Anorectal malformation
diseaseOn this page
Summary
Anorectal malformation (MONDO:0019938) is a disease (an umbrella term covering 5 Mondo subtypes) with 17 cohort genes (13 GWAS associations across 1 studies) and 9 clinical trials. Top therapeutic interventions include hyaluronic acid (non-animal stabilized).
At a glance
- Umbrella term: 5 Mondo subtypes
- Cohort genes: 17
- GWAS associations: 13
- ClinVar variants: 1
- Clinical trials: 9
Clinical features
No curated clinical features (Orphanet) for this disease.
Identifiers
Disease identifiers
| Field | Value |
|---|---|
| Canonical name | anorectal malformation |
| Mondo ID | MONDO:0019938 |
| MeSH | C537771 |
| Orphanet | 96346 |
| ICD-11 | 942572025 |
| SNOMED CT | 33225004 |
| GARD | 0019351 |
| Is cancer (heuristic) | no |
Data availability: 1 ClinVar variant · 13 GWAS associations (1 study).
Disease family
An umbrella term covering 5 Mondo subtypes.
Classification path: disease › human disease › disease by developmental or physiological process › disorder of development or morphogenesis › anorectal malformation
Related subtypes (189): precocious puberty, complex cortical dysplasia with other brain malformations, imperforate anus, microcephaly, demyelinating disease, hypospadias, bone development disease, primary basilar invagination, familial bicuspid aortic valve, camptodactyly of fingers, isolated congenital digital clubbing, aorta coarctation, gingival fibromatosis-progressive deafness syndrome, Eng-Strom syndrome, Morgagni-Stewart-Morel syndrome, familial partial lipodystrophy, Dunnigan type, megalodactyly, odontomatosis-aortae esophagus stenosis syndrome, otodental syndrome, oculodental syndrome, Rutherfurd type, spina bifida, steatocystoma multiplex-natal teeth syndrome, distal symphalangism, thumb deformity-alopecia-pigmentation anomaly syndrome, double uterus-hemivagina-renal agenesis syndrome, amelogenesis imperfecta type 1G, Bloom syndrome, cardiac valvular defect, developmental, isolated cerebellar hypoplasia/agenesis, cleft palate-stapes fixation-oligodontia syndrome, Jalili syndrome, craniodiaphyseal dysplasia, craniofacial dyssynostosis, deafness-oligodontia syndrome, duodenal atresia, Fowler syndrome, multiple intestinal atresia, natal teeth-intestinal pseudoobstruction-patent ductus syndrome, atresia of small intestine, mulibrey nanism, oculocerebral hypopigmentation syndrome, Cross type, familial osteodysplasia, Anderson type, pancreatic agenesis, postaxial polydactyly-dental and vertebral anomalies syndrome, familial primary pulmonary hypoplasia, renal tubular dysgenesis of genetic origin, Rothmund-Thomson syndrome, familial isolated congenital asplenia, subaortic stenosis, membranous, non-eruption of teeth-maxillary hypoplasia-genu valgum syndrome, corpus callosum agenesis-intellectual disability-coloboma-micrognathia syndrome, CK syndrome, Ogden syndrome, Nance-Horan syndrome, colonic atresia, Aicardi syndrome, torticollis-keloids-cryptorchidism-renal dysplasia syndrome, 46,XY complete gonadal dysgenesis, loose anagen syndrome, lung agenesis-heart defect-thumb anomalies syndrome, Chudley-McCullough syndrome, macrocephaly-autism syndrome, DNA ligase IV deficiency, horizontal gaze palsy with progressive scoliosis, cataract - congenital heart disease - neural tube defect syndrome, autosomal recessive frontotemporal pachygyria, craniofacial dysplasia - osteopenia syndrome, porencephaly-microcephaly-bilateral congenital cataract syndrome, congenital short bowel syndrome, familial median cleft of the upper and lower lips, progeroid features-hepatocellular carcinoma predisposition syndrome, progressive microcephaly-seizures-cortical blindness-developmental delay syndrome, aneurysm of sinus of Valsalva, blepharoptosis-cleft palate-ectrodactyly-dental anomalies syndrome, medullary sponge kidney, isolated congenital syngnathia, cleft lip and alveolus, diprosopus, T-B+ severe combined immunodeficiency due to IL-7Ralpha deficiency, high anorectal malformation, intermediate anorectal malformation, low anorectal malformation, microcephaly-polymicrogyria-corpus callosum agenesis syndrome, cordiform uterus, septate uterus, bicornuate uterus, uterine hypoplasia, agenesis and aplasia of uterine body, uterine cervical aplasia and agenesis, longitudinal vaginal septum, transverse vaginal septum, axial mesodermal dysplasia spectrum, multicystic dysplastic kidney, diabetic embryopathy, congenital microgastria, isolated cleft lip, cleft lip/palate, hereditary gingival fibromatosis, congenital bronchobiliary fistula, congenital hydrocephalus, maternal hyperthermia induced birth defects, diphallia, epibulbar lipodermoid-preauricular appendage-polythelia syndrome, bronchogenic cyst, duplication of urethra, hypohidrotic ectodermal dysplasia, Lowe-Kohn-Cohen syndrome, biliary atresia with splenic malformation syndrome, congenital pulmonary airway malformation, familial intestinal malrotation-facial anomalies syndrome, megalencephaly, cephalocele, cerebral cortical dysplasia, L1 syndrome, familial omphalocele syndrome with facial dysmorphism, penoscrotal transposition, pericardial and diaphragmatic defect, hypogonadotropic hypogonadism-severe microcephaly-sensorineural hearing loss-dysmorphism syndrome, congenital deformities of limbs, familial isolated clinodactyly of fingers, congenital shoulder dislocation, congenital elbow dislocation, congenital knee dislocation, congenital patella dislocation, macrodactyly of fingers, macrodactyly of toes, upper limb hypertrophy, lower limb hypertrophy, duplication of the pituitary gland, diencephalic-mesencephalic junction dysplasia, steroid dehydrogenase deficiency-dental anomalies syndrome, congenital achiasma, tracheal agenesis, renal agenesis, hypomyelination-cerebellar atrophy-hypoplasia of the corpus callosum syndrome, isolated splenogonadal fusion, Joubert syndrome, congenital generalized hypercontractile muscle stiffness syndrome, congenital bilateral absence of vas deferens, congenital portosystemic shunt, lissencephaly spectrum disorders, Berardinelli-Seip congenital lipodystrophy, congenital primary megaureter, craniorachischisis, vaginal atresia, bronchopulmonary dysplasia, dentinogenesis imperfecta-short stature-hearing loss-intellectual disability syndrome, aniridia, atypical Werner syndrome, X-linked intellectual disability-corpus callosum agenesis-spastic quadriparesis syndrome, anterior segment dysgenesis, congenital esophageal diverticulum, renal hypoplasia, renal dysplasia, overgrowth syndrome, developmental defect during embryogenesis, acalvaria, congenital aortic valve insufficiency, congenital anomaly of superior vena cava, congenital anomaly of hepatic vein, posterior hypospadias, isolated micropenis, isolated partial vaginal agenesis, pulmonary agenesis, congenital tricuspid malformation, Noonan syndrome and Noonan-related syndrome, coronary sinus stenosis, coronary sinus atresia, cartilage development disorder, syndactyly, polydactyly, brachydactyly, neurocristopathy, congenital absence of septum pellucidum, branchial arch disease, congenital anomaly of cardiovascular system, atelencephaly, aprosencephaly, aortic valve stenosis, hereditary lethal multiple congenital anomalies/dysmorphic syndrome, congenital agenesis of the scrotum, keratinization disease, lactation disease, COACH syndrome, constitutional delay of growth and puberty, isolated congenital femoral bifurcation, congenital peritoneal encapsulation, isolated short stature, congenital high airway obstruction syndrome
Subtypes (5): hereditary anorectal anomalies, rectal duplication, non-syndromic anorectal malformation with rectourethral fistula, bulbar type, non-syndromic anorectal malformation with rectourethral fistula, prostatic type, isolated anal canal duplication
Genetics & variants
GWAS landscape
13 GWAS associations across 1 studies. Top hits map to 19 distinct genes (as reported by GWAS).
Top associations by p-value
| rsID | p-value | Gene | Risk allele | Odds ratio |
|---|---|---|---|---|
| rs78824256 | 1e-18 | GAS6, GAS6-AS1 | T | |
| rs144223004 | 5e-18 | CSMD2, HMGB4 | T | |
| rs9974927 | 6e-17 | TRPM2 | G | |
| rs202062355 | 8e-17 | THBS2, THBS2-AS1 | T | |
| rs113740363 | 8e-17 | MUC5B | G | |
| rs202227463 | 3e-16 | PKP3 | A | |
| rs201778907 | 4e-16 | LTB4R2, CIDEB | G | |
| rs75287757 | 1e-15 | SUSD5 | T | |
| rs150068736 | 3e-13 | DPY19L3-DT, ZNF507 | G | |
| rs140019196 | 1e-12 | KLHL17 | G | |
| rs61734100 | 8e-11 | NLRP8 | G | |
| rs147828466 | 6e-10 | UROC1 | A | |
| rs139221232 | 6e-07 | RTEL1-TNFRSF6B, RTEL1 | T |
Top studies (by case count)
| Study | Lead author | Year | Cases | Controls | Title |
|---|---|---|---|---|---|
| GCST010206 | van de Putte R | 2019 | 568 | 1,860 | Exome chip association study excluded the involvement of rare coding variants with large effect sizes in the etiology of anorectal malformations. |
Variant details and genetic-evidence tiers
Tier distribution (top 50 variants)
| Tier | Variants |
|---|---|
| Tier 1: coding | 13 |
| Tier 2: splice/UTR | 0 |
| Tier 3: regulatory | 0 |
| Tier 4: intronic/intergenic | 0 |
MAF distribution
| Bucket | Variants |
|---|---|
| common (>=0.05) | 4 |
| low_freq (0.01-0.05) | 2 |
| rare (<0.01) | 7 |
| unknown | 0 |
Functional consequences
| Consequence | Count |
|---|---|
| missense_variant | 13 |
Top variants
| rsID | Chr | Pos | Alleles | MAF | Consequence | Gene | p-value | Tier |
|---|---|---|---|---|---|---|---|---|
| rs78824256 | 13 | 113834648 | C>A,G,T | 0 | missense_variant | GAS6, GAS6-AS1 | 1e-18 | Tier 1: coding |
| rs144223004 | 1 | 33864469 | C>A,G,T | 0 | missense_variant | CSMD2, HMGB4 | 5e-18 | Tier 1: coding |
| rs9974927 | 21 | 44401699 | T>G | 0.054 | missense_variant | TRPM2 | 6e-17 | Tier 1: coding |
| rs202062355 | 6 | 169241947 | C>T | 0 | missense_variant | THBS2, THBS2-AS1 | 8e-17 | Tier 1: coding |
| rs113740363 | 11 | 1260655 | A>G | 0 | missense_variant | MUC5B | 8e-17 | Tier 1: coding |
| rs202227463 | 11 | 403981 | G>A | 0.027 | missense_variant | PKP3 | 3e-16 | Tier 1: coding |
| rs201778907 | 14 | 24311010 | A>G | 0.027 | missense_variant | LTB4R2, CIDEB | 4e-16 | Tier 1: coding |
| rs75287757 | 3 | 33153772 | C>T | 0 | missense_variant | SUSD5 | 1e-15 | Tier 1: coding |
| rs150068736 | 19 | 32353984 | T>G | 0 | missense_variant | DPY19L3-DT, ZNF507 | 3e-13 | Tier 1: coding |
| rs140019196 | 1 | 965139 | A>G | 0 | missense_variant | KLHL17 | 1e-12 | Tier 1: coding |
| rs61734100 | 19 | 55976253 | C>G,T | 0.108 | missense_variant | NLRP8 | 8e-11 | Tier 1: coding |
| rs147828466 | 3 | 126517680 | G>A,T | 0.242 | missense_variant | UROC1 | 6e-10 | Tier 1: coding |
| rs139221232 | 20 | 63693256 | C>G,T | 0.188 | missense_variant | RTEL1-TNFRSF6B, RTEL1 | 6e-07 | Tier 1: coding |
ClinVar germline variants
1 retrieved; paginated sample, class counts are floors:
1 conflicting classifications of pathogenicity
| ClinVar | Variant (HGVS) | Gene | Classification | Review |
|---|---|---|---|---|
| 2429738 | NM_001265.6(CDX2):c.722A>G (p.Glu241Gly) | CDX2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
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 |
|---|---|---|
| RTEL1 | Orphanet:1775 | Dyskeratosis congenita |
| RTEL1 | Orphanet:2032 | Idiopathic pulmonary fibrosis |
| RTEL1 | Orphanet:3322 | Hoyeraal-Hreidarsson syndrome |
| UROC1 | Orphanet:210128 | Urocanic aciduria |
| MUC5B | Orphanet:171700 | Diffuse panbronchiolitis |
| MUC5B | Orphanet:2032 | Idiopathic pulmonary fibrosis |
| MUC5B | Orphanet:686465 | Fibrotic hypersensitivity pneumonitis |
Cohort genes → proteins
17 cohort genes, 16 distinct canonical proteins.
Evidence partition
| Subset | Genes |
|---|---|
| gwas_only | 16 |
| multi_evidence | 1 |
Cohort genes (full)
| Symbol | HGNC | Ensembl | UniProt | Name | Evidence |
|---|---|---|---|---|---|
| THBS2 | HGNC:11786 | ENSG00000186340 | P35442 | Thrombospondin-2 | gwas |
| TRPM2 | HGNC:12339 | ENSG00000142185 | O94759 | Transient receptor potential cation channel subfamily M member 2 | gwas |
| RTEL1 | HGNC:15888 | ENSG00000258366 | Q9NZ71 | Regulator of telomere elongation helicase 1 | gwas |
| CDX2 | HGNC:1806 | ENSG00000165556 | Q99626 | Homeobox protein CDX-2 | clinvar |
| LTB4R2 | HGNC:19260 | ENSG00000213906 | Q9NPC1 | Leukotriene B4 receptor 2 | gwas |
| CSMD2 | HGNC:19290 | ENSG00000121904 | Q7Z408 | CUB and sushi domain-containing protein 2 | gwas |
| CIDEB | HGNC:1977 | ENSG00000136305 | Q9UHD4 | Lipid transferase CIDEB | gwas |
| NLRP8 | HGNC:22940 | ENSG00000179709 | Q86W28 | NACHT, LRR and PYD domains-containing protein 8 | gwas |
| ZNF507 | HGNC:23783 | ENSG00000168813 | Q8TCN5 | Zinc finger protein 507 | gwas |
| KLHL17 | HGNC:24023 | ENSG00000187961 | Q6TDP4 | Kelch-like protein 17 | gwas |
| HMGB4 | HGNC:24954 | ENSG00000176256 | Q8WW32 | High mobility group protein B4 | gwas |
| UROC1 | HGNC:26444 | ENSG00000159650 | Q96N76 | Urocanate hydratase | gwas |
| SUSD5 | HGNC:29061 | ENSG00000173705 | O60279 | Sushi domain-containing protein 5 | gwas |
| GAS6-AS1 | HGNC:39826 | ENSG00000233695 | GAS6 antisense RNA 1 | gwas | |
| GAS6 | HGNC:4168 | ENSG00000183087 | Q14393 | Growth arrest-specific protein 6 | gwas |
| MUC5B | HGNC:7516 | ENSG00000117983 | Q9HC84 | Mucin-5B | gwas |
| PKP3 | HGNC:9025 | ENSG00000184363 | Q9Y446 | Plakophilin-3 | gwas |
Cohort function summary
Lead sentence per gene, UniProt-curated.
| Symbol | Protein name | Function (lead sentence) |
|---|---|---|
| THBS2 | Thrombospondin-2 | Adhesive glycoprotein that mediates cell-to-cell and cell-to-matrix interactions. |
| TRPM2 | Transient receptor potential cation channel subfamily M member 2 | Nonselective, voltage-independent cation channel that mediates Na(+) and Ca(2+) influx, leading to increased cytoplasmic Ca(2+) levels. |
| RTEL1 | Regulator of telomere elongation helicase 1 | A probable ATP-dependent DNA helicase implicated in telomere-length regulation, DNA repair and the maintenance of genomic stability. |
| CDX2 | Homeobox protein CDX-2 | Transcription factor which regulates the transcription of multiple genes expressed in the intestinal epithelium. |
| LTB4R2 | Leukotriene B4 receptor 2 | Low-affinity receptor for leukotrienes including leukotriene B4. |
| CIDEB | Lipid transferase CIDEB | Lipid transferase specifically expressed in hepatocytes, which promotes unilocular lipid droplet formation by mediating lipid droplet fusion. |
| NLRP8 | NACHT, LRR and PYD domains-containing protein 8 | Involved in inflammation. |
| ZNF507 | Zinc finger protein 507 | May be involved in transcriptional regulation. |
| KLHL17 | Kelch-like protein 17 | Substrate-recognition component of some cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complexes. |
| GAS6 | Growth arrest-specific protein 6 | Ligand for tyrosine-protein kinase receptors AXL, TYRO3 and MER whose signaling is implicated in cell growth and survival, cell adhesion and cell migration. |
| MUC5B | Mucin-5B | Gel-forming mucin that is thought to contribute to the lubricating and viscoelastic properties of whole saliva and cervical mucus. |
| PKP3 | Plakophilin-3 | A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion. |
Protein-family classification
Druggable: 4 · Difficult: 2 · Unknown: 11 · 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 |
|---|---|---|---|
| Complement | 2 | 31.5× | 0.009 |
| Ion channel | 1 | 6.6× | 0.355 |
| Other/Unknown | 11 | 1.2× | 0.523 |
| GPCR | 1 | 1.4× | 0.628 |
| Transcription factor | 2 | 1.0× | 0.628 |
Per-gene assignment
| Symbol | Family | Druggable? | EC | InterPro (top 3) |
|---|---|---|---|---|
| THBS2 | Other/Unknown | no | EGF, TSP1_rpt, VWF_dom | |
| TRPM2 | Ion channel | yes | NUDIX_hydrolase_dom, Ion_trans_dom, NUDIX_hydrolase-like_dom_sf | |
| RTEL1 | Other/Unknown | no | Helicase-like_DEXD_c2, ATP-dep_Helicase_C, RAD3-like_helicase_DEAD | |
| CDX2 | Transcription factor | no | HTH_motif, HD, Caudal_activation_dom | |
| LTB4R2 | GPCR | yes | GPCR_Rhodpsn, Leukotriene_B4_rcpt, Leukotriene_B4_typ-2_rcpt | |
| CSMD2 | Complement | yes | Sushi_SCR_CCP_dom, CUB_dom, Sperma_CUB_dom_sf | |
| CIDEB | Other/Unknown | no | CIDE-N_dom | |
| NLRP8 | Other/Unknown | no | Leu-rich_rpt, DAPIN, NACHT_NTPase | |
| ZNF507 | Transcription factor | no | Znf_C2H2_type, Znf_C2H2_sf, Zinc_finger/UBP_domain | |
| KLHL17 | Other/Unknown | no | BTB/POZ_dom, Kelch_1, Gal_Oxase/kelch_b-propeller | |
| HMGB4 | Other/Unknown | no | HMG_box_dom, HMG_box_dom_sf, HMGB | |
| UROC1 | Other/Unknown | no | Urocanase_CS, Urocanase-like, Urocanase_Rossmann-like | |
| SUSD5 | Complement | yes | Sushi_SCR_CCP_dom, Link_dom, C-type_lectin-like/link_sf | |
| GAS6-AS1 | Other/Unknown | no | ||
| GAS6 | Other/Unknown | no | EGF-type_Asp/Asn_hydroxyl_site, GLA_domain, EGF | |
| MUC5B | Other/Unknown | no | VWF_dom, VWF_type-D, TIL_dom | |
| PKP3 | Other/Unknown | no | Armadillo, ARM-like, ARM-type_fold |
Expression context
Cohort genes with no expression data: 0.
13 cohort genes are a single-cell marker in ≥1 SCXA experiment.
Breadth distribution (Bgee present_calls)
| Bucket | Genes |
|---|---|
| narrow (1-5 tissues) | 1 |
| moderate (6-20) | 0 |
| broad (>20) | 16 |
| unknown | 0 |
Top tissues across cohort
| Tissue | Cohort genes |
|---|---|
| right coronary artery | 2 |
| right hemisphere of cerebellum | 2 |
| mucosa of transverse colon | 2 |
| skin of abdomen | 2 |
| buccal mucosa cell | 2 |
| liver | 2 |
| right lobe of liver | 2 |
| male germ line stem cell (sensu Vertebrata) in testis | 2 |
| lower esophagus mucosa | 2 |
| descending thoracic aorta | 2 |
| pericardium | 1 |
| stromal cell of endometrium | 1 |
| caudate nucleus | 1 |
| nucleus accumbens | 1 |
| right frontal lobe | 1 |
| cerebellar hemisphere | 1 |
| sural nerve | 1 |
| rectum | 1 |
| transverse colon | 1 |
| esophagus mucosa | 1 |
Per-gene tissue summary (top 30)
| Symbol | Bgee breadth | FANTOM5 breadth | SCXA | Top tissues |
|---|---|---|---|---|
| THBS2 | 272 | ubiquitous | marker | pericardium, right coronary artery, stromal cell of endometrium |
| TRPM2 | 176 | broad | marker | right frontal lobe, caudate nucleus, nucleus accumbens |
| RTEL1 | 134 | ubiquitous | yes | sural nerve, right hemisphere of cerebellum, cerebellar hemisphere |
| CDX2 | 64 | broad | marker | mucosa of transverse colon, rectum, transverse colon |
| LTB4R2 | 131 | tissue_specific | yes | skin of abdomen, esophagus mucosa, zone of skin |
| CSMD2 | 166 | broad | marker | buccal mucosa cell, ventricular zone, kidney epithelium |
| CIDEB | 134 | broad | marker | right lobe of liver, liver, duodenum |
| NLRP8 | 3 | marker | secondary oocyte, oocyte, male germ line stem cell (sensu Vertebrata) in testis | |
| ZNF507 | 267 | ubiquitous | yes | endothelial cell, skeletal muscle tissue of rectus abdominis, corpus callosum |
| KLHL17 | 161 | ubiquitous | yes | lower esophagus mucosa, right hemisphere of cerebellum, granulocyte |
| HMGB4 | 122 | tissue_specific | marker | right testis, left testis, adult organism |
| UROC1 | 41 | tissue_specific | marker | right lobe of liver, liver, male germ line stem cell (sensu Vertebrata) in testis |
| SUSD5 | 221 | broad | marker | descending thoracic aorta, blood vessel layer, right coronary artery |
| GAS6-AS1 | 200 | broad | marker | buccal mucosa cell, right uterine tube, spleen |
| GAS6 | 284 | ubiquitous | marker | ascending aorta, thoracic aorta, descending thoracic aorta |
| MUC5B | 171 | tissue_specific | marker | trachea, gall bladder, mucosa of transverse colon |
| PKP3 | 206 | broad | marker | lower esophagus mucosa, skin of abdomen, skin of leg |
Protein interactions among cohort
Intra-cohort edges: 0.
Hub genes (top 10 by interactor count)
| Symbol | Interactor count |
|---|---|
| THBS2 | 3,405 |
| MUC5B | 2,659 |
| GAS6 | 2,339 |
| RTEL1 | 2,324 |
| CDX2 | 2,157 |
| PKP3 | 1,595 |
| CIDEB | 1,249 |
| ZNF507 | 1,246 |
| HMGB4 | 1,151 |
| KLHL17 | 989 |
Structural data
PDB: 8 · AlphaFold-only: 8 · No structure: 1
Cohort genes with PDB structures (top 30)
| Symbol | UniProt | PDB entries |
|---|---|---|
| TRPM2 | O94759 | 15 |
| CDX2 | Q99626 | 4 |
| GAS6 | Q14393 | 4 |
| RTEL1 | Q9NZ71 | 3 |
| THBS2 | P35442 | 2 |
| MUC5B | Q9HC84 | 2 |
| CIDEB | Q9UHD4 | 1 |
| KLHL17 | Q6TDP4 | 1 |
AlphaFold-only cohort genes (top 30 by pLDDT)
| Symbol | UniProt | pLDDT |
|---|---|---|
| UROC1 | Q96N76 | 95.68 |
| HMGB4 | Q8WW32 | 88.21 |
| LTB4R2 | Q9NPC1 | 81.39 |
| NLRP8 | Q86W28 | 80.26 |
| PKP3 | Q9Y446 | 69.24 |
| SUSD5 | O60279 | 55.97 |
| ZNF507 | Q8TCN5 | 51.87 |
| CSMD2 | Q7Z408 |
Function
Pathway analysis
Distinct Reactome pathways touched by cohort: 58. Enrichment computed across 17 evidence-associated genes (9 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 9 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| Pathway | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| Eicosanoid ligand-binding receptors | 1 | 253.8× | 0.062 | LTB4R2 |
| Leukotriene receptors | 1 | 211.5× | 0.062 | LTB4R2 |
| Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus | 1 | 141.0× | 0.062 | GAS6 |
| Gamma-carboxylation of protein precursors | 1 | 126.9× | 0.062 | GAS6 |
| Removal of aminoterminal propeptides from gamma-carboxylated proteins | 1 | 126.9× | 0.062 | GAS6 |
| POU5F1 (OCT4), SOX2, NANOG repress genes related to differentiation | 1 | 126.9× | 0.062 | CDX2 |
| Histidine catabolism | 1 | 126.9× | 0.062 | UROC1 |
| Incretin synthesis, secretion, and inactivation | 1 | 115.3× | 0.062 | CDX2 |
| Cytosolic iron-sulfur cluster assembly | 1 | 84.6× | 0.062 | RTEL1 |
| Defective GALNT3 causes HFTC | 1 | 79.3× | 0.062 | MUC5B |
| Defective GALNT12 causes CRCS1 | 1 | 79.3× | 0.062 | MUC5B |
| Defective C1GALT1C1 causes TNPS | 1 | 74.6× | 0.062 | MUC5B |
| Resolution of D-Loop Structures | 1 | 70.5× | 0.062 | RTEL1 |
| Extension of Telomeres | 1 | 66.8× | 0.062 | RTEL1 |
| Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) | 1 | 57.7× | 0.065 | CDX2 |
| Termination of O-glycan biosynthesis | 1 | 55.2× | 0.065 | MUC5B |
| Telomere Extension By Telomerase | 1 | 50.8× | 0.066 | RTEL1 |
| Dectin-2 family | 1 | 47.0× | 0.066 | MUC5B |
| TRP channels | 1 | 45.3× | 0.066 | TRPM2 |
| Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA) | 1 | 43.8× | 0.066 | RTEL1 |
| Telomere Maintenance | 1 | 40.9× | 0.067 | RTEL1 |
| Defective B3GALTL causes PpS | 1 | 34.3× | 0.069 | THBS2 |
| Homology Directed Repair | 1 | 34.3× | 0.069 | RTEL1 |
| HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA) | 1 | 34.3× | 0.069 | RTEL1 |
| O-glycosylation of TSR domain-containing proteins | 1 | 33.4× | 0.069 | THBS2 |
| Peptide hormone metabolism | 1 | 30.2× | 0.071 | CDX2 |
| Dengue Virus Attachment and Entry | 1 | 28.8× | 0.071 | GAS6 |
| Signaling by PDGF | 1 | 28.2× | 0.071 | THBS2 |
| DNA Double-Strand Break Repair | 1 | 27.6× | 0.071 | RTEL1 |
| C-type lectin receptors (CLRs) | 1 | 26.4× | 0.072 | MUC5B |
GO biological processes by enrichment
Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 16 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| GO term | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| dendritic cell differentiation | 2 | 131.7× | 0.015 | TRPM2, GAS6 |
| DNA strand displacement | 1 | 1053.2× | 0.023 | RTEL1 |
| negative regulation of oligodendrocyte apoptotic process | 1 | 1053.2× | 0.023 | GAS6 |
| negative regulation of telomere maintenance in response to DNA damage | 1 | 1053.2× | 0.023 | RTEL1 |
| positive regulation of telomeric loop disassembly | 1 | 1053.2× | 0.023 | RTEL1 |
| negative regulation of renal albumin absorption | 1 | 1053.2× | 0.023 | GAS6 |
| cellular response to vitamin K | 1 | 526.6× | 0.026 | GAS6 |
| telomeric loop disassembly | 1 | 526.6× | 0.026 | RTEL1 |
| positive regulation of glomerular filtration | 1 | 351.1× | 0.026 | GAS6 |
| fusion of virus membrane with host plasma membrane | 1 | 351.1× | 0.026 | GAS6 |
| cellular response to temperature stimulus | 1 | 351.1× | 0.026 | TRPM2 |
| negative regulation of single-species biofilm formation in or on host organism | 1 | 351.1× | 0.026 | MUC5B |
| negative regulation of mRNA catabolic process | 1 | 351.1× | 0.026 | PKP3 |
| mitotic telomere maintenance via semi-conservative replication | 1 | 351.1× | 0.026 | RTEL1 |
| negative regulation of t-circle formation | 1 | 351.1× | 0.026 | RTEL1 |
| calcium ion transmembrane transport | 2 | 26.3× | 0.026 | TRPM2, GAS6 |
| regulation of cytokine production involved in immune response | 1 | 263.3× | 0.027 | PKP3 |
| obsolete L-histidine catabolic process to glutamate and formamide | 1 | 263.3× | 0.027 | UROC1 |
| obsolete L-histidine catabolic process to glutamate and formate | 1 | 263.3× | 0.027 | UROC1 |
| regulation of hair follicle development | 1 | 263.3× | 0.027 | PKP3 |
| maintenance of postsynaptic density structure | 1 | 263.3× | 0.027 | CSMD2 |
| hematopoietic stem cell migration to bone marrow | 1 | 210.7× | 0.028 | GAS6 |
| lipid droplet fusion | 1 | 210.7× | 0.028 | CIDEB |
| positive regulation of telomere capping | 1 | 210.7× | 0.028 | RTEL1 |
| regulation of somitogenesis | 1 | 175.5× | 0.028 | CDX2 |
| negative regulation of interleukin-1 production | 1 | 175.5× | 0.028 | GAS6 |
| B cell chemotaxis | 1 | 175.5× | 0.028 | GAS6 |
| receptor-mediated virion attachment to host cell | 1 | 175.5× | 0.028 | GAS6 |
| positive regulation of telomere maintenance via telomere lengthening | 1 | 175.5× | 0.028 | RTEL1 |
| desmosome assembly | 1 | 150.5× | 0.028 | PKP3 |
Therapeutics
Drug target analysis
Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 15
Druggability breadth: 4 of 17 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 |
|---|---|
| TRPM2 | CLOTRIMAZOLE |
| LTB4R2 | VALSARTAN |
Top cohort targets by molecule count
| Symbol | Molecules | Max phase |
|---|---|---|
| LTB4R2 | 6 | 4 |
| TRPM2 | 5 | 4 |
| THBS2 | 0 | 0 |
| RTEL1 | 0 | 0 |
| CDX2 | 0 | 0 |
| CSMD2 | 0 | 0 |
| CIDEB | 0 | 0 |
| NLRP8 | 0 | 0 |
| ZNF507 | 0 | 0 |
| KLHL17 | 0 | 0 |
Drugs targeting cohort genes (top 30)
| Molecule | Max phase | Targets in cohort |
|---|---|---|
| CLOTRIMAZOLE | 4 | TRPM2 |
| COPPER | 4 | TRPM2 |
| ADENOSINE PHOSPHATE | 4 | TRPM2 |
| ECONAZOLE | 4 | TRPM2 |
| VALSARTAN | 4 | LTB4R2 |
| IRBESARTAN | 4 | LTB4R2 |
| CANDESARTAN | 3 | LTB4R2 |
| FLUFENAMIC ACID | 2 | TRPM2 |
| ABLUKAST | 2 | LTB4R2 |
| CP-195543 | 2 | LTB4R2 |
| ETALOCIB | 2 | LTB4R2 |
Bioactivity and enzyme data
Enzyme cohort genes (≥1 EC): 0.
Cohort genes with ChEMBL bioactivity (full, sorted by assay count)
| Symbol | Assays | Type breakdown |
|---|---|---|
| LTB4R2 | 81 | Binding:48, Functional:33 |
| TRPM2 | 59 | Binding:58, Functional:1 |
| KLHL17 | 1 | Binding:1 |
| GAS6 | 1 | Binding:1 |
Pharmacogenomics
Cohort genes with a PharmGKB record: 16; with CPIC/DPWG dosing guidelines: 0.
No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).
Chemical tractability of cohort targets
11 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) |
|---|---|---|
| CLOTRIMAZOLE | 4 | TRPM2 |
| COPPER | 4 | TRPM2 |
| ADENOSINE PHOSPHATE | 4 | TRPM2 |
| ECONAZOLE | 4 | TRPM2 |
| VALSARTAN | 4 | LTB4R2 |
| IRBESARTAN | 4 | LTB4R2 |
| CANDESARTAN | 3 | LTB4R2 |
| FLUFENAMIC ACID | 2 | TRPM2 |
| ABLUKAST | 2 | LTB4R2 |
| CP-195543 | 2 | LTB4R2 |
| ETALOCIB | 2 | LTB4R2 |
Druggability pyramid
Cohort genes binned by druggability tier (high → low):
| Tier | Definition | Genes | Symbols |
|---|---|---|---|
| A | Approved (phase 4 drug) | 2 | TRPM2, LTB4R2 |
| B | Phased (≥1) drug, not yet approved | 0 | |
| C | Druggable family + PDB, no drug | 0 | |
| D | Druggable family + AlphaFold only, no drug | 2 | CSMD2, SUSD5 |
| E | Difficult family or no structure, no drug | 13 | THBS2, RTEL1, CDX2, CIDEB, NLRP8, ZNF507, KLHL17, HMGB4, UROC1, GAS6-AS1 (+3 more) |
Undrugged target profiles
15 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).
| Symbol | ChEMBL assays | Drugged partners (top 3) |
|---|---|---|
| THBS2 | 0 | — |
| RTEL1 | 0 | — |
| CDX2 | 0 | — |
| CSMD2 | 0 | — |
| CIDEB | 0 | — |
| NLRP8 | 0 | — |
| ZNF507 | 0 | — |
| KLHL17 | 1 | — |
| HMGB4 | 0 | — |
| UROC1 | 0 | — |
| SUSD5 | 0 | — |
| GAS6-AS1 | 0 | — |
| GAS6 | 1 | — |
| MUC5B | 0 | — |
| PKP3 | 0 | — |
Clinical trials & evidence
Clinical trials
Clinical trials: 9.
Phase distribution (across all retrieved trials)
| Phase | Trials |
|---|---|
| Not specified | 7 |
| PHASE4 | 1 |
| EARLY_PHASE1 | 1 |
Top trials by phase / activity
| NCT | Phase | Status | Title |
|---|---|---|---|
| NCT03746834 | PHASE4 | COMPLETED | NASHA/Dx as a Perianal Implant for the Treatment of Persistent Fecal Incontience After Anorectal Malformation |
| NCT07392203 | EARLY_PHASE1 | NOT_YET_RECRUITING | Role of (Saline- Glycerin) Rectal Enema in Treatment of Fecal Incontinence in Children |
| NCT07603232 | Not specified | ENROLLING_BY_INVITATION | Long-Term Health Outcomes in Children Born With Hirschsprung’s Disease and Anorectal Malformations at the Colorectal Centre of Excellence in Quebec |
| NCT00909415 | Not specified | COMPLETED | Urodynamic Evaluation in Patients With Anorectal Malformation According to Spinal Cord Abnormalities |
| NCT02029248 | Not specified | COMPLETED | National Study on the Quality of Life of Patients With Anorectal Malformation |
| NCT02624232 | Not specified | UNKNOWN | Long-term Outcome in Patients With Anorectal Malformations |
| NCT03174028 | Not specified | UNKNOWN | Laparoscopically Assisted Anorectal Pull-through Versus Posterior Sagittal Anorectoplasty |
| NCT03185637 | Not specified | COMPLETED | Children’s Surgery in Sub-Saharan Africa |
| NCT03666767 | Not specified | COMPLETED | Management and Outcomes of Congenital Anomalies in Low-, Middle- and High-Income Countries |
Drugs tested across these trials (top 30)
| Molecule | Max phase | Trials referencing |
|---|---|---|
| HYALURONIC ACID (NON-ANIMAL STABILIZED) | 3 | 1 |