TWIST1

twist family bHLH transcription factor 1, the group of Basic helix-loop-helix proteins

Basic information

Region (hg38): 7:19020991-19117636

Previous symbols: [ "ACS3", "BPES3", "TWIST", "CRS" ]

Links

ENSG00000122691 ∙ NCBI:7291 ∙ OMIM:601622 ∙ HGNC:12428 ∙ Uniprot:Q15672 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• TWIST1-related craniosynostosis (Strong), mode of inheritance: AD
• Saethre-Chotzen syndrome (Strong), mode of inheritance: AD
• TWIST1-related craniosynostosis (Strong), mode of inheritance: AD
• Saethre-Chotzen syndrome (Strong), mode of inheritance: AD
• Saethre-Chotzen syndrome (Definitive), mode of inheritance: AD
• Saethre-Chotzen syndrome (Supportive), mode of inheritance: AD
• isolated scaphocephaly (Supportive), mode of inheritance: AD
• isolated plagiocephaly (Supportive), mode of inheritance: AD
• isolated brachycephaly (Supportive), mode of inheritance: AD
• TWIST1-related craniosynostosis (Strong), mode of inheritance: AD
• Saethre-Chotzen syndrome (Strong), mode of inheritance: AD
• Sweeney-Cox syndrome (Limited), mode of inheritance: AD
• Saethre-Chotzen syndrome (Definitive), mode of inheritance: AD
• TWIST1-related craniosynostosis (Moderate), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Saethre-Chotzen syndrome; Robinow-Sorauf syndrome; Craniosynostosis 1; Sweeney-Cox syndrome	AD	General	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	Audiologic/Otolaryngologic; Craniofacial; Musculoskeletal	1240778; 7120316; 7120317; 8968762; 8988167; 8988166; 9585583; 10465122; 11977182; 12116251; 11772178; 12791045; 16251895; 17437280; 17343269; 19373776; 20301368; 27884935; 28369379

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TWIST1 gene.

• TWIST1-related craniosynostosis;Saethre-Chotzen syndrome (18 variants)
• Saethre-Chotzen syndrome;TWIST1-related craniosynostosis (16 variants)
• Saethre-Chotzen syndrome (9 variants)
• not provided (7 variants)
• Sweeney-Cox syndrome (3 variants)
• TWIST1-related craniosynostosis (2 variants)
• Robinow-Sorauf syndrome (2 variants)
• Saethre-Chotzen syndrome;TWIST1-related craniosynostosis;Robinow-Sorauf syndrome (1 variants)
• Inborn genetic diseases (1 variants)
• TWIST1-related disorder (1 variants)
• Saethre-Chotzen syndrome with eyelid anomalies (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TWIST1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				15		15
missense	9	20	68	2		99
nonsense	15	2	2			19
start loss						0
frameshift	18	4	4			26
inframe indel	4	1	18	2	1	26
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding			1	4	1	6
Total	46	27	93	23	2

Variants in TWIST1

This is a list of pathogenic ClinVar variants found in the TWIST1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
7-19116526-C-A			Benign (Oct 16, 2018)
7-19116714-T-C			Uncertain significance (May 24, 2024)
7-19116715-A-G			Uncertain significance (Oct 22, 2019)
7-19116722-C-G		Saethre-Chotzen syndrome;TWIST1-related craniosynostosis	Likely benign (Mar 06, 2023)
7-19116723-G-T			Uncertain significance (Jan 06, 2023)
7-19116735-C-T		Saethre-Chotzen syndrome;TWIST1-related craniosynostosis	Pathogenic (Jun 05, 2020)
7-19116736-A-T			Uncertain significance (May 01, 2024)
7-19116757-C-T		Saethre-Chotzen syndrome;TWIST1-related craniosynostosis	Uncertain significance (May 15, 2023)
7-19116759-G-A		TWIST1-related craniosynostosis	Uncertain significance (May 22, 2022)
7-19116762-A-G		TWIST1-related craniosynostosis;Saethre-Chotzen syndrome	Uncertain significance (Oct 30, 2017)
7-19116766-C-T		TWIST1-related craniosynostosis	Pathogenic (Apr 01, 2007)
7-19116776-C-A		TWIST1-related craniosynostosis;Saethre-Chotzen syndrome	Likely benign (Oct 25, 2020)
7-19116777-C-A			Uncertain significance (Jul 01, 2023)
7-19116781-C-A		Saethre-Chotzen syndrome	Pathogenic (Jan 15, 1999)
7-19116784-G-GAGCCACAT		TWIST1-related craniosynostosis;Saethre-Chotzen syndrome	Uncertain significance (Jun 13, 2022)
7-19116791-A-T			Uncertain significance (Mar 08, 2021)
7-19116792-T-C			Uncertain significance (Feb 10, 2023)
7-19116792-T-G			Uncertain significance (Apr 16, 2021)
7-19116794-G-C			Likely pathogenic (Aug 19, 2022)
7-19116799-A-G			Uncertain significance (Dec 12, 2023)
7-19116803-TG-T		TWIST1-related craniosynostosis;Saethre-Chotzen syndrome	Uncertain significance (Jul 02, 2021)
7-19116811-T-TG		TWIST1-related craniosynostosis;Saethre-Chotzen syndrome	Uncertain significance (Apr 17, 2021)
7-19116813-G-GA		Robinow-Sorauf syndrome	Pathogenic (Aug 21, 2018)
7-19116814-A-T		Saethre-Chotzen syndrome;TWIST1-related craniosynostosis	Uncertain significance (Aug 11, 2023)
7-19116819-A-C			Uncertain significance (Feb 02, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TWIST1	protein_coding	protein_coding	ENST00000242261	1	96682

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.345	0.603	123095	0	1	123096	0.00000406

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.06	53	79.5	0.666	0.00000362	1281
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00000901	0.00000901
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• 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.
• Pathway: Proteoglycans in cancer - Homo sapiens (human);Neural Crest Differentiation;Adipogenesis;JAK-STAT;Transcription factor regulation in adipogenesis;miR-509-3p alteration of YAP1-ECM axis;Interleukin-4 and 13 signaling;EMT transition in Colorectal Cancer;EGF-EGFR Signaling Pathway;Transcriptional regulation by RUNX2;Gene expression (Transcription);tumor suppressor arf inhibits ribosomal biogenesis;Generic Transcription Pathway;RNA Polymerase II Transcription;HIF-2-alpha transcription factor network;Notch-mediated HES/HEY network;Regulation of RUNX2 expression and activity (Consensus)

Recessive Scores

• pRec: 0.493

Haploinsufficiency Scores

• pHI: 0.837
• hipred: Y
• hipred_score: 0.713
• ghis: 0.592

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: K
• gene_indispensability_pred: E
• gene_indispensability_score: 0.999

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Twist1
• Phenotype: growth/size/body region phenotype; cellular phenotype; craniofacial phenotype; limbs/digits/tail phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); digestive/alimentary phenotype; muscle phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); embryo phenotype; skeleton phenotype

Zebrafish Information Network

• Gene name: twist1b
• Affected structure: whole organism
• Phenotype tag: abnormal
• Phenotype quality: wholly ventralized

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;ossification;osteoblast differentiation;in utero embryonic development;neuron migration;neural tube closure;aortic valve morphogenesis;mitral valve morphogenesis;endocardial cushion morphogenesis;cardiac neural crest cell migration involved in outflow tract morphogenesis;muscle organ development;positive regulation of gene expression;positive regulation of epithelial to mesenchymal transition;negative regulation of phosphatidylinositol 3-kinase signaling;cytokine-mediated signaling pathway;regulation of bone mineralization;positive regulation of fatty acid beta-oxidation;negative regulation of tumor necrosis factor production;positive regulation of tumor necrosis factor production;negative regulation of histone phosphorylation;negative regulation of histone acetylation;embryonic forelimb morphogenesis;embryonic hindlimb morphogenesis;negative regulation of peroxisome proliferator activated receptor signaling pathway;outer ear morphogenesis;odontogenesis;embryonic digit morphogenesis;negative regulation of apoptotic process;negative regulation of DNA-binding transcription factor activity;negative regulation of DNA damage response, signal transduction by p53 class mediator;negative regulation of osteoblast differentiation;positive regulation of angiogenesis;negative regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;rhythmic process;negative regulation of skeletal muscle tissue development;embryonic cranial skeleton morphogenesis;positive regulation of epithelial cell proliferation;roof of mouth development;cranial suture morphogenesis;embryonic camera-type eye formation;eyelid development in camera-type eye;cellular response to growth factor stimulus;cellular response to hypoxia;positive regulation of monocyte chemotactic protein-1 production;positive regulation of DNA-templated transcription, initiation;positive regulation of cell motility;negative regulation of oxidative phosphorylation uncoupler activity;positive regulation of transcription regulatory region DNA binding;negative regulation of cellular senescence;positive regulation of interleukin-6 secretion;negative regulation of double-strand break repair;cell proliferation involved in heart valve development;positive regulation of endocardial cushion to mesenchymal transition involved in heart valve formation
• Cellular component: nucleus;nucleoplasm
• Molecular function: DNA-binding transcription factor activity, RNA polymerase II-specific;protein binding;transcription factor binding;protein domain specific binding;protein homodimerization activity;bHLH transcription factor binding;protein heterodimerization activity;E-box binding