRUITING	Fetoscopic Endoluminal Tracheal Occlusion
NCT03750266	Not specified	RECRUITING	3D Animation and Models to Aid Management of Fetal CDH
NCT03788122	Not specified	RECRUITING	Fetal Surgery Interview Study: Parental Perceptions of Fetal Surgery
NCT03980717	Not specified	RECRUITING	Fetal Endotracheal Occlusion (FETO) in the Resolution of Pulmonary Hypertension in Fetuses With Severe CDH
NCT04052828	Not specified	RECRUITING	Fetal Endoscopic Tracheal Occlusion (FETO) Trial for Congenital Diaphragmatic Hernia (CDH)
NCT04114578	Not specified	RECRUITING	Exploratory Observational Prospective Study in Neonatal and Pediatric Congenital Diaphragmatic Hernia
NCT04429750	Not specified	RECRUITING	Intact Cord Resuscitation in CDH
NCT04583644	Not specified	RECRUITING	Pilot Trial of Fetoscopic Endoluminal Tracheal Occlusion (FETO) in Severe Left Congenital Diaphragmatic Hernia (CDH)
NCT04774848	Not specified	RECRUITING	High Frequency Oscillatory Ventilation Versus High Frequency Jet Ventilation for Congenital Diaphragmatic Hernia
NCT05051254	Not specified	RECRUITING	Respiratory Muscles and Work of Breathing in Children
NCT05100693	Not specified	RECRUITING	Smart Removal for Congenital Diaphragmatic Hernia
NCT05354505	Not specified	RECRUITING	Fetal Endoscopic Tracheal Occlusion (FETO) Trial for Congenital Diaphragmatic Hernia (CDH)
NCT05421676	Not specified	RECRUITING	Fetal Endoscopic Tracheal Occlusion for CDH (CDH)
NCT05450653	Not specified	RECRUITING	Trial of FETO for Severe Congenital Diaphragmatic Hernia
NCT05461222	Not specified	RECRUITING	Fetal Endoscopic Tracheal Occlusion (FETO) for Severe Congenital Diaphragmatic Hernia
NCT05666986	Not specified	RECRUITING	Engagement in Physical Activities and Sports in Adolescents With Diaphragmatic Hernia
NCT05962346	Not specified	RECRUITING	Fetal Endoscopic Tracheal Occlusion for Congenital Diaphragmatic Hernia
NCT06179472	Not specified	ACTIVE_NOT_RECRUITING	Infant Survival and Long-term Outcome Following Fetoscopic Endoluminal Tracheal Occlusion in Severe Left and Right Congenital Diaphragmatic Hernia, A Phase III Trial

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
MILRINONE	4	1
SILDENAFIL	4	1
AUTOLOGOUS CORD BLOOD	3	1