TWIST1

Summary

TWIST1 (twist family bHLH transcription factor 1, HGNC:12428) is a protein-coding gene on chromosome 7p21.1, encoding Twist-related protein 1 (Q15672). Acts as a transcriptional regulator. It is haploinsufficient (ClinGen: sufficient evidence).

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.

Source: NCBI Gene 7291 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Saethre-Chotzen syndrome (Definitive, ClinGen) — +6 more curated relationships
• GWAS associations: 22
• Clinical variants (ClinVar): 201 total — 49 pathogenic, 14 likely-pathogenic
• Phenotypes (HPO): 147
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Transcription factor: yes — 85 downstream targets (CollecTRI)
• MANE Select transcript: NM_000474

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12428
Approved symbol	TWIST1
Name	twist family bHLH transcription factor 1
Location	7p21.1
Locus type	gene with protein product
Status	Approved
Aliases	SCS, H-twist, BPES2, bHLHa38, CRS1
Ensembl gene	ENSG00000122691
Ensembl biotype	protein_coding
OMIM	601622
Entrez	7291

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 nonsense_mediated_decay, 1 protein_coding

ENST00000242261, ENST00000354571, ENST00000443687

RefSeq mRNA: 1 — MANE Select: NM_000474 NM_000474

CCDS: CCDS5367

Canonical transcript exons

ENST00000242261 — 2 exons

Exon	Start	End
ENSE00000831889	19116671	19117636
ENSE00001423703	19115468	19116131

Expression profiles

Bgee: expression breadth ubiquitous, 233 present calls, max score 97.10.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 29.1233 / max 946.2288, expressed in 1241 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
82949	24.3658	1143
82948	4.4584	995
82946	0.2473	121
82947	0.0518	12

Top tissues by expression

275 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
periodontal ligament	UBERON:0008266	97.10	gold quality
mucosa of paranasal sinus	UBERON:0005030	96.62	gold quality
oocyte	CL:0000023	95.71	gold quality
buccal mucosa cell	CL:0002336	95.27	gold quality
tendon of biceps brachii	UBERON:0008188	94.30	gold quality
pericardium	UBERON:0002407	93.67	gold quality
parietal pleura	UBERON:0002400	92.70	gold quality
mammary duct	UBERON:0001765	92.08	gold quality
placenta	UBERON:0001987	91.79	gold quality
stromal cell of endometrium	CL:0002255	91.70	gold quality
subcutaneous adipose tissue	UBERON:0002190	91.13	gold quality
skin of hip	UBERON:0001554	91.04	gold quality
thoracic mammary gland	UBERON:0005200	90.50	gold quality
mammary gland	UBERON:0001911	90.47	gold quality
nipple	UBERON:0002030	89.86	gold quality
epithelium of mammary gland	UBERON:0003244	89.80	gold quality
upper arm skin	UBERON:0004263	89.31	gold quality
blood vessel layer	UBERON:0004797	89.24	gold quality
adipose tissue	UBERON:0001013	88.87	gold quality
secondary oocyte	CL:0000655	88.74	gold quality
connective tissue	UBERON:0002384	88.62	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	88.12	gold quality
upper leg skin	UBERON:0004262	87.36	gold quality
cartilage tissue	UBERON:0002418	87.20	gold quality
zone of skin	UBERON:0000014	86.66	gold quality
descending thoracic aorta	UBERON:0002345	86.27	gold quality
skin of leg	UBERON:0001511	86.16	gold quality
oral cavity	UBERON:0000167	85.93	gold quality
skin of abdomen	UBERON:0001416	85.91	gold quality
tendon	UBERON:0000043	85.75	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-56	yes	844.57
E-MTAB-9388	yes	12.17
E-ANND-3	yes	10.82
E-MTAB-7249	yes	2.46

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

85 targets.

Target	Regulation
ACAN	Repression
AKR1C2	Activation
AKT2	Activation
ALX3	Unknown
AR	Unknown
ATM	Activation
BCL2	Unknown
BGLAP	Unknown
BMI1	Activation
CAT
CCL2	Activation
CCN5
CD24	Unknown
CD44	Activation
CDH1	Repression
CDH11	Activation
CDH17
CDH2	Unknown
CDH5	Unknown
CDKN1A	Unknown
CDKN2A	Repression
CLDN4	Unknown
CLDN7	Unknown
CLU	Unknown
COL1A2	Activation
COL2A1	Repression
CTPS1	Activation
CXCL12	Activation
CXCL8	Activation
DKK1	Unknown

JASPAR motifs

Motif	Name	Family
MA1123.1	TWIST1	Tal-related
MA1123.2	TWIST1	Tal-related
MA1123.3	TWIST1	Tal-related

JASPAR matrix evidence (PMIDs): PMID:25762439, PMID:29453333

Upstream regulators (CollecTRI, top): ATF3, CTNNB1, DLX4, ETV4, EZH2, FOXO1, FOXO3, FOXQ1, HDAC2, HIF1A, HMGA1, HMGA2, KLF17, NCOA1, NKX3-1, OVOL2, PER2, POU2F1, PPARD, PROX1, RELA, RUNX2, SNAI1, SOX2, SOX5, SOX9, SP1, STAT3, SUZ12, TP53

miRNA regulators (miRDB)

86 targeting TWIST1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-9-5P	100.00	72.28	2361
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-489-3P	99.80	66.46	839
HSA-MIR-4517	99.76	69.19	1867
HSA-MIR-7856-5P	99.75	69.99	2901

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Twist1 and Twist2 antagonize the ARF/p53 pathway. This is the first report suggesting a role for Twist genes as oncogenes (PMID:10485844)
• new TWIST mutation (7p21) with variable eyelid manifestations supports locus homogeneity of BPES at 3q22 (PMID:11474656)
• Deletion of 18 nucleotides or insertion of three, 15, or 21 nucleotides was not consistently associated with clinical disease and was conclude that they are at most weakly pathogenic. (PMID:11748846)
• Identified direct paternal transmission of a novel missense TWIST mutation in the highly conserved Helix II domain of this bHLH-family gene. (PMID:11754069)
• Deficience causes skull osteoblast apoptosis due to increased TNFalpha expression and caspase-2 activation. (PMID:11854168)
• Cooperative E-box regulation of human GLI1 by this protein and USF (PMID:11948912)
• Characterization of a dominant negative C. elegans Twist mutant protein with implications for human Saethre-Chotzen syndrome (PMID:12015302)
• inactivation reduces CBFA1/RUNX2 expression and DNA binding to the osteocalcin promoter in osteoblasts (PMID:12270142)
• One variant is associated with Robinow-Sorauf syndrome. (PMID:12791045)
• The risk for developmental delay in patients with deletions involving the TWIST gene is approximately 90%. (PMID:14513358)
• novel role for TWIST, a basic helix-loop-helix protein, which plays a central role in cell type determination and differentiation, during generation of acquired resistance to taxol in a nasopharyngeal carcinoma cell line, HNE1-T3 (PMID:14724576)
• TWIST1 plays an essential role in tumor metastasis. (PMID:15210113)
• Twist was highly and selectively expressed in T cells of patients with Sezary Syndrome. (PMID:15313894)
• loss of HOXA5 expression could lead to the functional activation of Twist resulting in aberrant cell cycle regulation and promoting breast carcinogenesis (PMID:15545268)
• A reporter assay with the p21 promoter demonstrated that Snail inhibited expression of p21 induced by E2A. Co-expression of Snail with Twist showed additive inhibitory effects. (PMID:15555546)
• H-Twist overexpression in neuroblastomas is responsible for the inhibition of the ARF/p53 pathway involved in the Myc-dependent apoptotic response. (PMID:15607966)
• Misregulation of Twist1 dimerization by post-translational mechanisms underlies phenotypes of individuals with Saethre-Chotzen syndrome (PMID:15735646)
• This analysis further dissects the structure-function relationships of TWIST and corroborates with phenotypic observations of disease expressivity. (PMID:15880747)
• TWIST gene is involved in high-grade pediatric osteosarcomas and is a new marker with a possible initial predictive value. (PMID:15900593)
• Results have identified TWIST as a critical regulator of prostate cancer cell growth and suggest a potential therapeutic approach to inhibit the growth and metastasis of androgen-independent prostate cancer through inactivation of the TWIST gene. (PMID:15958559)
• Overexpression of TWIST protein in a human glioma cell line significantly enhanced tumor cell invasion, a hallmark of high-grade gliomas. (PMID:16229805)
• Twist1 is induced by canonical Wnt signaling and expression of Twist1 strongly inhibited chondrocyte gene expression. (PMID:16293629)
• Twist over-expression induces angiogenesis in a mouse breast cancer model (PMID:16322226)
• Twist may play an important role in the invasion and metastasis of nasopharyngeal carcinoma (PMID:16412561)
• Dimer partner selection is an important mediator of Twist1 function in transgenic mice, providing a mechanistic understanding of craniosynostosis due to TWIST haploinsufficiency. (PMID:16502419)
• This provides genetic evidence that Twist1, Msx2 and Efna4 function together in boundary formation and the pathogenesis of coronal synostosis. (PMID:16540516)
• Twist overexpression plays a role in destabilizing the genome, thus promoting chromosomal instability. (PMID:16737925)
• These results implicate Twist proteins in regulation of TNFalpha production by antiinflammatory factors and pathways, and provide a mechanism by which type I IFNs and Axl receptors suppress inflammatory cytokine production. (PMID:16831897)
• Twist may act as a negative regulator of osteoblastic differentiation in periodontal ligament cells (PMID:16888803)
• Twist haploinsufficiency results in decreased Cbl-mediated PI3K degradation in osteoblasts. (PMID:17003487)
• Patients with TWIST gene mutations may have more ophthalmic abnormalities, including more strabismus, ptosis, NLDO, astigmatism, vertical deviations, and amblyopia compared with patients with FGFR3 gene mutations. (PMID:17070479)
• suggest critical implication of the CCT repeats in association with Sp1 and Sp3 factors in sustaining expression of the TWIST1 gene in mesenchymal cells (PMID:17157810)
• Twist, a novel oncogene, is upregulated in pancreatic cancer (PMID:17236203)
• Induction of Twist by a human viral oncoprotein LMP1 directly contributes to the metastatic nature of nasopharyngeal carcinoma. (PMID:17332324)
• Twist is a positive transcriptional regulator of AKT2 expression;Twist-AKT2 signaling is involved in promoting invasive ability and survival of breast cancer cells. (PMID:17332325)
• Some TWIST1 mutations in the RUNX2 binding site are associated with craniosynostosis. (PMID:17343269)
• TWIST may serve as a prognostic marker for high-grade prostatic cancer in humans; up-regulation of TWIST with aberrant expression of E-cadherin may predict development of metastatic disease. (PMID:17394502)
• Data suggest that Twist-1 and -2 play an important role in NF-kappaB-dependent chemoresistance. (PMID:17403902)
• no evidence that mosaicism for mutations, normally associated with syndromal forms of craniosynostosis, occur in single suture craniosynostosis (PMID:17414280)
• findings suggest that reduced expression of TWIST suppresses the multistep process of peritoneal dissemination (detachment from the primary lesion, adhesion to MCs and invasion of MCs. (PMID:17487558)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
mus_musculus	Twist1	ENSMUSG00000035799
rattus_norvegicus	Twist1	ENSRNOG00000011101
drosophila_melanogaster	twi	FBGN0003900
drosophila_melanogaster	HLH54F	FBGN0022740
drosophila_melanogaster	Hand	FBGN0032209
drosophila_melanogaster	Fer3	FBGN0037937
drosophila_melanogaster	CG33557	FBGN0053557
caenorhabditis_elegans		WBGENE00001953
caenorhabditis_elegans		WBGENE00001956

Paralogs (13): HAND1 (ENSG00000113196), TCF21 (ENSG00000118526), TCF15 (ENSG00000125878), FERD3L (ENSG00000146618), TCF23 (ENSG00000163792), HAND2 (ENSG00000164107), PTF1A (ENSG00000168267), MSC (ENSG00000178860), FIGLA (ENSG00000183733), BHLHA9 (ENSG00000205899), TWIST2 (ENSG00000233608), SCX (ENSG00000260428), TCF24 (ENSG00000261787)

Protein

Protein identifiers

Twist-related protein 1 — Q15672 (reviewed: Q15672)

Alternative names: Class A basic helix-loop-helix protein 38, H-twist

All UniProt accessions (3): Q15672, H7BY00, H7C4D7

UniProt curated annotations — full annotation on UniProt →

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 pro-inflammatory 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-BMAL1 heterodimer.

Subunit / interactions. Efficient DNA binding requires dimerization with another bHLH protein. Homodimer or heterodimer with E proteins such as TCF3. ID1 binds preferentially to TCF3 but does not interact efficiently with TWIST1 so ID1 levels control the amount of TCF3 available to dimerize with TWIST1 and thus determine the type of dimer formed.

Subcellular location. Nucleus.

Tissue specificity. Subset of mesodermal cells.

Disease relevance. Saethre-Chotzen syndrome (SCS) [MIM:101400] A craniosynostosis syndrome characterized by coronal synostosis, brachycephaly, low frontal hairline, facial asymmetry, hypertelorism, broad halluces, and clinodactyly. The disease is caused by variants affecting the gene represented in this entry. 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. The disease is caused by variants affecting the gene represented in this entry. 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. The disease is caused by variants affecting the gene represented in this entry. 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. The disease is caused by variants affecting the gene represented in this entry.

RefSeq proteins (1): NP_000465* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011598	bHLH_dom	Domain
IPR036638	HLH_DNA-bd_sf	Homologous_superfamily
IPR047093	TWIST1_bHLH	Domain
IPR050283	E-box_TF_Regulators	Family

Pfam: PF00010

UniProt features (28 total): sequence variant 11, sequence conflict 7, compositionally biased region 4, region of interest 2, helix 2, chain 1, domain 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
8OSB	X-RAY DIFFRACTION	2.9
2MJV	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15672-F1	68.89	0.23

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-6785807	Interleukin-4 and Interleukin-13 signaling
R-HSA-8878166	Transcriptional regulation by RUNX2
R-HSA-8939902	Regulation of RUNX2 expression and activity
R-HSA-9725371	Nuclear events stimulated by ALK signaling in cancer
R-HSA-9764725	Negative Regulation of CDH1 Gene Transcription

MSigDB gene sets: 797 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_UP, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR, GOBP_LIPID_MODIFICATION, GOBP_FATTY_ACID_CATABOLIC_PROCESS, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_CELL_MIGRATION_INVOLVED_IN_HEART_DEVELOPMENT, GOBP_REGULATION_OF_SKELETAL_MUSCLE_TISSUE_DEVELOPMENT, GOBP_MUSCLE_TISSUE_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, HNF3ALPHA_Q6, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_EPITHELIAL_TO_MESENCHYMAL_TRANSITION

GO Biological Process (58): negative regulation of transcription by RNA polymerase II (GO:0000122), ossification (GO:0001503), osteoblast differentiation (GO:0001649), in utero embryonic development (GO:0001701), neuron migration (GO:0001764), neural tube closure (GO:0001843), aortic valve morphogenesis (GO:0003180), mitral valve morphogenesis (GO:0003183), endocardial cushion morphogenesis (GO:0003203), cardiac neural crest cell migration involved in outflow tract morphogenesis (GO:0003253), regulation of transcription by RNA polymerase II (GO:0006357), muscle organ development (GO:0007517), positive regulation of gene expression (GO:0010628), positive regulation of epithelial to mesenchymal transition (GO:0010718), negative regulation of macrophage cytokine production (GO:0010936), positive regulation of cell migration (GO:0030335), regulation of bone mineralization (GO:0030500), positive regulation of fatty acid beta-oxidation (GO:0032000), developmental process (GO:0032502), negative regulation of tumor necrosis factor production (GO:0032720), positive regulation of interleukin-6 production (GO:0032755), positive regulation of tumor necrosis factor production (GO:0032760), embryonic forelimb morphogenesis (GO:0035115), embryonic hindlimb morphogenesis (GO:0035116), negative regulation of peroxisome proliferator activated receptor signaling pathway (GO:0035359), outer ear morphogenesis (GO:0042473), embryonic digit morphogenesis (GO:0042733), negative regulation of apoptotic process (GO:0043066), negative regulation of DNA damage response, signal transduction by p53 class mediator (GO:0043518), negative regulation of osteoblast differentiation (GO:0045668), positive regulation of angiogenesis (GO:0045766), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of transcription by RNA polymerase II (GO:0045944), rhythmic process (GO:0048511), negative regulation of skeletal muscle tissue development (GO:0048642), embryonic cranial skeleton morphogenesis (GO:0048701), negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051898), cranial suture morphogenesis (GO:0060363), embryonic camera-type eye formation (GO:0060900), eyelid development in camera-type eye (GO:0061029)

GO Molecular Function (17): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), cis-regulatory region sequence-specific DNA binding (GO:0000987), DNA-binding transcription repressor activity (GO:0001217), transcription coregulator binding (GO:0001221), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), protein domain specific binding (GO:0019904), protein homodimerization activity (GO:0042803), histone deacetylase binding (GO:0042826), bHLH transcription factor binding (GO:0043425), E-box binding (GO:0070888), DNA-binding transcription factor binding (GO:0140297), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515), identical protein binding (GO:0042802), protein dimerization activity (GO:0046983)

GO Cellular Component (3): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Signaling by Interleukins	1
Generic Transcription Pathway	1
Transcriptional regulation by RUNX2	1
Signaling by ALK fusions and activated point mutants	1
Regulation of CDH1 Gene Transcription	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transcription cis-regulatory region binding	4
protein binding	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
negative regulation of DNA-templated transcription	2
cell migration	2
regulation of DNA-templated transcription	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
DNA-binding transcription factor activity	2
transcription factor binding	2
cellular anatomical structure	2
multicellular organismal process	1
ossification	1
cell differentiation	1
chordate embryonic development	1
generation of neurons	1
primary neural tube formation	1
tube closure	1
aortic valve development	1
heart valve morphogenesis	1
mitral valve development	1
atrioventricular valve morphogenesis	1
heart morphogenesis	1
endocardial cushion development	1
mesenchyme morphogenesis	1
neural crest cell migration	1
outflow tract morphogenesis	1
cell migration involved in heart development	1
cardiac neural crest cell development involved in outflow tract morphogenesis	1
animal organ development	1
muscle structure development	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
epithelial to mesenchymal transition	1
regulation of epithelial to mesenchymal transition	1
positive regulation of cell differentiation	1
positive regulation of multicellular organismal process	1
negative regulation of cytokine production involved in immune response	1
macrophage cytokine production	1

Protein interactions and networks

STRING

3276 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TWIST1	G3BP2	Q9UN86	946
TWIST1	SNAI2	O43623	936
TWIST1	TP53	P04637	914
TWIST1	RUNX2	Q13950	905
TWIST1	MSX2	P35548	898
TWIST1	SNAI1	O95863	894
TWIST1	ZEB1	P37275	890
TWIST1	BMI1	P35226	886
TWIST1	R4GMX3	R4GMX3	884
TWIST1	FGFR3	P22607	881
TWIST1	FGFR2	P18443	878
TWIST1	CDH1	P12830	849
TWIST1	FGFR1	P11362	847
TWIST1	EP300	Q09472	846
TWIST1	SMAD4	Q13485	845

IntAct

86 interactions, top by confidence:

A	B	Type	Score
TWIST1	TCF4	psi-mi:“MI:0915”(physical association)	0.850
TWIST1	TCF4	psi-mi:“MI:0403”(colocalization)	0.850
TWIST1	TP53	psi-mi:“MI:0915”(physical association)	0.820
TP53	TWIST1	psi-mi:“MI:0407”(direct interaction)	0.820
TWIST1	TP53	psi-mi:“MI:0914”(association)	0.820
TP53	TWIST1	psi-mi:“MI:0915”(physical association)	0.820
TWIST1	TP53	psi-mi:“MI:0407”(direct interaction)	0.820
H4C16	BRD4	psi-mi:“MI:0915”(physical association)	0.740
BRD4	H4C16	psi-mi:“MI:0914”(association)	0.740
H4C16	BRD4	psi-mi:“MI:0914”(association)	0.740
TCF3	TWIST1	psi-mi:“MI:0915”(physical association)	0.710
TWIST1	TCF3	psi-mi:“MI:0915”(physical association)	0.710
TWIST1	TCF3	psi-mi:“MI:0403”(colocalization)	0.710
CETN1	SFI1	psi-mi:“MI:0914”(association)	0.640
KMT5A	TWIST1	psi-mi:“MI:0915”(physical association)	0.630
KMT5A	TWIST1	psi-mi:“MI:0407”(direct interaction)	0.630

BioGRID (145): BCL6 (Reconstituted Complex), TP53 (Reconstituted Complex), TCF4 (Reconstituted Complex), YY1 (Reconstituted Complex), NEIL3 (Reconstituted Complex), YY2 (Reconstituted Complex), ZIC3 (Reconstituted Complex), TWIST1 (Synthetic Lethality), TWIST1 (Two-hybrid), TWIST1 (Affinity Capture-MS), TWIST1 (Affinity Capture-MS), BTRC (Affinity Capture-Western), TWIST1 (Affinity Capture-Western), PAQR3 (Affinity Capture-Western), TWIST1 (Affinity Capture-Western)

ESM2 similar proteins: O35437, O43680, O60682, O88940, O93507, O96004, P22091, P24899, P27792, P48985, P57100, P59101, P70447, P70562, P70595, P70660, P70661, P79782, P97832, Q02346, Q02575, Q02576, Q02577, Q12870, Q15672, Q5E9S3, Q60539, Q60756, Q64124, Q64221, Q64279, Q7JGP2, Q7RTU7, Q8BGW3, Q8MI03, Q8MI06, Q8MIB5, Q8MIB9, Q8MID5, Q8MIE7

Diamond homologs: A8E5T6, B6VQA1, O13125, O13126, O16867, O35437, O42202, O42606, O43680, O57598, O60682, O73615, O73823, O88940, O93507, O96004, O96642, P13903, P17542, P22091, P24899, P26687, P46581, P48985, P48987, P57100, P57101, P57102, P59101, P61295, P61296, P70661, P79765, P79782, P97831, P97832, Q02575, Q02576, Q02577, Q0VCE2

SIGNOR signaling

60 interactions.

A	Effect	B	Mechanism
AKT1	up-regulates	TWIST1	phosphorylation
MAPK1	up-regulates	TWIST1	phosphorylation
MAPK11	up-regulates	TWIST1	phosphorylation
MAPK14	up-regulates	TWIST1	phosphorylation
MAPK3	up-regulates	TWIST1	phosphorylation
MAPK8	up-regulates	TWIST1	phosphorylation
CSNK2A1	up-regulates	TWIST1	phosphorylation
TWIST1	down-regulates	CSNK2A1
AKT	up-regulates	TWIST1	phosphorylation
CTDSP1	“down-regulates activity”	TWIST1	dephosphorylation
EZH2	“down-regulates quantity by repression”	TWIST1	“transcriptional regulation”
POU2F1	“up-regulates quantity by expression”	TWIST1	“transcriptional regulation”
PER2	“down-regulates quantity by repression”	TWIST1	“transcriptional regulation”
HDAC2	“down-regulates quantity by repression”	TWIST1	“transcriptional regulation”
SUZ12	“down-regulates quantity by repression”	TWIST1	“transcriptional regulation”
RUNX2	“up-regulates quantity by expression”	TWIST1	“transcriptional regulation”
TWIST1	“down-regulates quantity by repression”	CDH1	“transcriptional regulation”
TWIST1	“up-regulates quantity by expression”	AKR1C2	“transcriptional regulation”
TWIST1	“up-regulates quantity by expression”	ATM	“transcriptional regulation”
TWIST1	“up-regulates quantity by expression”	CD44	“transcriptional regulation”
TWIST1	“up-regulates quantity by expression”	ICAM1	“transcriptional regulation”
TWIST1	“up-regulates quantity by expression”	ITGB1	“transcriptional regulation”
TWIST1	“up-regulates quantity by expression”	CTPS1	“transcriptional regulation”
TWIST1	“down-regulates quantity by repression”	F2R	“transcriptional regulation”
TWIST1	“up-regulates quantity by expression”	FN1	“transcriptional regulation”
TWIST1	“up-regulates quantity by expression”	HGF	“transcriptional regulation”
TWIST1	“up-regulates quantity by expression”	FAP	“transcriptional regulation”
TWIST1	“up-regulates quantity by expression”	SNAI2	“transcriptional regulation”
TWIST1	“up-regulates quantity by expression”	MMP2	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 33 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Regulation of PD-L1(CD274) transcription	6	22.5×	9e-05
Formation of the beta-catenin:TCF transactivating complex	5	20.7×	8e-04
Estrogen-dependent gene expression	5	13.0×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
chromatin organization	6	18.6×	7e-05
chromatin remodeling	6	13.7×	3e-04
DNA damage response	7	11.7×	1e-04
regulation of cell cycle	5	11.7×	3e-03
positive regulation of apoptotic process	5	8.9×	7e-03
positive regulation of gene expression	7	8.5×	9e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

201 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	49
Likely pathogenic	14
Uncertain significance	90
Likely benign	19
Benign	1

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1075081	NM_000474.4(TWIST1):c.54_73del (p.Ser18fs)	Pathogenic
1338420	NM_000474.4(TWIST1):c.108del (p.Arg37fs)	Pathogenic
1351855	NM_000474.4(TWIST1):c.400ATC[1] (p.Ile135del)	Pathogenic
1357752	NC_000007.13:g.(?19156336)(19157207_?)del	Pathogenic
1418275	NM_000474.4(TWIST1):c.349G>T (p.Glu117Ter)	Pathogenic
1434196	NM_000474.4(TWIST1):c.258_261dup (p.Gly88fs)	Pathogenic
1451820	NM_000474.4(TWIST1):c.338_339dup (p.Asn114fs)	Pathogenic
1457074	NM_000474.4(TWIST1):c.395_415dup (p.Arg132_Leu138dup)	Pathogenic
1458491	NM_000474.4(TWIST1):c.310G>T (p.Glu104Ter)	Pathogenic
1703561	GRCh37/hg19 7p21.1(chr7:19152100-19157785)	Pathogenic
1722762	NM_000474.4(TWIST1):c.-18C>T	Pathogenic
2036363	NM_000474.4(TWIST1):c.141_145del (p.Gly48fs)	Pathogenic
2093953	NM_000474.4(TWIST1):c.347G>C (p.Arg116Pro)	Pathogenic
2444186	NM_000474.4(TWIST1):c.319C>T (p.Gln107Ter)	Pathogenic
2572412	NM_000474.4(TWIST1):c.351G>T (p.Glu117Asp)	Pathogenic
2572990	NM_000474.4(TWIST1):c.408del (p.Thr137fs)	Pathogenic
2920608	NM_000474.4(TWIST1):c.325C>T (p.Gln109Ter)	Pathogenic
2921667	NM_000474.4(TWIST1):c.211del (p.Gln71fs)	Pathogenic
2941524	NM_000474.4(TWIST1):c.290_294del (p.Gly97fs)	Pathogenic
2947590	NM_000474.4(TWIST1):c.79dup (p.Gln27fs)	Pathogenic
3376165	NM_000474.4(TWIST1):c.346C>T (p.Arg116Trp)	Pathogenic
3757740	NM_000474.4(TWIST1):c.102del (p.Gly36fs)	Pathogenic
3758878	NM_000474.4(TWIST1):c.156_165dup (p.Ala56fs)	Pathogenic
3759623	NM_000474.4(TWIST1):c.124del (p.Ser42fs)	Pathogenic
4083363	NM_000474.4(TWIST1):c.7C>T (p.Gln3Ter)	Pathogenic
444875	NM_000474.4(TWIST1):c.350A>T (p.Glu117Val)	Pathogenic
444876	NM_000474.4(TWIST1):c.350A>G (p.Glu117Gly)	Pathogenic
458686	NM_000474.4(TWIST1):c.397_417dup (p.Lys133_Pro139dup)	Pathogenic
4783656	NM_000474.4(TWIST1):c.364C>T (p.Gln122Ter)	Pathogenic
489149	NM_000474.4(TWIST1):c.419C>A (p.Ser140Ter)	Pathogenic

SpliceAI

136 predictions. Top by Δscore:

Variant	Effect	Δscore
7:19116665:CCTTA:C	donor_loss	0.9400
7:19116666:CTTAC:C	donor_loss	0.9400
7:19116667:TTACC:T	donor_loss	0.9400
7:19116668:TAC:T	donor_loss	0.9400
7:19116669:A:AT	donor_loss	0.9400
7:19116670:C:G	donor_loss	0.9400
7:19115828:A:C	acceptor_gain	0.9200
7:19116129:CAT:C	acceptor_gain	0.9100
7:19116770:G:C	donor_gain	0.8900
7:19116143:C:T	acceptor_gain	0.8700
7:19115824:A:C	acceptor_gain	0.8500
7:19116132:C:CC	acceptor_gain	0.8400
7:19116130:ATC:A	acceptor_loss	0.8200
7:19116131:TCTGC:T	acceptor_loss	0.8200
7:19116132:CTG:C	acceptor_loss	0.8200
7:19116133:T:A	acceptor_loss	0.8200
7:19115827:CA:C	acceptor_gain	0.8100
7:19116134:G:C	acceptor_loss	0.8100
7:19116794:G:C	donor_gain	0.7800
7:19116748:T:TA	donor_gain	0.7700
7:19116804:G:A	donor_gain	0.7700
7:19116669:A:AC	donor_gain	0.7500
7:19116670:C:CC	donor_gain	0.7500
7:19116127:GACAT:G	acceptor_gain	0.6800
7:19115828:A:AC	acceptor_gain	0.6300
7:19116663:GTCCT:G	donor_loss	0.6300
7:19116664:TCCTT:T	donor_loss	0.6300
7:19116136:A:T	acceptor_loss	0.6200
7:19116671:C:G	donor_loss	0.6200
7:19116143:C:CT	acceptor_gain	0.6100

AlphaMissense

1313 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:19116742:C:G	G194R	1.000
7:19116742:C:T	G194R	1.000
7:19116746:C:A	M192I	1.000
7:19116746:C:G	M192I	1.000
7:19116746:C:T	M192I	1.000
7:19116747:A:G	M192T	1.000
7:19116749:C:A	R191S	1.000
7:19116749:C:G	R191S	1.000
7:19116750:C:A	R191M	1.000
7:19116750:C:G	R191T	1.000
7:19116751:T:A	R191W	1.000
7:19116752:C:A	W190C	1.000
7:19116752:C:G	W190C	1.000
7:19116754:A:G	W190R	1.000
7:19116754:A:T	W190R	1.000
7:19116760:A:G	S188P	1.000
7:19116761:G:C	F187L	1.000
7:19116761:G:T	F187L	1.000
7:19116762:A:C	F187C	1.000
7:19116762:A:G	F187S	1.000
7:19116763:A:C	F187V	1.000
7:19116763:A:G	F187L	1.000
7:19116763:A:T	F187I	1.000
7:19116765:G:T	A186D	1.000
7:19116766:C:G	A186P	1.000
7:19116774:A:G	L183P	1.000
7:19116774:A:T	L183H	1.000
7:19116834:A:G	L163P	1.000
7:19116834:A:T	L163H	1.000
7:19116846:A:G	L159P	1.000

dbSNP variants (sampled 300 via entrez): RS1000849825 (7:19118642 C>T), RS1000882345 (7:19118432 G>A), RS1000888985 (7:19116283 G>A), RS1001785482 (7:19118189 G>A), RS1002148856 (7:19114833 TA>T,TAA), RS1002706240 (7:19117468 T>A,G), RS1004859652 (7:19113418 T>C), RS1004991564 (7:19118935 A>G), RS1005131044 (7:19119128 C>G), RS1005403792 (7:19113797 G>A,T), RS1005656103 (7:19116381 A>G), RS1005709966 (7:19118536 C>A,T), RS1005793813 (7:19116522 G>A,T), RS1005991737 (7:19117886 C>A,G,T), RS1006029158 (7:19115559 G>C)

Disease associations

OMIM: gene MIM:601622 | disease phenotypes: MIM:101400, MIM:123100, MIM:180750, MIM:617746

GenCC curated gene-disease

Disease	Classification	Inheritance
Saethre-Chotzen syndrome	Definitive	Autosomal dominant
TWIST1-related craniosynostosis	Strong	Autosomal dominant
Sweeney-Cox syndrome	Strong	Autosomal dominant
Robinow-Sorauf syndrome	Strong	Autosomal dominant
isolated scaphocephaly	Supportive	Autosomal dominant
isolated plagiocephaly	Supportive	Autosomal dominant
isolated brachycephaly	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (3)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Sweeney-Cox syndrome	Limited	AD
Saethre-Chotzen syndrome	Definitive	AD
TWIST1-related craniosynostosis	Moderate	AD

Mondo (7): Saethre-Chotzen syndrome (MONDO:0007042), TWIST1-related craniosynostosis (MONDO:0007399), Robinow-Sorauf syndrome (MONDO:0008391), Sweeney-Cox syndrome (MONDO:0060592), (MONDO:0018112), (MONDO:0018113), (MONDO:0018114)

Orphanet (3): OBSOLETE: Isolated oxycephaly (Orphanet:63440), Saethre-Chotzen syndrome (Orphanet:794), Robinow-Sorauf syndrome (Orphanet:3106)

HPO phenotypes

147 total (30 of 147 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000160	Narrow mouth
HP:0000175	Cleft palate
HP:0000189	Narrow palate
HP:0000193	Bifid uvula
HP:0000218	High palate
HP:0000220	Velopharyngeal insufficiency
HP:0000248	Brachycephaly
HP:0000260	Wide anterior fontanel
HP:0000262	Turricephaly
HP:0000263	Oxycephaly
HP:0000268	Dolichocephaly
HP:0000269	Prominent occiput
HP:0000270	Delayed cranial suture closure
HP:0000272	Malar flattening
HP:0000286	Epicanthus
HP:0000294	Low anterior hairline
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000324	Facial asymmetry
HP:0000327	Hypoplasia of the maxilla
HP:0000337	Broad forehead
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000349	Widow’s peak
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000377	Abnormal pinna morphology
HP:0000378	Cupped ear

GWAS associations

22 associations (top):

Study	Trait	p-value
GCST001762_934	Obesity-related traits	4.000000e-07
GCST002875_21	Diisocyanate-induced asthma	1.000000e-06
GCST003542_192	Night sleep phenotypes	3.000000e-06
GCST004125_22	Type 2 diabetes (age of onset)	2.000000e-06
GCST005116_33	Male-pattern baldness	7.000000e-63
GCST006009_16	Pulse pressure	5.000000e-13
GCST007096_94	Pulse pressure	1.000000e-37
GCST007097_130	Pulse pressure	1.000000e-11
GCST007097_131	Pulse pressure	3.000000e-15
GCST007099_80	Systolic blood pressure	9.000000e-14
GCST007267_317	Systolic blood pressure	3.000000e-21
GCST007268_31	Diastolic blood pressure	3.000000e-11
GCST007269_208	Pulse pressure	5.000000e-54
GCST007703_113	Systolic blood pressure	6.000000e-07
GCST007705_34	Pulse pressure	6.000000e-14
GCST010158_1	Large artery stroke (CCS or TOAST classification)	4.000000e-16
GCST010159_1	Large artery stroke (CCS and TOAST classification)	3.000000e-10
GCST010160_1	Large artery stroke (TOAST classification)	8.000000e-14
GCST010161_1	Large artery stroke (CCSp classification)j	1.000000e-12
GCST010479_4	Coronary artery disease	1.000000e-14
GCST010866_122	Coronary artery disease	1.000000e-31
GCST010867_67	Coronary artery disease	8.000000e-09

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0005116	urinary metabolite measurement
EFO:0006995	response to diisocyanate
EFO:0005763	pulse pressure measurement
EFO:0006335	systolic blood pressure
EFO:0006336	diastolic blood pressure

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C537183	Robinow Sorauf syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

102 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects binding, decreases reaction, increases abundance, decreases expression, affects cotreatment (+3 more)	8
Arsenic	decreases expression, affects expression, decreases response to substance, increases abundance, increases expression (+3 more)	6
Valproic Acid	affects cotreatment, increases expression	6
Particulate Matter	affects cotreatment, affects reaction, increases expression, decreases reaction, decreases expression (+1 more)	6
Air Pollutants	increases abundance, increases expression, decreases expression, decreases reaction	4
trichostatin A	affects cotreatment, increases expression	3
Estradiol	decreases expression, affects cotreatment	3
Aflatoxin B1	affects expression, decreases expression, decreases methylation	3
osimertinib	increases cleavage, decreases response to substance, decreases cleavage, affects response to substance, decreases reaction	2
thymoquinone	decreases expression, decreases reaction, increases reaction	2
methylmercuric chloride	decreases expression, increases expression	2
bisphenol A	decreases expression, increases methylation	2
mercuric bromide	increases expression, affects cotreatment	2
cordycepin	decreases expression, decreases localization, affects cotreatment, increases reaction	2
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	decreases reaction, increases abundance, increases expression, increases reaction, decreases expression	2
SB 203580	decreases reaction, increases abundance, increases expression, decreases expression	2
U 0126	decreases reaction, increases expression, increases abundance, increases reaction	2
stattic	decreases reaction, increases abundance, increases expression, increases reaction	2
Panobinostat	affects cotreatment, increases expression	2
Benzo(a)pyrene	increases expression, affects methylation	2
Cisplatin	increases expression, decreases reaction, decreases expression	2
Doxorubicin	decreases expression, increases expression, affects cotreatment	2
Glucose	decreases expression, increases expression	2
Niclosamide	decreases expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Progesterone	affects cotreatment, decreases expression	2
Smoke	decreases expression, increases abundance	2
Tretinoin	increases expression	2
aristolochic acid I	increases expression	1
ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate	decreases expression	1

Cellosaurus cell lines

7 cell lines: 5 cancer cell line, 1 embryonic stem cell, 1 spontaneously immortalized cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B8A5	Abcam Raji TWIST1 KO	Cancer cell line	Male
CVCL_B926	Lis04_Twist1	Embryonic stem cell	Female
CVCL_C0AZ	Abcam THP-1 TWIST1 KO	Cancer cell line	Male
CVCL_C7CM	Abcam PC-3 TWIST1 KO	Cancer cell line	Male
CVCL_DR99	MCF-7/Twist	Cancer cell line	Female
CVCL_DS00	MCF-10A/Twist	Spontaneously immortalized cell line	Female
CVCL_TV28	HAP1 TWIST1 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

11 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05474924	PHASE4	UNKNOWN	The Role of Budesonide Intrapolyp Injection in CRSwNP
NCT04676399	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Improving Pain Management Via Spinal Cord Stimulation and Blood Pressure Reduction
NCT03670147	Not specified	TERMINATED	Paresthesia Free Spinal Cord Stimulation (PF-SCS)
NCT04463316	Not specified	RECRUITING	GROWing Up With Rare GENEtic Syndromes
NCT04548375	Not specified	RECRUITING	Multicenter Outcome Registry of AnaLgesic Effect of SCS(MORALES) Registry Protocol
NCT05466110	Not specified	UNKNOWN	Spinal Cord Stimulation Versus Instrumentation for FBSS
NCT05540756	Not specified	WITHDRAWN	Study on the Use of Intraoperative Neurophysiological Monitoring in Spinal Cord Stimulator Trials
NCT07535372	Not specified	NOT_YET_RECRUITING	ASO Treatment for Syndromic Craniosynostoses
NCT02997020	Not specified	ACTIVE_NOT_RECRUITING	Ivacaftor for Acquired CFTR Dysfunction in Chronic Rhinosinusitis (EDSPD Protocol)
NCT03379701	Not specified	COMPLETED	Applications of Nanotechnology and Chemical Sensors for the Detection and Identification of Chronic Sinusitis Subtypes by Respiratory Samples
NCT04868695	Not specified	RECRUITING	Subjective and Objective Outcome of ESS in CRSwNP