Treacher Collins syndrome 1

Summary

Treacher Collins syndrome 1 (MONDO:0007944) is a disease caused by TCOF1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: TCOF1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 770

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Treacher Collins syndrome 1
Mondo ID	MONDO:0007944
OMIM	154500
DOID	DOID:0080789
GARD	0024589
Is cancer (heuristic)	no

Also known as: TCOF1 Treacher-Collins syndrome · TCS1 · Treacher Collins syndrome type 1 · Treacher-Collins syndrome 1 · Treacher-Collins syndrome caused by mutation in TCOF1

Data availability: 770 ClinVar variants · 3 GenCC gene-disease records.

Disease family

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 › Treacher Collins syndrome 1

Related subtypes (3): 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

600 retrieved; paginated sample, class counts are floors:

179 likely benign, 177 uncertain significance, 89 pathogenic, 45 benign, 43 likely pathogenic, 38 conflicting classifications of pathogenicity, 22 benign/likely benign, 7 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2734804	NM_001371623.1(TCOF1):c.1A>T (p.Met1Leu)	LOC129994985	Pathogenic	criteria provided, single submitter
381618	NM_001371623.1(TCOF1):c.50A>G (p.His17Arg)	LOC129994985	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068832	NM_001371623.1(TCOF1):c.2709del (p.Lys904fs)	TCOF1	Pathogenic	criteria provided, single submitter
1069272	NM_001371623.1(TCOF1):c.1504_1505insT (p.Lys502fs)	TCOF1	Pathogenic	criteria provided, single submitter
1070758	NM_001371623.1(TCOF1):c.2103_2106del (p.Ser701fs)	TCOF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1070759	NM_001371623.1(TCOF1):c.4210_4214del (p.Lys1404fs)	TCOF1	Pathogenic	criteria provided, single submitter
1070760	NM_001371623.1(TCOF1):c.4342_4343del (p.Lys1448fs)	TCOF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070982	NM_001371623.1(TCOF1):c.1578del (p.Lys528fs)	TCOF1	Pathogenic	criteria provided, single submitter
1072690	NC_000005.9:g.(?149775825)(149778631_?)del	TCOF1	Pathogenic	criteria provided, single submitter
1072904	NM_001371623.1(TCOF1):c.1425_1426del (p.Arg476fs)	TCOF1	Pathogenic	criteria provided, single submitter
1074227	NM_001371623.1(TCOF1):c.1328_1350del (p.Ala443fs)	TCOF1	Pathogenic	criteria provided, single submitter
1074353	NM_001371623.1(TCOF1):c.3337_3338insCTCT (p.Gln1113fs)	TCOF1	Pathogenic	criteria provided, single submitter
1075984	NM_001371623.1(TCOF1):c.3698_3702del (p.Ser1233fs)	TCOF1	Pathogenic	criteria provided, single submitter
127080	NM_001371623.1(TCOF1):c.1637_1640del (p.Glu546fs)	TCOF1	Pathogenic	criteria provided, single submitter
127081	NM_001371623.1(TCOF1):c.3107dup (p.Ser1036fs)	TCOF1	Pathogenic	no assertion criteria provided
1323681	NM_001371623.1(TCOF1):c.4080del (p.Arg1361fs)	TCOF1	Pathogenic	criteria provided, single submitter
1329860	NM_001371623.1(TCOF1):c.645del (p.Lys215fs)	TCOF1	Pathogenic	criteria provided, single submitter
1376566	NM_001371623.1(TCOF1):c.2819_2822del (p.Asp940fs)	TCOF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1394356	NM_001371623.1(TCOF1):c.4345+2T>C	TCOF1	Pathogenic	criteria provided, single submitter
1403903	NM_001371623.1(TCOF1):c.462del (p.Lys155fs)	TCOF1	Pathogenic	criteria provided, single submitter
1422006	NM_001371623.1(TCOF1):c.1622G>A (p.Trp541Ter)	TCOF1	Pathogenic	criteria provided, single submitter
1442692	NM_001371623.1(TCOF1):c.618_619del (p.Ser206_Ser207insTer)	TCOF1	Pathogenic	criteria provided, single submitter
1449595	NM_001371623.1(TCOF1):c.1824_1825delinsTT (p.Glu609Ter)	TCOF1	Pathogenic	criteria provided, single submitter
1451564	NM_001371623.1(TCOF1):c.163C>T (p.Gln55Ter)	TCOF1	Pathogenic	criteria provided, single submitter
1453106	NM_001371623.1(TCOF1):c.1173del (p.Lys393fs)	TCOF1	Pathogenic	criteria provided, single submitter
1456141	NM_001371623.1(TCOF1):c.523G>T (p.Glu175Ter)	TCOF1	Pathogenic	criteria provided, single submitter
1459152	NM_001371623.1(TCOF1):c.109-1del	TCOF1	Pathogenic	criteria provided, single submitter
1459153	NM_001371623.1(TCOF1):c.1999dup (p.Arg667fs)	TCOF1	Pathogenic	criteria provided, single submitter
1686255	NM_001371623.1(TCOF1):c.3047-1G>A	TCOF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1687307	NM_001371623.1(TCOF1):c.2257C>T (p.Gln753Ter)	TCOF1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 6 · 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
TCOF1	Definitive	Autosomal dominant	Treacher-Collins syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TCOF1	Orphanet:861	Treacher-Collins syndrome
TGM1	Orphanet:100976	Bathing suit ichthyosis
TGM1	Orphanet:281122	Self-improving collodion baby
TGM1	Orphanet:281127	Acral self-healing collodion baby
TGM1	Orphanet:313	Lamellar ichthyosis
TGM1	Orphanet:79394	Congenital ichthyosiform erythroderma

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TCOF1	HGNC:11654	ENSG00000070814	Q13428	Treacle protein	gencc,clinvar
TGM1	HGNC:11777	ENSG00000092295	P22735	Protein-glutamine gamma-glutamyltransferase K	clinvar

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.
TGM1	Protein-glutamine gamma-glutamyltransferase K	Catalyzes the cross-linking of proteins and the conjugation of polyamines to proteins.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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	1	14.6×	0.135
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TCOF1	Other/Unknown	no		Treacle_dom, LisH, Treacle
TGM1	Antibody/Immunoglobulin	yes	2.3.2.13	Transglutaminase_N, Transglutaminase-like, Transglutaminase_C

Expression context

Cohort genes with no expression data: 0.

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

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
dorsal motor nucleus of vagus nerve	1
oocyte	1
sural nerve	1
esophagus mucosa	1
lower esophagus mucosa	1
skin of leg	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
TGM1	135	broad	marker	lower esophagus mucosa, esophagus mucosa, skin of leg

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TCOF1	2,769
TGM1	1,978

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TGM1	P22735	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TCOF1	Q13428	41.78

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Formation of the cornified envelope	1	87.8×	0.027	TGM1
Keratinization	1	55.7×	0.027	TGM1
Developmental Biology	1	14.5×	0.069	TGM1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cell envelope organization	1	2808.7×	0.003	TGM1
nucleolar large rRNA transcription by RNA polymerase I	1	1685.2×	0.003	TCOF1
neural crest formation	1	936.2×	0.004	TCOF1
cornification	1	526.6×	0.004	TGM1
positive regulation of keratinocyte proliferation	1	495.6×	0.004	TGM1
neural crest cell development	1	401.2×	0.005	TCOF1
positive regulation of cell cycle	1	221.7×	0.007	TGM1
keratinocyte differentiation	1	123.9×	0.010	TGM1
protein modification process	1	122.1×	0.010	TGM1
regulation of translation	1	109.4×	0.010	TCOF1
skeletal system development	1	62.9×	0.016	TCOF1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) 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
TGM1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	TCOF1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
TGM1	11	Binding:11
TCOF1	8	Binding:8

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TGM1	2.3.2.13	protein-glutamine gamma-glutamyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	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	1	TCOF1
C	Druggable family + PDB, no drug	1	TGM1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TGM1	11	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.