TWIST1
protein-codingtwist family bHLH transcription factor 1, the group of Basic helix-loop-helix proteins
Gene summary
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]
- ACS3
- BPES3
- TWIST
- CRS
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~96.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0007042
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0007042
Submitter: ClinGen
TWIST1 has been repeatedly been described in association with autosomal dominant Saethre-Chotzen syndrome (SCS), an unusual form of acrocephalosyndactyly characterized by bicoronal synostosis causing brachycephaly or acrocephaly, high forehead with low anterior hairline, ptosis, hypertelorism, lacrimal duct stenosis, high palate, small ears with prominent crus, facial asymmetry, partial cutaneous syndactyly of hands and feet, and hallux valgus (7120317, 10649491). This syndrome was first described independently by Saethre and Chotzen in 1931 and 1932, respectively. The mechanism of disease is haploinsufficiency caused by either protein degradation or subcellular mislocalization based upon the variant’s location in TWIST1 (10749989). Numerous variants (nonsense, frameshift etc.) have been identified in patients with SCS. This gene-disease association is supported by genetic, segregation, and experimental evidence. After completing a lumping and splitting evaluation, the ClinGen Craniofacial Malformations expert panel decided to lump Saethre-Chotzen syndrome and Robinow-Sorauf syndrome; these conditions are not distinct entities and lack differences in phenotype, molecular mechanism, and inheritance pattern. This is consistent with the published literature (12791045). Notably, TWIST1 has also been described in association with non-syndromic Craniosynostosis and Sweeney-Cox syndrome. These conditions will be assessed separately. In summary, TWIST is definitively associated with autosomal dominant Saethre-Chotzen syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Craniofacial Malformations Gene Curation Expert panel on 1/28/21 (SOP version 8).
Inheritance Pattern: AD
Disease ID:MONDO:0007399
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0007399
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0007042
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0060592
Submitter: ClinGen
TWIST1 was first reported by Kim et al. in 2017 in relation to autosomal dominant Sweeney-Cox syndrome, a condition characterized by distinct facial dysostosis. Features include hypertelorism, deficiencies of the eyelids and facial bones, cleft palate/velopharyngeal insufficiency, and low-set cupped ears (PMID: 28369379). Three unique missense variants, all occurring de novo at the Glu117 codon, have been reported in patients (PMIDs: 28369379, 30450715). Evidence supporting this gene-disease relationship includes case-level and experimental evidence. Of note, TWIST1 has also been assessed in association with Saethre-Chotzen syndrome and reached a definitive classification. Indicating it is an ultra-rare condition, only 3 cases of Sweeney-Cox syndrome have been published to date; therefore, there is limited but suggestive evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Craniofacial malformation expert panel on 3/25/2021.
Inheritance Pattern: AD
Disease ID:MONDO:0008391
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0060592
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0007042
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0007399
Submitter: ClinGen
TWIST1 has been associated with isolated Craniosynostosis. At least 8 probands with Craniosynostosis but without additional syndromic features have been described in the literature. This gene-disease relationship is supported by genetic and experimental evidence, including mouse models. Notably, TWIST1 has also been curated for Saethre-Chotzen syndrome and Sweeney Cox syndrome by the ClinGen Craniofacial malformations GCEP and came to definitive and limited classifications, respectively. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This curation was approved by the ClinGen Craniofacial malformations GCEP on 6/3/21 (SOP 8).
Inheritance Pattern: AD
Disease ID:MONDO:0007042
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0007399
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0007042
Submitter: Laboratory for Molecular Medicine
This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.
Inheritance Pattern: AD
Disease ID:MONDO:0007042
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0018112
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0018114
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic; Craniofacial; Musculoskeletal
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to TWIST1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000474.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 26 | 1 | 27 | |||
| missense | 13 | 40 | 107 | 7 | 167 | |
| nonsense | 25 | 6 | 1 | 32 | ||
| start loss | 0 | |||||
| frameshift | 25 | 10 | 5 | 40 | ||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 63 | 56 | 113 | 33 | 1 | 266 |
Highest pathogenic variant AF is 0.000006581459
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000465.1 | 1 | MANE Select | |
| Ensembl | ENSP00000242261.5 | 1 | MANE Select | |
| Ensembl | ENSP00000346582.5 | 1 | Standard | |
| Ensembl | ENSP00000416986.1 | 1 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| twist1b | Danio rerio | Structure: whole organism Quality: wholly ventralized abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Proteoglycans in cancer - Homo sapiens (human)
- Neural Crest Differentiation
- Adipogenesis
- JAK-STAT
- Transcription factor regulation in adipogenesis
Biological Process
- negative regulation of transcription by RNA polymerase II
- ossification
- osteoblast differentiation
- in utero embryonic development
- neuron migration
Molecular Function
- DNA-binding transcription factor activity, RNA polymerase II-specific
- protein binding
- transcription factor binding
- protein domain specific binding
- protein homodimerization activity
Cellular Component
- nucleus
- nucleoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000242261
- Coding exons
- 1
- Length
- 96682
- Individuals with no LoFs
- 123095
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 1
- Defined
- 123096
- p
- 0.00000406
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.06 | 53 | 79.5 | 0.666 | 0.00000362 | 1281 |
| Missense (PolyPhen) | 7 | 34.261 | 0.20431 | 375 | ||
| Synonymous | -2.88 | 59 | 36.8 | 1.60 | 0.00000176 | 416 |
| Loss of Function | 1.52 | 1 | 4.47 | 0.224 | 1.93e-7 | 56 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.0000090 | 0.0000090 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Acts as a transcriptional regulator. Inhibits myogenesis by sequestrating E proteins, inhibiting trans-activation by MEF2, and inhibiting DNA-binding by MYOD1 through physical interaction. This interaction probably involves the basic domains of both proteins. Also represses expression of proinflammatory cytokines such as TNFA and IL1B. Regulates cranial suture patterning and fusion. Activates transcription as a heterodimer with E proteins. Regulates gene expression differentially, depending on dimer composition. Homodimers induce expression of FGFR2 and POSTN while heterodimers repress FGFR2 and POSTN expression and induce THBS1 expression. Heterodimerization is also required for osteoblast differentiation. Represses the activity of the circadian transcriptional activator: NPAS2-ARNTL/BMAL1 heterodimer (By similarity). {ECO:0000250|UniProtKB:P26687, ECO:0000269|PubMed:12553906, ECO:0000269|PubMed:25981568}.;
- Disease
- DISEASE: Robinow-Sorauf syndrome (RSS) [MIM:180750]: An autosomal dominant syndrome characterized by craniosynostosis, asymmetry of orbits, flat face, hypertelorism, a thin, long, and pointed nose, shallow orbits, strabismus, and broad great toes with a duplication of the distal phalanx. RSS is clinically similar to Saethre-Chotzen syndrome, with the most characteristic additional feature in Robinow-Sorauf syndrome being a bifid or partially duplicated hallux. {ECO:0000269|PubMed:10465122}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Craniosynostosis 1 (CRS1) [MIM:123100]: A primary abnormality of skull growth involving premature fusion of one or more cranial sutures. The growth velocity of the skull often cannot match that of the developing brain resulting in an abnormal head shape and, in some cases, increased intracranial pressure, which must be treated promptly to avoid permanent neurodevelopmental disability. {ECO:0000269|PubMed:17343269}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Sweeney-Cox syndrome (SWCOS) [MIM:617746]: An autosomal dominant syndrome characterized by facial dysostosis, including hypertelorism, deficiencies of the eyelids and facial bones, cleft palate/velopharyngeal insufficiency, and low-set cupped ears. {ECO:0000269|PubMed:28369379}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.493
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- K
- Indispensability pred.
- E
- Indispensability score
- 0.999
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |