TWIST1

Chr 7

twist family bHLH transcription factor 1

Also known as: ACS3, BPES2, BPES3, CRS, CRS1, CSO, SCS, SWCOS

NCBI Gene: 7291ENSG00000122691UniProt: Q15672

This gene encodes a basic helix-loop-helix (bHLH) transcription factor that plays an important role in embryonic development. The encoded protein forms both homodimers and heterodimers that bind to DNA E box sequences and regulate the transcription of genes involved in cranial suture closure during skull development. This protein may also regulate neural tube closure, limb development and brown fat metabolism. This gene is hypermethylated and overexpressed in multiple human cancers, and the encoded protein promotes tumor cell invasion and metastasis, as well as metastatic recurrence. Mutations in this gene cause Saethre-Chotzen syndrome in human patients, which is characterized by craniosynostosis, ptosis and hypertelorism. [provided by RefSeq, Jul 2020]

Primary Disease Associations & Inheritance

UniProtSaethre-Chotzen syndrome
UniProtRobinow-Sorauf syndrome
UniProtCraniosynostosis 1
UniProtSweeney-Cox syndrome
312
ClinVar variants
140
Pathogenic / LP
0.34
pLI score
6
Active trials
Clinical Summary— TWIST1
🧬
Gene-Disease Validity (ClinGen)
Sweeney-Cox syndrome · ADLimited

Limited evidence — not for standalone diagnostic reporting

3 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.22) despite low pLI — interpret in context.
📋
ClinVar Variants
140 Pathogenic / Likely Pathogenic· 128 VUS of 312 total submissions
💊
Clinical Trials
6 active or recruiting trials — potential therapeutic options may be available
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.06LOEUF
pLI 0.345
Z-score 1.52
OE 0.22 (0.08–1.06)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.06Z-score
OE missense 0.67 (0.53–0.84)
53 obs / 79.5 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.22 (0.08–1.06)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.67 (0.53–0.84)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.60
0≤1.21.6
LoF obs/exp: 1 / 4.5Missense obs/exp: 53 / 79.5Syn Z: -2.88

ClinVar Variant Classifications

312 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic103
Likely Pathogenic37
VUS128
Likely Benign28
Benign2
Conflicting14
103
Pathogenic
37
Likely Pathogenic
128
VUS
28
Likely Benign
2
Benign
14
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
22
13
68
0
103
Likely Pathogenic
7
22
8
0
37
VUS
7
93
28
0
128
Likely Benign
0
2
8
18
28
Benign
0
0
1
1
2
Conflicting
—14
Total3613011319312

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

TWIST1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

TWIST1-related Saethre-Chotzen syndrome

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. DisordersSkeletal
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

📖
GeneReview available — TWIST1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
TWIST1+FAP+ fibroblasts in the pathogenesis of intestinal fibrosis in Crohn's disease.
Zhang Y et al.·J Clin Invest
2024
LGR5 expressing skin fibroblasts define a major cellular hub perturbed in scleroderma.
Gur C et al.·Cell
2022
PKM2-Driven Lactate Overproduction Triggers Endothelial-To-Mesenchymal Transition in Ischemic Flap via Mediating TWIST1 Lactylation.
Xu Y et al.·Adv Sci (Weinh)
2024
Twist1 regulates macrophage plasticity to promote renal fibrosis through galectin-3.
Wu Q et al.·Cell Mol Life Sci
2022
A multi-stem cell basis for craniosynostosis and calvarial mineralization.
Bok S et al.·Nature
2023
ZFP281 drives a mesenchymal-like dormancy program in early disseminated breast cancer cells that prevents metastatic outgrowth in the lung.
Nobre AR et al.·Nat Cancer
2022
Molecular Features of Cancer-associated Fibroblast Subtypes and their Implication on Cancer Pathogenesis, Prognosis, and Immunotherapy Resistance.
Galbo PM Jr et al.·Clin Cancer Res
2021
Phosphorylation of USP29 by CDK1 Governs TWIST1 Stability and Oncogenic Functions.
Guan T et al.·Adv Sci (Weinh)
2023
Discovery of Natural Compound α-Hederin via Large-Scale Screening as a Targeted JAK/STAT3 Inhibitor for Ovarian Cancer Therapy.
Wang J et al.·Adv Sci (Weinh)
2025
MET promotes hepatocellular carcinoma development through the promotion of TRIB3-mediated FOXO1 degradation.
Wang T et al.·Clin Mol Hepatol
2025
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Prader-Willi SyndromePWS-like SyndromeSilver Russel Syndrome

GROWing Up With Rare GENEtic Syndromes

RECRUITING
NCT04463316dr. Laura C. G. de Graaff-HerderStarted 2018-10-01
Retrospective file studies
Myelodysplastic SyndromesAcute Myelogenous Leukemia

Role of BMP Pathway in MDS Progression

NOT YET RECRUITING
NCT06175923Hospices Civils de LyonStarted 2024-01-27
Collection of EDTA (disodium salt of ethylenediaminetetraacetic acid) tubes of marrow during routine care
Hypophosphatasia

The Effect of Monoallelic Variants in the ALPL Gene on the Natural Course of Hypophosphatasia in Russia

RECRUITING
NCT07390240AstraZenecaStarted 2025-12-29
Craniofacial Defects, SubtleSkull DefectCraniosynostoses

Functionalized Bioink Delivering Biomolecules for the Treatment of Craniofacial Diseases

ACTIVE NOT RECRUITING
NCT06533150Fondazione Policlinico Universitario Agostino Gemelli IRCCSStarted 2024-10-07
multiomic profiling
Craniosynostosis

Network Of Clinical Research Studies On Craniosynostosis, Skull Malformations With Premature Fusion Of Skull Bones

ACTIVE NOT RECRUITING
NCT03025763Icahn School of Medicine at Mount SinaiStarted 2015-01-13
Craniosynostosis Network Environmental Survey2D/3D PhotographyBuccal Swab Cell Sampling
AortopathiesThoracic Aortic AneurysmAortic Valve Disease

Pathogenetic Basis of Aortopathy and Aortic Valve Disease

ACTIVE NOT RECRUITING
NCT03440697Yale UniversityStarted 2015-12-10

External Resources

Links to major genomics databases and tools