TCF12-related craniosynostosis

Summary

TCF12-related craniosynostosis (MONDO:0014128) is a disease caused by TCF12 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: TCF12 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 63

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	TCF12-related craniosynostosis
Mondo ID	MONDO:0014128
OMIM	615314
Orphanet	672979
DOID	DOID:0061011
UMLS	C3715051
MedGen	811568
GARD	0018047
Is cancer (heuristic)	no

Also known as: craniosynostosis 3 · craniosynostosis caused by mutation in TCF12 · craniosynostosis type 3 · CRS3 · TCF12 craniosynostosis · TCF12-related craniosynostosis

Data availability: 63 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › syndromic craniosynostosis › TCF12-related craniosynostosis

Related subtypes (39): Crouzon syndrome, Beare-Stevenson cutis gyrata syndrome, Shprintzen-Goldberg syndrome, acrocephalopolydactyly, Antley-Bixler syndrome, C syndrome, cranioectodermal dysplasia, cardiocranial syndrome, Pfeiffer type, craniosynostosis-fibular aplasia syndrome, Baller-Gerold syndrome, craniotelencephalic dysplasia, Summitt syndrome, X-linked intellectual disability-plagiocephaly syndrome, Lowry-MacLean syndrome, pseudoaminopterin syndrome, craniosynostosis 4, holoprosencephaly-craniosynostosis syndrome, Hunter-McAlpine craniosynostosis, Curry-Jones syndrome, craniomicromelic syndrome, Muenke syndrome, craniosynostosis-anal anomalies-porokeratosis syndrome, craniosynostosis 2, cloverleaf skull-multiple congenital anomalies syndrome, craniosynostosis-intracranial calcifications syndrome, Crouzon syndrome-acanthosis nigricans syndrome, craniosynostosis and dental anomalies, lethal occipital encephalocele-skeletal dysplasia syndrome, autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome, cloverleaf skull-asphyxiating thoracic dysplasia syndrome, craniosynostosis, Philadelphia type, craniosynostosis-cataract syndrome, familial scaphocephaly syndrome, craniosynostosis-hydrocephalus-Arnold-Chiari malformation type I-radioulnar synostosis syndrome, osteosclerosis-developmental delay-craniosynostosis syndrome, craniosynostosis, Herrmann-Opitz type, trigonocephaly-broad thumbs syndrome, acrocephalosyndactyly, Weiss-Kruszka syndrome

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

63 retrieved; paginated sample, class counts are floors:

26 pathogenic, 18 likely pathogenic, 10 uncertain significance, 4 conflicting classifications of pathogenicity, 3 pathogenic/likely pathogenic, 1 likely benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1064628	NM_207037.2(TCF12):c.1261-3C>G	TCF12	Pathogenic	criteria provided, single submitter
1077132	NM_207037.2(TCF12):c.207del (p.Tyr70fs)	TCF12	Pathogenic	criteria provided, single submitter
127269	NM_207037.2(TCF12):c.1000_1001del (p.Gln334fs)	TCF12	Pathogenic	criteria provided, single submitter
127270	NM_207037.2(TCF12):c.1071del (p.Ser358fs)	TCF12	Pathogenic	criteria provided, single submitter
127271	NM_207037.2(TCF12):c.1366dup (p.Ile456fs)	TCF12	Pathogenic	criteria provided, multiple submitters, no conflicts
1335906	NM_207037.2(TCF12):c.826-2A>G	TCF12	Pathogenic	no assertion criteria provided
1527944	NM_207037.2(TCF12):c.268C>T (p.Arg90Ter)	TCF12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3075708	NM_207037.2(TCF12):c.1879dup (p.Met627fs)	TCF12	Pathogenic	criteria provided, single submitter
3255079	NM_207037.2(TCF12):c.1054_1055dup (p.Ser353fs)	TCF12	Pathogenic	criteria provided, single submitter
3340445	NM_207037.2(TCF12):c.791del (p.Ser264fs)	TCF12	Pathogenic	criteria provided, single submitter
3382313	NM_207037.2(TCF12):c.1223T>A (p.Leu408Ter)	TCF12	Pathogenic	criteria provided, single submitter
374377	NM_207037.2(TCF12):c.1876C>T (p.Arg626Ter)	TCF12	Pathogenic	criteria provided, multiple submitters, no conflicts
3775901	NM_207037.2(TCF12):c.1713del (p.Asp572fs)	TCF12	Pathogenic	criteria provided, single submitter
436958	NM_207037.2(TCF12):c.1642_1645del (p.Glu548fs)	TCF12	Pathogenic	criteria provided, multiple submitters, no conflicts
4685482	NM_207037.2(TCF12):c.1468-1G>A	TCF12	Pathogenic	criteria provided, single submitter
4796476	NM_207037.2(TCF12):c.347C>A (p.Ser116Ter)	TCF12	Pathogenic	criteria provided, single submitter
488842	NM_207037.2(TCF12):c.812C>A (p.Ser271Ter)	TCF12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
489259	NM_207037.2(TCF12):c.1128G>A (p.Trp376Ter)	TCF12	Pathogenic	criteria provided, multiple submitters, no conflicts
55911	NM_207037.2(TCF12):c.842C>G (p.Ser281Ter)	TCF12	Pathogenic	criteria provided, multiple submitters, no conflicts
55912	NM_207037.2(TCF12):c.1491dup (p.Val498fs)	TCF12	Pathogenic	criteria provided, multiple submitters, no conflicts
55913	NM_207037.2(TCF12):c.722C>G (p.Ser241Ter)	TCF12	Pathogenic	no assertion criteria provided
55914	NM_207037.2(TCF12):c.1646del (p.Lys549fs)	TCF12	Pathogenic	no assertion criteria provided
55915	NM_207037.2(TCF12):c.1963G>T (p.Glu655Ter)	TCF12	Pathogenic	no assertion criteria provided
55917	NM_207037.2(TCF12):c.1912C>G (p.Gln638Glu)	TCF12	Pathogenic	no assertion criteria provided
692240	NM_207037.2(TCF12):c.786dup (p.Ser263fs)	TCF12	Pathogenic	criteria provided, multiple submitters, no conflicts
871063	NM_207037.2(TCF12):c.778_779del (p.Met260fs)	TCF12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
871064	NM_207037.2(TCF12):c.1453C>T (p.Arg485Ter)	TCF12	Pathogenic	criteria provided, multiple submitters, no conflicts
930393	NM_207037.2(TCF12):c.1541C>A (p.Ser514Ter)	TCF12	Pathogenic	criteria provided, multiple submitters, no conflicts
984943	NM_207037.2(TCF12):c.1907_1908del (p.Lys636fs)	TCF12	Pathogenic	criteria provided, single submitter
1705297	NM_207037.2(TCF12):c.325+2T>C	TCF12	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 2 · 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
TCF12	Definitive	Autosomal dominant	TCF12-related craniosynostosis	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TCF12	Orphanet:209916	Extraskeletal myxoid chondrosarcoma
TCF12	Orphanet:35099	Non-syndromic bicoronal craniosynostosis

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TCF12	HGNC:11623	ENSG00000140262	Q99081	Transcription factor 12	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TCF12	Transcription factor 12	Transcriptional regulator.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TCF12	Transcription factor	no		bHLH_dom, HLH_DNA-bd_sf, NeuroDiff_E-box_TFs

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ganglionic eminence	1
periodontal ligament	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TCF12	295	ubiquitous	marker	periodontal ligament, ventricular zone, ganglionic eminence

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TCF12	1,978

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TCF12	Q99081	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 1 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
TGFBR3 expression	1	456.8×	0.007	TCF12
Myogenesis	1	380.7×	0.007	TCF12
NGF-stimulated transcription	1	285.5×	0.007	TCF12
Negative Regulation of CDH1 Gene Transcription	1	120.2×	0.011	TCF12
CHD1 and CHD2 subfamily	1	108.8×	0.011	TCF12
RUNX1 regulates transcription of genes involved in differentiation of HSCs	1	95.2×	0.011	TCF12

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to gonadotropin-releasing hormone	1	5617.3×	0.002	TCF12
positive regulation of neuron differentiation	1	198.3×	0.020	TCF12
muscle organ development	1	166.8×	0.020	TCF12
gene expression	1	79.9×	0.031	TCF12
immune response	1	47.1×	0.036	TCF12
nervous system development	1	45.9×	0.036	TCF12
positive regulation of gene expression	1	38.7×	0.037	TCF12
cell differentiation	1	29.1×	0.043	TCF12
positive regulation of transcription by RNA polymerase II	1	14.9×	0.075	TCF12
regulation of transcription by RNA polymerase II	1	11.7×	0.086	TCF12

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
TCF12	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TCF12	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

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	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	TCF12

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)
TCF12	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.