TWIST1

Chr 7AD

twist family bHLH transcription factor 1

ENSG00000122691 UniProt: Q15672 OMIM: 601622

The protein is a basic helix-loop-helix transcription factor that binds to DNA E box sequences and regulates transcription of genes controlling cranial suture closure, neural tube closure, and limb development. Mutations cause autosomal dominant craniosynostosis syndromes including Saethre-Chotzen syndrome, Robinow-Sorauf syndrome, and Sweeney-Cox syndrome, typically presenting with premature skull suture fusion, ptosis, and hypertelorism. The pathogenic mechanism involves haploinsufficiency leading to disrupted transcriptional regulation of developmental genes.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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 (By similarity)

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Craniosynostosis 1MIM #123100

Robinow-Sorauf syndromeMIM #180750

Saethre-Chotzen syndrome with or without eyelid anomaliesMIM #101400

Sweeney-Cox syndromeMIM #617746

Clinical highlights

Gene–disease validity (ClinGen)

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

291

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.06

LOEUF

LOF

Mechanism· G2P

Some data sources returned errors (1)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

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?

1.06Z-score

OE missense 0.67 (0.53–0.84)

53 obs / 79.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.22 (0.08–1.06)

0≤0.351.4

Missense OE?0.67 (0.53–0.84)

0≤0.61.4

Synonymous OE?1.60

0≤1.21.6

LoF obs/exp: 1 / 4.5Missense obs/exp: 53 / 79.5Syn Z: -2.88

Background carrier burden — how many people carry a rare variant somewhere in TWIST1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 260

298 rare PASS variants

Rare truncating (LoF)

1 in 22,000

25 rare PASS variants

Rare synonymous (reference)

1 in 160

177 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TWIST1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 270	1 in 22,000
South Asian	~43k	1 in 260	≈ 1 in 34,000
Remaining (unassigned)	~30k	1 in 280	≈ 1 in 26,000
European (Finnish)	~27k	1 in 500	none seen
Admixed American	~22k	1 in 190	none seen
African / African American	~21k	1 in 240	none seen
East Asian	~20k	1 in 460	≈ 1 in 14,000
Ashkenazi Jewish	~13k	1 in 460	≈ 1 in 3,400
Middle Eastern	~2,884	1 in 360	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.