TWIST1-related craniosynostosis

Summary

TWIST1-related craniosynostosis (MONDO:0007399) is a disease caused by TWIST1 (GenCC Strong), with 6 cohort genes and 4 clinical trials. Top therapeutic interventions include prednisolone.

At a glance

• Causal gene: TWIST1 (GenCC Strong)
• Cohort genes: 6
• ClinVar variants: 255
• Clinical trials: 4

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	TWIST1-related craniosynostosis
Mondo ID	MONDO:0007399
OMIM	123100
DOID	DOID:0061010
SNOMED CT	57219006
UMLS	C4551902
MedGen	1646646
GARD	0018045
NORD	1606
Is cancer (heuristic)	no

Also known as: craniosynostosis 1 · craniosynostosis type 1 · CRS · CRS1 · Primary Craniosynostosis · TWIST1-related craniosynostosis

Data availability: 255 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone development disease › dysostosis › synostosis › craniosynostosis › isolated craniosynostosis › isolated oxycephaly › TWIST1-related craniosynostosis

Related subtypes (1): craniosynostosis 6

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

255 retrieved; paginated sample, class counts are floors:

83 uncertain significance, 61 pathogenic, 44 likely benign, 18 conflicting classifications of pathogenicity, 16 pathogenic/likely pathogenic, 12 likely pathogenic, 12 benign, 9 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1070490	NC_000019.9:g.(?_42759120)_42759196del	ERF	Pathogenic	criteria provided, single submitter
1310308	NM_006494.4(ERF):c.652C>T (p.Arg218Ter)	ERF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455895	NM_006494.4(ERF):c.71C>G (p.Ser24Ter)	ERF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1502851	NM_006494.4(ERF):c.911_913del (p.Ser304del)	ERF	Pathogenic	criteria provided, multiple submitters, no conflicts
2122554	NM_006494.4(ERF):c.272dup (p.Arg92fs)	ERF	Pathogenic	criteria provided, single submitter
2133130	NM_006494.4(ERF):c.1021del (p.Gln341fs)	ERF	Pathogenic	criteria provided, single submitter
2810553	NM_006494.4(ERF):c.997_1034del (p.Leu332_His333insTer)	ERF	Pathogenic	criteria provided, single submitter
3654560	NM_006494.4(ERF):c.856dup (p.Met286fs)	ERF	Pathogenic	criteria provided, single submitter
3686735	NM_006494.4(ERF):c.253del (p.Leu85fs)	ERF	Pathogenic	criteria provided, single submitter
420168	NM_006494.4(ERF):c.1201_1202del (p.Lys401fs)	ERF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
423954	NM_006494.4(ERF):c.1072_1073del (p.Pro358fs)	ERF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4715860	NM_006494.4(ERF):c.121G>T (p.Glu41Ter)	ERF	Pathogenic	criteria provided, single submitter
476627	NM_006494.4(ERF):c.619C>T (p.Arg207Ter)	ERF	Pathogenic	criteria provided, multiple submitters, no conflicts
476628	NM_006494.4(ERF):c.733del (p.Leu245fs)	ERF	Pathogenic	criteria provided, single submitter
543070	NM_006494.4(ERF):c.566_567del (p.Asp188_Cys189insTer)	ERF	Pathogenic	criteria provided, multiple submitters, no conflicts
55923	NM_006494.4(ERF):c.547C>T (p.Arg183Ter)	ERF	Pathogenic	criteria provided, multiple submitters, no conflicts
55924	NM_006494.4(ERF):c.891_892del (p.Gly299fs)	ERF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
55925	NM_006494.4(ERF):c.256C>T (p.Arg86Cys)	ERF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
582072	NM_006494.4(ERF):c.223C>T (p.Gln75Ter)	ERF	Pathogenic	criteria provided, single submitter
583126	NM_006494.4(ERF):c.-44_22+11del	ERF	Pathogenic	criteria provided, single submitter
936483	NM_006494.4(ERF):c.144G>A (p.Trp48Ter)	ERF	Pathogenic	criteria provided, single submitter
964211	NM_006494.4(ERF):c.427del (p.Arg143fs)	ERF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075291	NM_000474.4(TWIST1):c.587G>A (p.Trp196Ter)	LOC129998021	Pathogenic	criteria provided, single submitter
1455499	NM_000474.4(TWIST1):c.467T>G (p.Ile156Ser)	LOC129998021	Pathogenic	criteria provided, single submitter
2070030	NM_000474.4(TWIST1):c.465C>G (p.Tyr155Ter)	LOC129998021	Pathogenic	criteria provided, multiple submitters, no conflicts
2504943	NM_000474.4(TWIST1):c.399_423dup (p.Lys142fs)	LOC129998021	Pathogenic	criteria provided, multiple submitters, no conflicts
3235827	NM_000474.4(TWIST1):c.481C>T (p.Gln161Ter)	LOC129998021	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3760234	NM_000474.4(TWIST1):c.480C>A (p.Tyr160Ter)	LOC129998021	Pathogenic	criteria provided, single submitter
458685	NC_000007.14:g.(?19116693)(19117341_?)del	LOC129998021	Pathogenic	criteria provided, single submitter
4783655	NM_000474.4(TWIST1):c.480C>G (p.Tyr160Ter)	LOC129998021	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 17 · Orphanet: 8 · 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
TWIST1	Strong	Autosomal dominant	TWIST1-related craniosynostosis	17

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TWIST1	Orphanet:35093	Non-syndromic sagittal craniosynostosis
TWIST1	Orphanet:35099	Non-syndromic bicoronal craniosynostosis
TWIST1	Orphanet:794	Saethre-Chotzen syndrome
KAT6B	Orphanet:3047	Blepharophimosis-intellectual disability syndrome, SBBYS type
KAT6B	Orphanet:85201	Genitopatellar syndrome
ZNF526	Orphanet:528084	Non-specific syndromic intellectual disability
ERF	Orphanet:207	Crouzon syndrome
ERF	Orphanet:647681	Craniosynostosis-facial dysmorphism-Chiari-1 malformation-developmental and language delay syndrome

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TWIST1	HGNC:12428	ENSG00000122691	Q15672	Twist-related protein 1	gencc,clinvar
KAT6B	HGNC:17582	ENSG00000156650	Q8WYB5	Histone acetyltransferase KAT6B	clinvar
ACTMAP	HGNC:24758	ENSG00000188493	Q5BKX5	Actin maturation protease	clinvar
ZNF526	HGNC:29415	ENSG00000167625	Q8TF50	Zinc finger protein 526	clinvar
ERF	HGNC:3444	ENSG00000105722	P50548	ETS domain-containing transcription factor ERF	clinvar
ETF1	HGNC:3477	ENSG00000120705	P62495	Eukaryotic peptide chain release factor subunit 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TWIST1	Twist-related protein 1	Acts as a transcriptional regulator.
KAT6B	Histone acetyltransferase KAT6B	Histone acetyltransferase which may be involved in both positive and negative regulation of transcription.
ACTMAP	Actin maturation protease	Actin maturation protease that specifically mediates the cleavage of immature acetylated N-terminal actin, thereby contributing to actin maturation.
ZNF526	Zinc finger protein 526	Probable transcription factor.
ERF	ETS domain-containing transcription factor ERF	Potent transcriptional repressor that binds to the H1 element of the Ets2 promoter.
ETF1	Eukaryotic peptide chain release factor subunit 1	Component of the eRF1-eRF3-GTP ternary complex, a ternary complex that mediates translation termination in response to the termination codons.

Protein-family classification

Druggable: 0 · Difficult: 3 · Unknown: 3 · 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	3	4.1×	0.053
Other/Unknown	3	0.9×	0.758

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TWIST1	Transcription factor	no		bHLH_dom, HLH_DNA-bd_sf, TWIST1_bHLH
KAT6B	Transcription factor	no	2.3.1.48	Znf_PHD, HAT_MYST-type, Histone_H1/H5_H15
ACTMAP	Other/Unknown	no		ACTMAP
ZNF526	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf
ERF	Other/Unknown	no		Ets_dom, WH-like_DNA-bd_sf, WH_DNA-bd_sf
ETF1	Other/Unknown	no		Peptide_chain-rel_eRF1/aRF1, eRF1_Pelota-like_N, eRF1_2

Expression context

Cohort genes with no expression data: 0.

5 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
primordial germ cell in gonad	2
mucosa of paranasal sinus	1
oocyte	1
periodontal ligament	1
cortical plate	1
sural nerve	1
ventricular zone	1
hindlimb stylopod muscle	1
pancreatic ductal cell	1
ileal mucosa	1
stromal cell of endometrium	1
gall bladder	1
mucosa of stomach	1
right uterine tube	1
islet of Langerhans	1
mucosa of sigmoid colon	1
upper leg skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TWIST1	233	ubiquitous	marker	periodontal ligament, mucosa of paranasal sinus, oocyte
KAT6B	140	ubiquitous	yes	cortical plate, ventricular zone, sural nerve
ACTMAP	266	ubiquitous	marker	pancreatic ductal cell, primordial germ cell in gonad, hindlimb stylopod muscle
ZNF526	177	ubiquitous	marker	primordial germ cell in gonad, ileal mucosa, stromal cell of endometrium
ERF	242	ubiquitous	marker	right uterine tube, mucosa of stomach, gall bladder
ETF1	293	ubiquitous	marker	islet of Langerhans, upper leg skin, mucosa of sigmoid colon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TWIST1	3,507
KAT6B	2,214
ERF	1,115
ZNF526	1,063
ACTMAP	1,011
ETF1	313

Structural data

PDB: 4 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ETF1	P62495	33
KAT6B	Q8WYB5	3
TWIST1	Q15672	2
ERF	P50548	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ACTMAP	Q5BKX5	83.63
ZNF526	Q8TF50	63.80

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. Enrichment computed across 6 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Protein hydroxylation	1	135.9×	0.055	ETF1
Oncogene Induced Senescence	1	84.0×	0.055	ERF
Nuclear events stimulated by ALK signaling in cancer	1	81.6×	0.055	TWIST1
Transcriptional regulation by RUNX2	1	63.4×	0.055	TWIST1
Regulation of RUNX2 expression and activity	1	45.3×	0.057	TWIST1
Eukaryotic Translation Termination	1	30.1×	0.057	ETF1
Negative Regulation of CDH1 Gene Transcription	1	30.1×	0.057	TWIST1
Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)	1	29.4×	0.057	ETF1
Interleukin-4 and Interleukin-13 signaling	1	25.7×	0.057	TWIST1
Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC)	1	24.4×	0.057	ETF1
Chromatin organization	1	20.4×	0.057	KAT6B
HATs acetylate histones	1	19.8×	0.057	KAT6B
Chromatin modifying enzymes	1	18.1×	0.057	KAT6B
Regulation of expression of SLITs and ROBOs	1	17.3×	0.057	ETF1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cell proliferation involved in heart valve development	1	3370.4×	0.009	TWIST1
positive regulation of endocardial cushion to mesenchymal transition involved in heart valve formation	1	3370.4×	0.009	TWIST1
cytoplasmic translational termination	1	1685.2×	0.009	ETF1
embryonic camera-type eye formation	1	1685.2×	0.009	TWIST1
negative regulation of double-strand break repair	1	1123.5×	0.011	TWIST1
negative regulation of skeletal muscle tissue development	1	842.6×	0.011	TWIST1
regulation of translational termination	1	561.7×	0.011	ETF1
negative regulation of peroxisome proliferator activated receptor signaling pathway	1	561.7×	0.011	TWIST1
cranial suture morphogenesis	1	561.7×	0.011	TWIST1
cardiac neural crest cell migration involved in outflow tract morphogenesis	1	481.5×	0.011	TWIST1
translational termination	1	481.5×	0.011	ETF1
regulation of developmental process	1	481.5×	0.011	KAT6B
positive regulation of DNA-templated transcription initiation	1	374.5×	0.012	TWIST1
mitral valve morphogenesis	1	337.0×	0.012	TWIST1
positive regulation of fatty acid beta-oxidation	1	306.4×	0.012	TWIST1
outer ear morphogenesis	1	306.4×	0.012	TWIST1
regulation of hemopoiesis	1	306.4×	0.012	KAT6B
negative regulation of macrophage cytokine production	1	240.7×	0.014	TWIST1
positive regulation of monocyte chemotactic protein-1 production	1	240.7×	0.014	TWIST1
negative regulation of DNA damage response, signal transduction by p53 class mediator	1	224.7×	0.014	TWIST1
eyelid development in camera-type eye	1	210.7×	0.014	TWIST1
protein methylation	1	187.2×	0.015	ETF1
regulation of transcription by RNA polymerase II	3	7.0×	0.015	TWIST1, KAT6B, ERF
endocardial cushion morphogenesis	1	168.5×	0.015	TWIST1
positive regulation of cell motility	1	153.2×	0.016	TWIST1
regulation of bone mineralization	1	146.5×	0.016	TWIST1
developmental process	1	134.8×	0.017	TWIST1
negative regulation of cellular senescence	1	129.6×	0.017	TWIST1
negative regulation of miRNA transcription	1	124.8×	0.017	TWIST1
embryonic hindlimb morphogenesis	1	116.2×	0.017	TWIST1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 6

Druggability breadth: 2 of 6 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TWIST1	0	0
KAT6B	0	0
ACTMAP	0	0
ZNF526	0	0
ERF	0	0
ETF1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
KAT6B	22	Binding:20, Functional:2
ETF1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
KAT6B	2.3.1.48	histone acetyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; 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	6	TWIST1, KAT6B, ACTMAP, ZNF526, ERF, ETF1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TWIST1	0	—
KAT6B	22	—
ACTMAP	0	—
ZNF526	0	—
ERF	0	—
ETF1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3
PHASE4	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05474924	PHASE4	UNKNOWN	The Role of Budesonide Intrapolyp Injection in CRSwNP
NCT02997020	Not specified	ACTIVE_NOT_RECRUITING	Ivacaftor for Acquired CFTR Dysfunction in Chronic Rhinosinusitis (EDSPD Protocol)
NCT04868695	Not specified	RECRUITING	Subjective and Objective Outcome of ESS in CRSwNP
NCT03379701	Not specified	COMPLETED	Applications of Nanotechnology and Chemical Sensors for the Detection and Identification of Chronic Sinusitis Subtypes by Respiratory Samples

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
PREDNISOLONE	4	1