Treacher-Collins syndrome

Summary

Treacher-Collins syndrome (MONDO:0002457) is a disease caused by TCOF1 (GenCC Definitive), with 4 cohort genes and 1 clinical trial. The dominant Reactome pathway is Positive epigenetic regulation of rRNA expression (3 cohort genes).

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Causal gene: TCOF1 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 13
• Phenotypes (HPO): 68
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

6 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000		Europe	Validated
Prevalence at birth	1-9 / 100 000	2	Europe	Validated
Point prevalence	1-9 / 1 000 000		France	Validated
Prevalence at birth	1-9 / 1 000 000	0.63	France	Validated
Prevalence at birth	1-9 / 100 000	6.9	Japan	Validated
Point prevalence	1-9 / 100 000		Japan	Not yet validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0000272	Malar flattening	Very frequent (80-99%)
HP:0000278	Retrognathia	Very frequent (80-99%)
HP:0000327	Hypoplasia of the maxilla	Very frequent (80-99%)
HP:0000347	Micrognathia	Very frequent (80-99%)
HP:0000494	Downslanted palpebral fissures	Very frequent (80-99%)
HP:0001999	Abnormal facial shape	Very frequent (80-99%)
HP:0002652	Skeletal dysplasia	Very frequent (80-99%)
HP:0004348	Abnormality of bone mineral density	Very frequent (80-99%)
HP:0010669	Hypoplasia of the zygomatic bone	Very frequent (80-99%)
HP:0010807	Open bite	Very frequent (80-99%)
HP:0011219	Short face	Very frequent (80-99%)
HP:0011800	Midface retrusion	Very frequent (80-99%)
HP:0000164	Abnormality of the dentition	Frequent (30-79%)
HP:0000294	Low anterior hairline	Frequent (30-79%)
HP:0000356	Abnormality of the outer ear	Frequent (30-79%)
HP:0000358	Posteriorly rotated ears	Frequent (30-79%)
HP:0000370	Abnormality of the middle ear	Frequent (30-79%)
HP:0000405	Conductive hearing impairment	Frequent (30-79%)
HP:0000413	Atresia of the external auditory canal	Frequent (30-79%)
HP:0000431	Wide nasal bridge	Frequent (30-79%)
HP:0000486	Strabismus	Frequent (30-79%)
HP:0000505	Visual impairment	Frequent (30-79%)
HP:0000561	Absent eyelashes	Frequent (30-79%)
HP:0000612	Iris coloboma	Frequent (30-79%)
HP:0000625	Eyelid coloboma	Frequent (30-79%)
HP:0000689	Dental malocclusion	Frequent (30-79%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0002007	Frontal bossing	Frequent (30-79%)
HP:0008551	Microtia	Frequent (30-79%)
HP:0009804	Tooth agenesis	Frequent (30-79%)
HP:0011386	Narrow internal auditory canal	Frequent (30-79%)
HP:0002381	Aphasia	Occasional (5-29%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000046	Small scrotum	Occasional (5-29%)
HP:0000143	Rectovaginal fistula	Occasional (5-29%)
HP:0000154	Wide mouth	Occasional (5-29%)
HP:0000160	Narrow mouth	Occasional (5-29%)
HP:0000162	Glossoptosis	Occasional (5-29%)
HP:0000175	Cleft palate	Occasional (5-29%)
HP:0000204	Cleft upper lip	Occasional (5-29%)
HP:0000218	High palate	Occasional (5-29%)
HP:0000248	Brachycephaly	Occasional (5-29%)
HP:0000316	Hypertelorism	Occasional (5-29%)
HP:0000384	Preauricular skin tag	Occasional (5-29%)
HP:0000453	Choanal atresia	Occasional (5-29%)
HP:0000518	Cataract	Occasional (5-29%)
HP:0000568	Microphthalmia	Occasional (5-29%)
HP:0000643	Blepharospasm	Occasional (5-29%)
HP:0000682	Abnormality of dental enamel	Occasional (5-29%)
HP:0000778	Hypoplasia of the thymus	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Treacher-Collins syndrome
Mondo ID	MONDO:0002457
OMIM	154500
Orphanet	861
DOID	DOID:2908
ICD-11	969026676
NCIT	C75018
SNOMED CT	62767009
UMLS	C0242387
MedGen	66078
GARD	0009124
MedDRA	10051456
NORD	1785
Is cancer (heuristic)	no

Also known as: Franceschetti-Klein syndrome · mandibulofacial dysostosis without limb anomalies · MFD1 · TCOF · TCS · Treacher Collins Syndrome · Treacher Collins syndrome · Treacher-Collins syndrome

Data availability: 13 ClinVar variants · 6 GenCC gene-disease records · 4 cell lines.

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › Treacher-Collins syndrome

Related subtypes (191): autosomal dominant polycystic liver disease, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, tuberous sclerosis, hereditary breast ovarian cancer syndrome, autosomal dominant polycystic kidney disease, Lynch syndrome, branchio-oto-renal syndrome, autosomal dominant Aarskog syndrome, acroosteolysis dominant type, ADULT syndrome, autosomal dominant Alport syndrome, amelogenesis imperfecta type 1B, Townes-Brocks syndrome, nevoid basal cell carcinoma syndrome, blepharophimosis, ptosis, and epicanthus inversus syndrome, autosomal dominant brachyolmia, branchiooculofacial syndrome, pheochromocytoma/paraganglioma syndrome 4, cataract-aberrant oral frenula-growth delay syndrome, cherubism, autosomal dominant chondrodysplasia punctata, autosomal dominant popliteal pterygium syndrome, blepharocheilodontic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Beare-Stevenson cutis gyrata syndrome, autosomal dominant vibratory urticaria, neurohypophyseal diabetes insipidus, autosomal dominant Kenny-Caffey syndrome, Rapp-Hodgkin syndrome, Ehlers-Danlos syndrome, classic type, autosomal dominant Ehlers-Danlos syndrome, vascular type, multiple endocrine neoplasia type 1, Coffin-Siris syndrome 1, isolated congenital adermatoglyphia, Flynn-Aird syndrome, Frasier syndrome, hand-foot-genital syndrome, Holt-Oram syndrome, hyperkeratosis-hyperpigmentation syndrome, autosomal dominant ichthyosis vulgaris, hyper-IgE recurrent infection syndrome 1, autosomal dominant, autosomal dominant keratitis, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, LADD syndrome, trichorhinophalangeal syndrome type II, Noonan syndrome with multiple lentigines, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, Marfan syndrome, melanoma, cutaneous malignant, susceptibility to, 2, autosomal dominant primary microcephaly, autosomal dominant progressive external ophthalmoplegia, monilethrix, Muir-Torre syndrome, autosomal dominant myoglobinuria, autosomal dominant centronuclear myopathy, nail-patella syndrome, multiple endocrine neoplasia type 2B, autosomal dominant omodysplasia, pheochromocytoma/paraganglioma syndrome 1, Pelger-Huet anomaly, multiple endocrine neoplasia type 2A, piebaldism, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, generalized juvenile polyposis/juvenile polyposis coli, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Peutz-Jeghers syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, autosomal dominant distal renal tubular acidosis, retinoschisis, autosomal dominant, autosomal dominant Robinow syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, autosomal dominant sideroblastic anemia, spondyloepiphyseal dysplasia tarda, autosomal dominant, proximal symphalangism, calcaneonavicular coalition, thanatophoric dysplasia type 1, trichorhinophalangeal syndrome type I, Muckle-Wells syndrome, autosomal dominant hypophosphatemic rickets, von Hippel-Lindau disease, Denys-Drash syndrome, autosomal dominant severe congenital neutropenia, Costello syndrome, EEC syndrome, multiple cutaneous and mucosal venous malformations, diffuse nonepidermolytic palmoplantar keratoderma, Timothy syndrome, pheochromocytoma/paraganglioma syndrome 2, spondyloepimetaphyseal dysplasia with multiple dislocations, Brooke-Spiegler syndrome, macrocephaly-autism syndrome, pheochromocytoma/paraganglioma syndrome 3, Duane-radial ray syndrome, PCWH syndrome, heart-hand syndrome, Slovenian type, congenital stationary night blindness autosomal dominant 3, mandibulofacial dysostosis-microcephaly syndrome, multiple endocrine neoplasia type 4, juvenile cataract-microcornea-renal glucosuria syndrome, Crouzon syndrome-acanthosis nigricans syndrome, Birk-Barel syndrome, thrombophilia due to protein S deficiency, autosomal dominant, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, colorectal cancer, hereditary nonpolyposis, type 6, colorectal cancer, hereditary nonpolyposis, type 7, brain small vessel disease 2A, autosomal dominant, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, hypopigmentation-punctate palmoplantar keratoderma syndrome, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, intellectual disability, autosomal dominant 29, intellectual disability, autosomal dominant 30, Houge-Janssens syndrome 2, severe achondroplasia-developmental delay-acanthosis nigricans syndrome, dyskeratosis congenita, autosomal dominant 6, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, autosomal dominant complex spastic paraplegia, early-onset autosomal dominant Alzheimer disease, muscular dystrophy, limb-girdle, autosomal dominant, Feingold syndrome, Carney complex, neuronopathy, distal hereditary motor, autosomal dominant, autosomal dominant coarctation of aorta, autosomal dominant spondylocostal dysostosis, autosomal dominant hypohidrotic ectodermal dysplasia, Cowden disease, autosomal dominant distal myopathy, autosomal dominant rhegmatogenous retinal detachment, palmoplantar keratoderma-spastic paralysis syndrome, Alagille syndrome due to a JAG1 point mutation, PTEN hamartoma tumor syndrome, gastric adenocarcinoma and proximal polyposis of the stomach, autosomal dominant proximal renal tubular acidosis, autosomal dominant spastic ataxia, Waardenburg syndrome, hereditary retinoblastoma, autosomal dominant hypocalcemia, Li-Fraumeni syndrome, Loeys-Dietz syndrome, hereditary hemorrhagic telangiectasia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, microcephalic osteodysplastic dysplasia, Saul-Wilson type, autosomal dominant intermediate Charcot-Marie-Tooth disease, autosomal dominant cutis laxa, autosomal dominant nonsyndromic hearing loss, autosomal dominant optic atrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, autosomal dominant cerebellar ataxia, autosomal dominant osteopetrosis, autosomal dominant epidermolytic ichthyosis, ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, distal arthrogryposis type 2B1, neurofibromatosis, autosomal dominant cataract, arthrogryposis, distal, type 2B2, arthrogryposis, distal, type 2B3, Charcot-Marie-Tooth disease, demyelinating, type 1G, Delpire-McNeill syndrome, LAMA5-related multisystemic syndrome, autosomal dominant oculocutaneous albinism, Charcot-Marie-tooth disease, axonal, type 2DD, Pilarowski-Bjornsson syndrome, intellectual disability, autosomal dominant, fatty acyl-CoA reductase 1 upregulation, GUCY2D-related dominant retinopathy, RPE65-related dominant retinopathy, autosomal dominant titinopathy, NOG-related symphalangism spectrum disorder, ALPL-related autosomal dominant hypophosphatasia, MYH10-related neurodevelopmental disorder with congenital anomalies, spastic paraplegia 30A, autosomal dominant, TMEM127-related tumor predisposition, MAX-related tumor predisposition, BMPR1A-related juvenile polyposis syndrome, RP1-related dominant retinopathy, Birt-Hogg-Dube syndrome, inclusion body myopathy and brain white matter abnormalities, KINSSHIP syndrome, autosomal dominant nebulin-related myopathy, IMPG1-related dominant retinopathy, PROM1-related dominant retinopathy, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome, ALG8-related autosomal dominant polycystic kidney and/or liver disease, NOTCH1-related AOS spectrum disorder, FLNB-associated autosomal dominant filamin related bone disorder, familial antiphospholipid syndrome

Subtypes (4): Treacher Collins syndrome 1, Treacher Collins syndrome 3, Treacher Collins syndrome 2, Treacher Collins syndrome 4

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

13 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
932311	NM_019014.6(POLR1B):c.2046T>A (p.Ser682Arg)	POLR1B	Pathogenic	no assertion criteria provided
932312	NM_019014.6(POLR1B):c.3007C>T (p.Arg1003Cys)	POLR1B	Pathogenic	no assertion criteria provided
932313	NM_019014.6(POLR1B):c.3007C>A (p.Arg1003Ser)	POLR1B	Pathogenic	no assertion criteria provided
156464	NM_015972.4(POLR1D):c.163C>G (p.Leu55Val)	POLR1D	Pathogenic	no assertion criteria provided
1321195	NM_001371623.1(TCOF1):c.1075del (p.Leu359fs)	TCOF1	Pathogenic	criteria provided, single submitter
1329860	NM_001371623.1(TCOF1):c.645del (p.Lys215fs)	TCOF1	Pathogenic	criteria provided, single submitter
3963	NM_001371623.1(TCOF1):c.4372_4376del (p.Lys1458fs)	TCOF1	Pathogenic	criteria provided, multiple submitters, no conflicts
947528	NM_001371623.1(TCOF1):c.1021_1022del (p.Ser341fs)	TCOF1	Pathogenic	criteria provided, multiple submitters, no conflicts
2456453	NM_001371623.1(TCOF1):c.4052C>T (p.Ser1351Leu)	TCOF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3780699	NM_001371623.1(TCOF1):c.3773C>T (p.Ser1258Phe)	TCOF1	Uncertain significance	criteria provided, single submitter
767387	NM_001371623.1(TCOF1):c.2188C>T (p.Pro730Ser)	TCOF1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
2574640	NM_001371623.1(TCOF1):c.2490del (p.Pro830_Val831insTer)	TCOF1	not provided	no classification provided
2574641	NM_001371623.1(TCOF1):c.2853dup (p.Ala952fs)	TCOF1	not provided	no classification provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 26 · Orphanet: 5 · 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
POLR1D	Definitive	Autosomal dominant	Treacher Collins syndrome 2	7
TCOF1	Definitive	Autosomal dominant	Treacher-Collins syndrome	5
POLR1B	Strong	Autosomal dominant	Treacher Collins syndrome 4	5
POLR1C	Strong	Autosomal recessive	Treacher Collins syndrome 3	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TCOF1	Orphanet:861	Treacher-Collins syndrome
POLR1D	Orphanet:861	Treacher-Collins syndrome
POLR1B	Orphanet:861	Treacher-Collins syndrome
POLR1C	Orphanet:861	Treacher-Collins syndrome
POLR1C	Orphanet:88637	Hypomyelination-hypogonadotropic hypogonadism-hypodontia syndrome

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TCOF1	HGNC:11654	ENSG00000070814	Q13428	Treacle protein	gencc,clinvar
POLR1D	HGNC:20422	ENSG00000186184	P0DPB5	Protein POLR1D, isoform 2	gencc,clinvar
POLR1B	HGNC:20454	ENSG00000125630	Q9H9Y6	DNA-directed RNA polymerase I subunit RPA2	gencc,clinvar
POLR1C	HGNC:20194	ENSG00000171453	O15160	DNA-directed RNA polymerases I and III subunit RPAC1	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TCOF1	Treacle protein	Nucleolar protein that acts as a regulator of RNA polymerase I by connecting RNA polymerase I with enzymes responsible for ribosomal processing and modification.
POLR1B	DNA-directed RNA polymerase I subunit RPA2	Catalytic core component of RNA polymerase I (Pol I), a DNA-dependent RNA polymerase which synthesizes ribosomal RNA precursors using the four ribonucleoside triphosphates as substrates.
POLR1C	DNA-directed RNA polymerases I and III subunit RPAC1	DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 4 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	4	1.8×	0.097

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TCOF1	Other/Unknown	no		Treacle_dom, LisH, Treacle
POLR1D	Other/Unknown	no		POLR1D-like, RNA_pol_Rpb11_13-16kDa_CS, RBP11-like_dimer
POLR1B	Other/Unknown	no		DNA-dir_RNAP_su2_dom, RNA_pol_bsu_CS, RNA_pol_Rpb2_7
POLR1C	Other/Unknown	no		DNA-dir_RNA_pol_30-40kDasu_CS, DNA-dir_RNA_pol_insert, DNA-dir_RNA_pol_RpoA/D/Rpb3

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
secondary oocyte	2
sperm	2
dorsal motor nucleus of vagus nerve	1
oocyte	1
sural nerve	1
body of pancreas	1
lower esophagus mucosa	1
buccal mucosa cell	1
male germ cell	1
cervix squamous epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TCOF1	265	ubiquitous	marker	sural nerve, oocyte, dorsal motor nucleus of vagus nerve
POLR1D	288	ubiquitous	marker	body of pancreas, lower esophagus mucosa, secondary oocyte
POLR1B	284	ubiquitous	yes	buccal mucosa cell, sperm, male germ cell
POLR1C	286	ubiquitous	marker	secondary oocyte, sperm, cervix squamous epithelium

Protein interactions among cohort

Intra-cohort edges: 5.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
POLR1C	5,495
POLR1B	5,453
TCOF1	2,769
POLR1D	11

Intra-cohort edges

A	B	Sources
POLR1B	POLR1C	biogrid_interaction, intact, string_interaction
POLR1B	POLR1D	biogrid_interaction, intact
POLR1B	TCOF1	biogrid_interaction
POLR1C	POLR1D	biogrid_interaction, intact
POLR1C	TCOF1	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLR1D	P0DPB5	36
POLR1C	O15160	36
POLR1B	Q9H9Y6	7

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TCOF1	Q13428	41.78

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 22. Enrichment computed across 4 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Positive epigenetic regulation of rRNA expression	3	346.1×	2e-07	POLR1D, POLR1B, POLR1C
RNA Polymerase I Transcription Termination	3	326.3×	2e-07	POLR1D, POLR1B, POLR1C
RNA Polymerase I Promoter Clearance	3	292.8×	2e-07	POLR1D, POLR1B, POLR1C
RNA Polymerase I Transcription	3	285.5×	2e-07	POLR1D, POLR1B, POLR1C
Negative epigenetic regulation of rRNA expression	3	259.6×	2e-07	POLR1D, POLR1B, POLR1C
RNA Polymerase I Transcription Initiation	3	223.9×	3e-07	POLR1D, POLR1B, POLR1C
B-WICH complex positively regulates rRNA expression	3	121.5×	1e-06	POLR1D, POLR1B, POLR1C
RNA Polymerase I Promoter Escape	3	121.5×	1e-06	POLR1D, POLR1B, POLR1C
NoRC negatively regulates rRNA expression	3	104.8×	2e-06	POLR1D, POLR1B, POLR1C
Epigenetic regulation of gene expression	3	71.4×	6e-06	POLR1D, POLR1B, POLR1C
RNA Polymerase III Chain Elongation	2	423.0×	1e-05	POLR1D, POLR1C
RNA Polymerase III Transcription Termination	2	331.0×	2e-05	POLR1D, POLR1C
RNA Polymerase III Transcription Initiation From Type 2 Promoter	2	282.0×	3e-05	POLR1D, POLR1C
RNA Polymerase III Transcription Initiation From Type 1 Promoter	2	271.9×	3e-05	POLR1D, POLR1C
RNA Polymerase III Transcription Initiation From Type 3 Promoter	2	271.9×	3e-05	POLR1D, POLR1C
RNA Polymerase III Transcription Initiation	2	223.9×	4e-05	POLR1D, POLR1C
RNA Polymerase III Transcription	2	217.5×	4e-05	POLR1D, POLR1C
Cytosolic sensors of pathogen-associated DNA	2	190.3×	4e-05	POLR1D, POLR1C
RNA Polymerase III Abortive And Retractive Initiation	2	185.7×	4e-05	POLR1D, POLR1C
Gene expression (Transcription)	3	17.8×	2e-04	POLR1D, POLR1B, POLR1C
Innate Immune System	2	17.0×	0.005	POLR1D, POLR1C
Immune System	2	8.6×	0.017	POLR1D, POLR1C

GO biological processes by enrichment

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

GO term	Cohort genes	Fold	FDR	Sample cohort genes
neural crest formation	2	936.2×	2e-05	TCOF1, POLR1B
nucleologenesis	1	1404.3×	0.004	POLR1B
nucleolar large rRNA transcription by RNA polymerase I	1	842.6×	0.004	TCOF1
transcription elongation by RNA polymerase I	1	526.6×	0.005	POLR1D
transcription by RNA polymerase I	1	351.1×	0.006	POLR1C
rRNA transcription	1	247.8×	0.007	POLR1B
neural crest cell development	1	200.6×	0.007	TCOF1
transcription by RNA polymerase III	1	191.5×	0.007	POLR1D
embryo implantation	1	87.8×	0.014	POLR1B
regulation of translation	1	54.7×	0.020	TCOF1
skeletal system development	1	31.4×	0.031	TCOF1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TCOF1	1	2
POLR1C	1	2
POLR1D	0	0
POLR1B	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	POLR1C, TCOF1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TCOF1	8	Binding:8
POLR1C	7	Binding:7

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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)
MOLIBRESIB	2	POLR1C, TCOF1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	2	TCOF1, POLR1C
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	POLR1D, POLR1B

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
POLR1D	0	—
POLR1B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04931056	Not specified	COMPLETED	A Post Market Clinical Follow-up Study on Biomet Microfixation HTR PEKK (Midface), Facial & Mandibular Plates.