Esophageal atresia/tracheoesophageal fistula

Summary

Esophageal atresia/tracheoesophageal fistula (MONDO:0008586) is a disease with 27 cohort genes and 5 clinical trials. The dominant Reactome pathway is Impaired BRCA2 binding to PALB2 (3 cohort genes).

At a glance

• Prevalence: 1-5 / 10 000 (Europe) [Orphanet-validated]
• Cohort genes: 27
• ClinVar variants: 34
• Phenotypes (HPO): 60
• Clinical trials: 5

Clinical features

Epidemiology

Prevalence records

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

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000		Europe	Validated
Prevalence at birth	1-5 / 10 000	24.3	Europe	Validated
Prevalence at birth	1-5 / 10 000	19.5	Austria	Validated
Prevalence at birth	1-5 / 10 000	17.5	Belgium	Validated
Prevalence at birth	1-5 / 10 000	11.4	Croatia	Validated
Prevalence at birth	1-5 / 10 000	42.5	Denmark	Validated
Prevalence at birth	1-5 / 10 000	11.8	France	Validated
Prevalence at birth	1-5 / 10 000	23.8	Germany	Validated
Prevalence at birth	1-5 / 10 000	26.6	Hungary	Validated
Prevalence at birth	1-5 / 10 000	10.8	Ireland	Validated
Prevalence at birth	1-5 / 10 000	18.4	Italy	Validated
Prevalence at birth	1-5 / 10 000	24.9	Malta	Validated
Prevalence at birth	1-5 / 10 000	17.1	Netherlands	Validated
Prevalence at birth	1-5 / 10 000	34.4	Norway	Validated
Prevalence at birth	1-9 / 100 000	9.7	Poland	Validated
Prevalence at birth	1-5 / 10 000	18.9	Portugal	Validated
Prevalence at birth	1-5 / 10 000	15.7	Spain	Validated
Prevalence at birth	1-5 / 10 000	25.1	Switzerland	Validated
Prevalence at birth	1-5 / 10 000	22.4	United Kingdom	Validated
Prevalence at birth	1-5 / 10 000	22.3	Ukraine	Validated

Signs & symptoms

Clinical features (HPO)

60 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0002575	Tracheoesophageal fistula	Very frequent (80-99%)
HP:0001531	Failure to thrive in infancy	Frequent (30-79%)
HP:0002013	Vomiting	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002091	Restrictive ventilatory defect	Frequent (30-79%)
HP:0002205	Recurrent respiratory infections	Frequent (30-79%)
HP:0002579	Gastrointestinal dysmotility	Frequent (30-79%)
HP:0003781	Excessive salivation	Frequent (30-79%)
HP:0006510	Chronic pulmonary obstruction	Frequent (30-79%)
HP:0008872	Feeding difficulties in infancy	Frequent (30-79%)
HP:0010963	Absence of stomach bubble on fetal sonography	Frequent (30-79%)
HP:0012387	Bronchitis	Frequent (30-79%)
HP:0012523	Oral aversion	Frequent (30-79%)
HP:0100326	Immunologic hypersensitivity	Frequent (30-79%)
HP:0100633	Esophagitis	Frequent (30-79%)
HP:0000079	Abnormality of the urinary system	Occasional (5-29%)
HP:0000119	Abnormality of the genitourinary system	Occasional (5-29%)
HP:0000961	Cyanosis	Occasional (5-29%)
HP:0000980	Pallor	Occasional (5-29%)
HP:0001510	Growth delay	Occasional (5-29%)
HP:0001518	Small for gestational age	Occasional (5-29%)
HP:0001561	Polyhydramnios	Occasional (5-29%)
HP:0001604	Vocal cord paresis	Occasional (5-29%)
HP:0001607	Subglottic stenosis	Occasional (5-29%)
HP:0002020	Gastroesophageal reflux	Occasional (5-29%)
HP:0002021	Pyloric stenosis	Occasional (5-29%)
HP:0002098	Respiratory distress	Occasional (5-29%)
HP:0002835	Aspiration	Occasional (5-29%)
HP:0003468	Abnormal vertebral morphology	Occasional (5-29%)
HP:0004885	Episodic respiratory distress	Occasional (5-29%)
HP:0008755	Laryngotracheomalacia	Occasional (5-29%)
HP:0012252	Abnormal respiratory system morphology	Occasional (5-29%)
HP:0012718	Morphological abnormality of the gastrointestinal tract	Occasional (5-29%)
HP:0012732	Anorectal anomaly	Occasional (5-29%)
HP:0030084	Clinodactyly	Occasional (5-29%)
HP:0030680	Abnormal cardiovascular system morphology	Occasional (5-29%)
HP:0040064	Abnormality of limbs	Occasional (5-29%)
HP:0000104	Renal agenesis	Very rare (<1-4%)
HP:0000175	Cleft palate	Very rare (<1-4%)
HP:0000365	Hearing impairment	Very rare (<1-4%)
HP:0000453	Choanal atresia	Very rare (<1-4%)
HP:0000589	Coloboma	Very rare (<1-4%)
HP:0000598	Abnormality of the ear	Very rare (<1-4%)
HP:0000811	Abnormal external genitalia	Very rare (<1-4%)
HP:0001252	Hypotonia	Very rare (<1-4%)
HP:0001276	Hypertonia	Very rare (<1-4%)
HP:0001539	Omphalocele	Very rare (<1-4%)
HP:0001629	Ventricular septal defect	Very rare (<1-4%)
HP:0001636	Tetralogy of Fallot	Very rare (<1-4%)
HP:0001680	Coarctation of aorta	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	esophageal atresia/tracheoesophageal fistula
Mondo ID	MONDO:0008586
MeSH	C531835
OMIM	189960
Orphanet	1199
DOID	DOID:0080171
ICD-11	1582061097
SNOMED CT	95435007
UMLS	C0040588
MedGen	21228
GARD	0006381
MedDRA	10021530, 10030146
NORD	1108
Is cancer (heuristic)	no

Also known as: Esophageal Atresia and/or Tracheoesophageal Fistula · te fistula · TEF · tracheoesophageal fistula

Data availability: 34 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › digestive system disorder › upper digestive tract disorder › esophageal disorder › esophageal atresia/tracheoesophageal fistula

Related subtypes (19): esophageal atresia, esophageal varices, esophagitis, megaesophagus, esophageal tuberculosis, esophageal leukoplakia, dyskinesia of esophagus, esophageal diverticulosis, gastroesophageal reflux disease, achalasia, Barrett esophagus, esophageal duplication cyst, tubular duplication of the esophagus, laryngotracheoesophageal cleft, isolated tracheo-esophageal fistula, congenital esophageal diverticulum, neoplasm of esophagus, esophageal ulcer, congenital esophageal stenosis

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:

18 likely pathogenic, 8 pathogenic, 5 conflicting classifications of pathogenicity, 3 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
267840	46;XY;t(15;17)(q24;q21.3)dn		Pathogenic	criteria provided, single submitter
267897	46;XY;t(6;8)(q13;q13)dn		Pathogenic	criteria provided, single submitter
37989	NM_000059.4(BRCA2):c.5682C>G (p.Tyr1894Ter)	BRCA2	Pathogenic	reviewed by expert panel
38215	NM_000059.4(BRCA2):c.9117G>A (p.Pro3039=)	BRCA2	Pathogenic	reviewed by expert panel
51129	NM_000059.4(BRCA2):c.145G>T (p.Glu49Ter)	BRCA2	Pathogenic	reviewed by expert panel
51952	NM_000059.4(BRCA2):c.5857G>T (p.Glu1953Ter)	BRCA2	Pathogenic	reviewed by expert panel
4738	NM_032043.3(BRIP1):c.2392C>T (p.Arg798Ter)	BRIP1	Pathogenic	criteria provided, multiple submitters, no conflicts
916558	NM_004247.4(EFTUD2):c.2419del (p.Gln807fs)	EFTUD2	Pathogenic	no assertion criteria provided
916553	NM_001354761.2(ADD1):c.1A>G (p.Met1Val)	ADD1	Likely pathogenic	no assertion criteria provided
916554	NM_152698.3(AMER3):c.2236C>T (p.Arg746Ter)	AMER3	Likely pathogenic	no assertion criteria provided
916555	NM_003917.5(AP1G2):c.464G>A (p.Arg155His)	AP1G2	Likely pathogenic	no assertion criteria provided
916556	NM_005883.3(APC2):c.665T>C (p.Ile222Thr)	APC2	Likely pathogenic	no assertion criteria provided
916557	NM_001408.3(CELSR2):c.2858A>G (p.Asn953Ser)	CELSR2	Likely pathogenic	no assertion criteria provided
916559	NM_000819.5(GART):c.1907T>G (p.Leu636Arg)	GART	Likely pathogenic	no assertion criteria provided
916560	NM_014905.5(GLS):c.1940C>T (p.Thr647Ile)	GLS	Likely pathogenic	no assertion criteria provided
916561	NM_001520.4(GTF3C1):c.6040C>A (p.Pro2014Thr)	GTF3C1	Likely pathogenic	no assertion criteria provided
916562	NM_002163.4(IRF8):c.814G>A (p.Gly272Arg)	IRF8	Likely pathogenic	no assertion criteria provided
916564	NM_198317.3(KLHL17):c.1682C>A (p.Ala561Glu)	KLHL17	Likely pathogenic	no assertion criteria provided
916565	NM_203403.2(LURAP1L):c.346C>T (p.Arg116Cys)	LURAP1L	Likely pathogenic	no assertion criteria provided
916566	NM_032420.5(PCDH1):c.353A>G (p.Glu118Gly)	PCDH1	Likely pathogenic	no assertion criteria provided
916567	NM_001288772.2(PIK3C2G):c.761+2T>C	PIK3C2G	Likely pathogenic	no assertion criteria provided
916568	NM_000938.3(POLR2B):c.2123C>T (p.Ala708Val)	POLR2B	Likely pathogenic	no assertion criteria provided
916569	NM_005401.5(PTPN14):c.1919G>A (p.Arg640His)	PTPN14	Likely pathogenic	no assertion criteria provided
916570	NM_012414.4(RAB3GAP2):c.1379G>A (p.Arg460Gln)	RAB3GAP2	Likely pathogenic	no assertion criteria provided
916572	NM_015395.3(TECPR1):c.2617G>A (p.Asp873Asn)	TECPR1	Likely pathogenic	no assertion criteria provided
916573	NM_017442.4(TLR9):c.548C>G (p.Pro183Arg)	TLR9	Likely pathogenic	no assertion criteria provided
52256	NM_000059.4(BRCA2):c.7051G>A (p.Ala2351Thr)	BRCA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
96854	NM_000059.4(BRCA2):c.7625C>T (p.Thr2542Met)	BRCA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
126593	NM_024675.4(PALB2):c.11C>T (p.Pro4Leu)	PALB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1560845	NM_144643.4(SCLT1):c.638C>T (p.Thr213Ile)	SCLT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 32 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BRCA2	Orphanet:1331	Familial prostate cancer
BRCA2	Orphanet:1333	Familial pancreatic carcinoma
BRCA2	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
BRCA2	Orphanet:178	Chordoma
BRCA2	Orphanet:227535	Hereditary breast cancer
BRCA2	Orphanet:319462	Inherited cancer-predisposing syndrome due to biallelic BRCA2 mutations
BRCA2	Orphanet:440437	Familial colorectal cancer Type X
BRCA2	Orphanet:654	Nephroblastoma
BRCA2	Orphanet:667662	Breast implant-associated anaplastic large cell lymphoma
BRCA2	Orphanet:694963	Inflammatory breast cancer
BRCA2	Orphanet:70567	Cholangiocarcinoma
BRCA2	Orphanet:84	Fanconi anemia
RAB3GAP2	Orphanet:1387	Cataract-intellectual disability-hypogonadism syndrome
RAB3GAP2	Orphanet:2510	Micro syndrome
RAB3GAP2	Orphanet:401830	Autosomal recessive spastic paraplegia type 69
BRIP1	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
BRIP1	Orphanet:84	Fanconi anemia
WDFY3	Orphanet:528084	Non-specific syndromic intellectual disability
APC2	Orphanet:821	Sotos syndrome
PALB2	Orphanet:1333	Familial pancreatic carcinoma
PALB2	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
PALB2	Orphanet:178	Chordoma
PALB2	Orphanet:227535	Hereditary breast cancer
PALB2	Orphanet:84	Fanconi anemia
SCLT1	Orphanet:110	Bardet-Biedl syndrome
EFTUD2	Orphanet:79113	Mandibulofacial dysostosis-microcephaly syndrome
GLS	Orphanet:557056	Spastic ataxia-dysarthria due to glutaminase deficiency
GLS	Orphanet:557064	Neonatal epileptic encephalopathy due to glutaminase deficiency
IRF8	Orphanet:319600	Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency
ITSN1	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
SMAD6	Orphanet:402075	Familial bicuspid aortic valve
PTPN14	Orphanet:99141	Lymphedema-posterior choanal atresia syndrome

Cohort genes → proteins

27 cohort genes, 27 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	27

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BRCA2	HGNC:1101	ENSG00000139618	P51587	Breast cancer type 2 susceptibility protein	clinvar
TLR9	HGNC:15633	ENSG00000239732	Q9NR96	Toll-like receptor 9	clinvar
RAB3GAP2	HGNC:17168	ENSG00000118873	Q9H2M9	Rab3 GTPase-activating protein non-catalytic subunit	clinvar
SLC25A23	HGNC:19375	ENSG00000125648	Q9BV35	Mitochondrial adenyl nucleotide antiporter SLC25A23	clinvar
BRIP1	HGNC:20473	ENSG00000136492	Q9BX63	Fanconi anemia group J protein	clinvar
WDFY3	HGNC:20751	ENSG00000163625	Q8IZQ1	WD repeat and FYVE domain-containing protein 3	clinvar
TECPR1	HGNC:22214	ENSG00000205356	Q7Z6L1	Tectonin beta-propeller repeat-containing protein 1	clinvar
KLHL17	HGNC:24023	ENSG00000187961	Q6TDP4	Kelch-like protein 17	clinvar
APC2	HGNC:24036	ENSG00000115266	O95996	Adenomatous polyposis coli protein 2	clinvar
ADD1	HGNC:243	ENSG00000087274	P35611	Alpha-adducin	clinvar
PALB2	HGNC:26144	ENSG00000083093	Q86YC2	Partner and localizer of BRCA2	clinvar
SCLT1	HGNC:26406	ENSG00000151466	Q96NL6	Sodium channel and clathrin linker 1	clinvar
AMER3	HGNC:26771	ENSG00000178171	Q8N944	APC membrane recruitment protein 3	clinvar
EFTUD2	HGNC:30858	ENSG00000108883	Q15029	116 kDa U5 small nuclear ribonucleoprotein component	clinvar
LURAP1L	HGNC:31452	ENSG00000153714	Q8IV03	Leucine rich adaptor protein 1-like	clinvar
CELSR2	HGNC:3231	ENSG00000143126	Q9HCU4	Cadherin EGF LAG seven-pass G-type receptor 2	clinvar
GART	HGNC:4163	ENSG00000159131	P22102	Trifunctional purine biosynthetic protein adenosine-3	clinvar
GLS	HGNC:4331	ENSG00000115419	O94925	Glutaminase kidney isoform, mitochondrial	clinvar
GTF3C1	HGNC:4664	ENSG00000077235	Q12789	General transcription factor 3C polypeptide 1	clinvar
IRF8	HGNC:5358	ENSG00000140968	Q02556	Interferon regulatory factor 8	clinvar
AP1G2	HGNC:556	ENSG00000213983	O75843	AP-1 complex subunit gamma-like 2	clinvar
ITSN1	HGNC:6183	ENSG00000205726	Q15811	Intersectin-1	clinvar
SMAD6	HGNC:6772	ENSG00000137834	O43541	SMAD family member 6	clinvar
PCDH1	HGNC:8655	ENSG00000156453	Q08174	Protocadherin-1	clinvar
PIK3C2G	HGNC:8973	ENSG00000139144	O75747	Phosphatidylinositol 3-kinase C2 domain-containing subunit gamma	clinvar
POLR2B	HGNC:9188	ENSG00000047315	P30876	DNA-directed RNA polymerase II subunit RPB2	clinvar
PTPN14	HGNC:9647	ENSG00000152104	Q15678	Tyrosine-protein phosphatase non-receptor type 14	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BRCA2	Breast cancer type 2 susceptibility protein	Involved in double-strand break repair and/or homologous recombination.
TLR9	Toll-like receptor 9	Key component of innate and adaptive immunity.
RAB3GAP2	Rab3 GTPase-activating protein non-catalytic subunit	Regulatory subunit of the Rab3 GTPase-activating (Rab3GAP) complex composed of RAB3GAP1 and RAB3GAP2, which accelerates the otherwise slow GTP hydrolysis catalyzed by Rab proteins.
SLC25A23	Mitochondrial adenyl nucleotide antiporter SLC25A23	Electroneutral antiporter that mediates the transport of adenine nucleotides through the inner mitochondrial membrane.
BRIP1	Fanconi anemia group J protein	DNA-dependent ATPase and 5’-3’ DNA helicase required for the maintenance of chromosomal stability.
WDFY3	WD repeat and FYVE domain-containing protein 3	Required for selective macroautophagy (aggrephagy).
TECPR1	Tectonin beta-propeller repeat-containing protein 1	Tethering factor involved in autophagy.
KLHL17	Kelch-like protein 17	Substrate-recognition component of some cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complexes.
APC2	Adenomatous polyposis coli protein 2	Stabilizes microtubules and may regulate actin fiber dynamics through the activation of Rho family GTPases.
ADD1	Alpha-adducin	Membrane-cytoskeleton-associated protein that promotes the assembly of the spectrin-actin network.
PALB2	Partner and localizer of BRCA2	Plays a critical role in homologous recombination repair (HRR) through its ability to recruit BRCA2 and RAD51 to DNA breaks.
SCLT1	Sodium channel and clathrin linker 1	Adapter protein that links SCN10A to clathrin.
AMER3	APC membrane recruitment protein 3	Regulator of the canonical Wnt signaling pathway.
EFTUD2	116 kDa U5 small nuclear ribonucleoprotein component	Required for pre-mRNA splicing as component of the spliceosome, including pre-catalytic, catalytic and post-catalytic spliceosomal complexes.
CELSR2	Cadherin EGF LAG seven-pass G-type receptor 2	Receptor that may have an important role in cell/cell signaling during nervous system formation.
GART	Trifunctional purine biosynthetic protein adenosine-3	Trifunctional enzyme that catalyzes three distinct reactions as part of the ‘de novo’ inosine monophosphate biosynthetic pathway.
GLS	Glutaminase kidney isoform, mitochondrial	Catalyzes the first reaction in the primary pathway for the renal catabolism of glutamine.
GTF3C1	General transcription factor 3C polypeptide 1	Required for RNA polymerase III-mediated transcription.
IRF8	Interferon regulatory factor 8	Transcription factor that specifically binds to the upstream regulatory region of type I interferon (IFN) and IFN-inducible MHC class I genes (the interferon consensus sequence (ICS)).
AP1G2	AP-1 complex subunit gamma-like 2	May function in protein sorting in late endosomes or multivesucular bodies (MVBs).
ITSN1	Intersectin-1	Adapter protein that provides a link between the endocytic membrane traffic and the actin assembly machinery.
SMAD6	SMAD family member 6	Transforming growth factor-beta superfamily receptors signaling occurs through the Smad family of intracellular mediators.
PCDH1	Protocadherin-1	May be involved in cell-cell interaction processes and in cell adhesion.
PIK3C2G	Phosphatidylinositol 3-kinase C2 domain-containing subunit gamma	Generates phosphatidylinositol 3-phosphate (PtdIns3P) and phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2) that act as second messengers.
POLR2B	DNA-directed RNA polymerase II subunit RPB2	Catalytic core component of RNA polymerase II (Pol II), a DNA-dependent RNA polymerase which synthesizes mRNA precursors and many functional non-coding RNAs using the four ribonucleoside triphosphates as substrates.
PTPN14	Tyrosine-protein phosphatase non-receptor type 14	Protein tyrosine phosphatase which may play a role in the regulation of lymphangiogenesis, cell-cell adhesion, cell-matrix adhesion, cell migration, cell growth and also regulates TGF-beta gene expression, thereby modulating epithelial-mes…

Protein-family classification

Druggable: 6 · Difficult: 4 · Unknown: 17 · Druggable fraction: 0.22

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
Phosphatase	1	3.1×	0.779
Scaffold/PPI	3	1.9×	0.779
Other/Unknown	17	1.1×	0.779
Antibody/Immunoglobulin	1	1.1×	0.782
Kinase	1	1.0×	0.782
Enzyme (other)	2	0.9×	0.782
GPCR	1	0.9×	0.782
Transcription factor	1	0.3×	0.969

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BRCA2	Other/Unknown	no		BRCA2_repeat, NA-bd_OB-fold, BRCA2_OB_1
TLR9	Other/Unknown	no		TIR_dom, Leu-rich_rpt, Leu-rich_rpt_typical-subtyp
RAB3GAP2	Other/Unknown	no		Rab3GAP2, RAB3GAP2_C, RAB3GAP_N
SLC25A23	Other/Unknown	no		EF_hand_dom, MCP, EF-hand-dom_pair
BRIP1	Enzyme (other)	yes	3.6.4.12	Helicase-like_DEXD_c2, ATP-dep_Helicase_C, RAD3-like_helicase_DEAD
WDFY3	Transcription factor	no		Znf_FYVE, BEACH_dom, WD40_rpt
TECPR1	Other/Unknown	no		Peroxin/Ferlin, Beta-propeller_rpt_TECPR, TECPR1-like_DysF
KLHL17	Other/Unknown	no		BTB/POZ_dom, Kelch_1, Gal_Oxase/kelch_b-propeller
APC2	Other/Unknown	no		Armadillo, APC_rpt, SAMP
ADD1	Other/Unknown	no		Aldolase_II/adducin_N, Aldolase_II/adducin_N_sf, Aldolase-II_Adducin_sf
PALB2	Scaffold/PPI	no		WD40/YVTN_repeat-like_dom_sf, PALB2_WD40, WD40_repeat_dom_sf
SCLT1	Other/Unknown	no		SCLT1
AMER3	Other/Unknown	no		AMER
EFTUD2	Other/Unknown	no		EFG_V-like, T_Tr_GTP-bd_dom, EFTu-like_2
LURAP1L	Other/Unknown	no		LURAP1, LURA1/LRA25
CELSR2	GPCR	yes		EGF-type_Asp/Asn_hydroxyl_site, GPS, EGF
GART	Enzyme (other)	yes	2.1.2.2	PRibGlycinamide_synth, GART_AS, Formyl_transf_N
GLS	Scaffold/PPI	no	3.5.1.2	Ankyrin_rpt, Beta-lactam/transpept-like, Glutaminase
GTF3C1	Other/Unknown	no		TFIIIC_Bblock-bd, Tfc3-like_eWH, Tfc3-like
IRF8	Other/Unknown	no		Interferon_reg_fact_DNA-bd_dom, SMAD_FHA_dom_sf, SMAD-like_dom_sf
AP1G2	Antibody/Immunoglobulin	yes		Clathrin/coatomer_adapt-like_N, Clathrin_a/b/g-adaptin_app_Ig, GAE_dom
ITSN1	Scaffold/PPI	no		C2_dom, DH_dom, EH_dom
SMAD6	Other/Unknown	no		SMAD_dom, MAD_homology1_Dwarfin-type, SMAD_FHA_dom_sf
PCDH1	Other/Unknown	no		Cadherin-like_dom, Cadherin_N, Protocadherin
PIK3C2G	Kinase	yes	2.7.1.137	C2_dom, PI3K_Ras-bd_dom, PI3/4_kinase_cat_dom
POLR2B	Other/Unknown	no		DNA-dir_RNAP_su2_dom, RNA_pol_bsu_CS, RNA_pol_Rpb2_7
PTPN14	Phosphatase	yes	3.1.3.48	PTP_cat, FERM_domain, Tyr_Pase_dom

Expression context

Cohort genes with no expression data: 0.

23 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)	27
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ventricular zone	5
buccal mucosa cell	4
lower esophagus mucosa	3
right hemisphere of cerebellum	3
cortical plate	3
male germ line stem cell (sensu Vertebrata) in testis	2
secondary oocyte	2
granulocyte	2
calcaneal tendon	2
sural nerve	2
leukocyte	2
monocyte	2
cerebellar cortex	2
cerebellar hemisphere	2
right lung	2
ganglionic eminence	2
tibia	2
blood	1
lymph node	1
choroid plexus epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BRCA2	184	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, secondary oocyte, ventricular zone
TLR9	119	tissue_specific	marker	blood, granulocyte, lymph node
RAB3GAP2	295	ubiquitous	marker	choroid plexus epithelium, lateral nuclear group of thalamus, dorsal root ganglion
SLC25A23	271	ubiquitous	marker	nucleus accumbens, caudate nucleus, buccal mucosa cell
BRIP1	181	ubiquitous	marker	ventricular zone, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis
WDFY3	293	ubiquitous	marker	sural nerve, calcaneal tendon, corpus callosum
TECPR1	254	ubiquitous	marker	parotid gland, pancreatic ductal cell, ileal mucosa
KLHL17	161	ubiquitous	yes	lower esophagus mucosa, right hemisphere of cerebellum, granulocyte
APC2	199	broad	yes	paraflocculus, cortical plate, cerebellar vermis
ADD1	304	ubiquitous	marker	right hemisphere of cerebellum, nerve, tibial nerve
PALB2	232	ubiquitous	yes	secondary oocyte, buccal mucosa cell, oocyte
SCLT1	217	ubiquitous	marker	buccal mucosa cell, monocyte, leukocyte
AMER3	66	tissue_specific	yes	cortical plate, cerebellar cortex, cerebellar hemisphere
EFTUD2	253	ubiquitous	marker	bone marrow cell, tibialis anterior, ventricular zone
LURAP1L	222	ubiquitous	marker	islet of Langerhans, calcaneal tendon, right lung
CELSR2	248	ubiquitous	marker	ganglionic eminence, ventricular zone, right frontal lobe
GART	254	ubiquitous	marker	ventricular zone, ganglionic eminence, rectum
GLS	287	ubiquitous	marker	middle temporal gyrus, Brodmann (1909) area 23, pons
GTF3C1	287	ubiquitous	marker	lower esophagus mucosa, adenohypophysis, pituitary gland
IRF8	265	broad	marker	monocyte, mononuclear cell, leukocyte
AP1G2	270	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
ITSN1	293	ubiquitous	marker	sural nerve, tibia, cortical plate
SMAD6	277	ubiquitous	marker	right lung, renal glomerulus, metanephric glomerulus
PCDH1	256	ubiquitous	marker	lower esophagus mucosa, pharyngeal mucosa, type B pancreatic cell
PIK3C2G	148	tissue_specific	marker	corpus epididymis, hair follicle, upper leg skin
POLR2B	298	ubiquitous	marker	epithelium of nasopharynx, germinal epithelium of ovary, endothelial cell
PTPN14	257	ubiquitous	marker	buccal mucosa cell, parietal pleura, tibia

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EFTUD2	8,471
POLR2B	7,228
GART	5,868
PALB2	5,641
BRCA2	4,839
IRF8	3,554
TLR9	3,489
ITSN1	3,188
BRIP1	2,272
ADD1	2,157

Intra-cohort edges

A	B	Sources
BRCA2	BRIP1	string_interaction
BRCA2	PALB2	biogrid_interaction, intact, string_interaction
BRIP1	PALB2	string_interaction

Structural data

PDB: 18 · AlphaFold-only: 9 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EFTUD2	Q15029	68
GLS	O94925	50
GART	P22102	40
POLR2B	P30876	20
BRCA2	P51587	14
ITSN1	Q15811	11
PALB2	Q86YC2	4
GTF3C1	Q12789	4
AP1G2	O75843	4
PCDH1	Q08174	4
TLR9	Q9NR96	3
BRIP1	Q9BX63	3
PTPN14	Q15678	3
WDFY3	Q8IZQ1	2
TECPR1	Q7Z6L1	2
RAB3GAP2	Q9H2M9	1
KLHL17	Q6TDP4	1
PIK3C2G	O75747	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SCLT1	Q96NL6	82.44
SLC25A23	Q9BV35	78.93
IRF8	Q02556	75.54
SMAD6	O43541	72.34
LURAP1L	Q8IV03	66.08
ADD1	P35611	65.73
APC2	O95996	48.87
AMER3	Q8N944	45.30
CELSR2	Q9HCU4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 175. Enrichment computed across 27 evidence-associated genes (18 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 18 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Impaired BRCA2 binding to PALB2	3	76.1×	4e-04	BRCA2, BRIP1, PALB2
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	3	70.5×	4e-04	BRCA2, BRIP1, PALB2
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function	3	70.5×	4e-04	BRCA2, BRIP1, PALB2
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function	3	70.5×	4e-04	BRCA2, BRIP1, PALB2
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	3	65.6×	4e-04	BRCA2, BRIP1, PALB2
Homologous DNA Pairing and Strand Exchange	3	63.4×	4e-04	BRCA2, BRIP1, PALB2
Resolution of D-loop Structures through Holliday Junction Intermediates	3	50.1×	7e-04	BRCA2, BRIP1, PALB2
HDR through Homologous Recombination (HRR)	3	31.7×	0.002	BRCA2, BRIP1, PALB2
Impaired BRCA2 binding to RAD51	2	34.3×	0.029	BRCA2, BRIP1
Presynaptic phase of homologous DNA pairing and strand exchange	2	30.2×	0.034	BRCA2, BRIP1
mRNA Splicing - Minor Pathway	2	24.9×	0.045	EFTUD2, POLR2B
Impaired BRCA2 translocation to the nucleus	1	211.5×	0.064	BRCA2
Impaired BRCA2 binding to SEM1 (DSS1)	1	211.5×	0.064	BRCA2
Purine ribonucleoside monophosphate biosynthesis	1	57.7×	0.147	GART
Caspase-mediated cleavage of cytoskeletal proteins	1	52.9×	0.147	ADD1
Defective homologous recombination repair (HRR) due to PALB2 loss of function	1	52.9×	0.147	BRCA2
HDR through MMEJ (alt-NHEJ)	1	48.8×	0.147	BRCA2
TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling	1	48.8×	0.147	TLR9
Trafficking and processing of endosomal TLR	1	45.3×	0.147	TLR9
RUNX2 regulates bone development	1	45.3×	0.147	SMAD6
Glutamate and glutamine metabolism	1	45.3×	0.147	GLS
Diseases of DNA Double-Strand Break Repair	1	45.3×	0.147	BRCA2
Defective homologous recombination repair (HRR) due to BRCA2 loss of function	1	45.3×	0.147	BRCA2
FGFR2 mutant receptor activation	1	42.3×	0.147	POLR2B
Cytosolic iron-sulfur cluster assembly	1	42.3×	0.147	BRIP1
Synthesis of PIPs at the Golgi membrane	1	35.2×	0.147	PIK3C2G
Resolution of D-Loop Structures	1	35.2×	0.147	BRCA2
Signaling by FGFR2 IIIa TM	1	33.4×	0.147	POLR2B
Diseases of DNA repair	1	31.7×	0.147	BRCA2
IRE1alpha activates chaperones	1	28.8×	0.147	ADD1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 27 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
adenine biosynthetic process	1	624.1×	0.047	GART
cellular response to chloroquine	1	624.1×	0.047	TLR9
positive regulation of intestinal epithelial cell development	1	624.1×	0.047	TLR9
plasmacytoid dendritic cell differentiation	1	312.1×	0.047	IRF8
tRNA transcription	1	312.1×	0.047	GTF3C1
obsolete regulation of sequestering of calcium ion	1	312.1×	0.047	SLC25A23
clathrin-dependent synaptic vesicle endocytosis	1	312.1×	0.047	ITSN1
positive regulation of adherens junction organization	1	312.1×	0.047	ADD1
mitotic recombination-dependent replication fork processing	1	312.1×	0.047	BRCA2
regulation of dendritic cell cytokine production	1	208.1×	0.047	TLR9
L-glutamine catabolic process	1	208.1×	0.047	GLS
zygotic specification of dorsal/ventral axis	1	208.1×	0.047	SMAD6
purine ribonucleoside monophosphate biosynthetic process	1	208.1×	0.047	GART
meiotic DNA double-strand break processing involved in reciprocal meiotic recombination	1	208.1×	0.047	BRIP1
neural plate anterior/posterior regionalization	1	208.1×	0.047	CELSR2
establishment of protein localization to endoplasmic reticulum membrane	1	208.1×	0.047	RAB3GAP2
negative regulation of ATPase-coupled calcium transmembrane transporter activity	1	208.1×	0.047	TLR9
follicular B cell differentiation	1	156.0×	0.047	IRF8
detection of molecule of bacterial origin	1	156.0×	0.047	TLR9
cerebrospinal fluid secretion	1	156.0×	0.047	CELSR2
response to laminar fluid shear stress	1	156.0×	0.047	SMAD6
adenine nucleotide transport	1	156.0×	0.047	SLC25A23
cellular response to metal ion	1	156.0×	0.047	TLR9
positive regulation of protein lipidation	1	156.0×	0.047	RAB3GAP2
positive regulation of endoplasmic reticulum tubular network organization	1	156.0×	0.047	RAB3GAP2
positive regulation of caveolin-mediated endocytosis	1	156.0×	0.047	ITSN1
inner cell mass cell proliferation	2	73.4×	0.047	BRCA2, PALB2
positive regulation of interleukin-12 production	2	29.0×	0.047	TLR9, IRF8
nucleotide-excision repair	2	28.4×	0.047	BRCA2, BRIP1
macroautophagy	2	17.8×	0.047	RAB3GAP2, TECPR1

Therapeutics

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 3 · Phased (≥1): 7 · Undrugged: 20

Druggability breadth: 10 of 27 evidence-associated genes (37%) 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
TLR9	HYDROXYCHLOROQUINE
GART	PEMETREXED
PIK3C2G	LAPATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PIK3C2G	7	4
TLR9	5	4
GART	3	4
GLS	2	2
EFTUD2	1	2
GTF3C1	1	2
POLR2B	1	2
BRCA2	0	0
RAB3GAP2	0	0
SLC25A23	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
HYDROXYCHLOROQUINE	4	TLR9
PEMETREXED	4	GART
METHOTREXATE	4	GART
LAPATINIB	4	PIK3C2G
MIDOSTAURIN	4	PIK3C2G
CURCUMIN	3	TLR9
THIMEROSAL	3	TLR9
LESTAURTINIB	3	PIK3C2G
AFIMETORAN	2	TLR9
MHV-370	2	TLR9
MOLIBRESIB	2	EFTUD2, GTF3C1, POLR2B
LOMETREXOL	2	GART
TELAGLENASTAT	2	GLS
TG100-115	2	PIK3C2G
AZD-8154	2	PIK3C2G
PICTILISIB	2	PIK3C2G
IPN-60090	1	GLS
SAR-260301	1	PIK3C2G

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 5.

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

Symbol	Assays	Type breakdown
GLS	187	Binding:185, Functional:2
GART	133	Binding:129, Functional:4
TLR9	132	Binding:125, Functional:7
PIK3C2G	123	Binding:123
EFTUD2	8	Binding:8
POLR2B	8	Binding:8
GTF3C1	6	Binding:6
ITSN1	5	Binding:5
PTPN14	3	Binding:3
KLHL17	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BRIP1	3.6.4.12	DNA helicase
GART	2.1.2.2, 6.3.4.13	phosphoribosylglycinamide formyltransferase 1, phosphoribosylamine-glycine ligase
GLS	3.5.1.2	glutaminase
PIK3C2G	2.7.1.137, 2.7.1.154	phosphatidylinositol 3-kinase, phosphatidylinositol-4-phosphate 3-kinase
PTPN14	3.1.3.48	protein-tyrosine-phosphatase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TLR9	132
GART	133
GLS	187
PIK3C2G	123

Pharmacogenomics

Cohort genes with a PharmGKB record: 27; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

18 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)
HYDROXYCHLOROQUINE	4	TLR9
PEMETREXED	4	GART
METHOTREXATE	4	GART
LAPATINIB	4	PIK3C2G
MIDOSTAURIN	4	PIK3C2G
CURCUMIN	3	TLR9
THIMEROSAL	3	TLR9
LESTAURTINIB	3	PIK3C2G
AFIMETORAN	2	TLR9
MHV-370	2	TLR9
MOLIBRESIB	2	EFTUD2, GTF3C1, POLR2B
LOMETREXOL	2	GART
TELAGLENASTAT	2	GLS
TG100-115	2	PIK3C2G
AZD-8154	2	PIK3C2G
PICTILISIB	2	PIK3C2G
IPN-60090	1	GLS
SAR-260301	1	PIK3C2G

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	TLR9, GART, PIK3C2G
B	Phased (≥1) drug, not yet approved	4	EFTUD2, GLS, GTF3C1, POLR2B
C	Druggable family + PDB, no drug	3	BRIP1, AP1G2, PTPN14
D	Druggable family + AlphaFold only, no drug	1	CELSR2
E	Difficult family or no structure, no drug	16	BRCA2, RAB3GAP2, SLC25A23, WDFY3, TECPR1, KLHL17, APC2, ADD1, PALB2, SCLT1 (+6 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
BRCA2	0	—
RAB3GAP2	0	—
SLC25A23	0	—
BRIP1	0	—
WDFY3	0	—
TECPR1	0	—
KLHL17	1	—
APC2	0	—
ADD1	0	—
PALB2	0	—
SCLT1	0	—
AMER3	0	—
LURAP1L	0	—
CELSR2	0	—
IRF8	0	—
AP1G2	0	—
ITSN1	5	—
SMAD6	0	—
PCDH1	0	—
PTPN14	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 5.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	4
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03792360	PHASE1	WITHDRAWN	Adipose Derived SVF for Aero-digestive & Enterocutaneous Fistulae
NCT03730454	Not specified	ACTIVE_NOT_RECRUITING	Transanastomotic Tube for Proximal Esophageal Atresia With Distal Tracheoesophageal Fistula Repair
NCT02033772	Not specified	COMPLETED	Prospective Data Collection of Patients < 6 Months of Age Undergoing Thoracoscopic Surgery
NCT02364843	Not specified	TERMINATED	A Physiological Study to Determine the Enteral Threonine Requirements in Infants Aged 1 to 6 Months
NCT03455881	Not specified	UNKNOWN	Phenotypic and Genetic Assessment of Tracheal and Esophageal Birth Defects in Patients