TWIST2

Chr 2ADAR

twist family bHLH transcription factor 2

Also known as: AMS, BBRSAY, DERMO1, FFDD3, SETLSS, bHLHa39

NCBI Gene: 117581 ENSG00000233608 UniProt: Q8WVJ9 OMIM: 607556

TWIST2 encodes a basic helix-loop-helix transcription factor that binds E-box DNA sequences to regulate gene expression, inhibiting muscle differentiation and osteoblast maturation while repressing inflammatory cytokine expression. Mutations cause focal facial dermal dysplasia type 3 (Setleis type), characterized by distinctive facial features and skin abnormalities. This condition follows an autosomal dominant inheritance pattern.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a basic helix-loop-helix type transcription factor and shares similarity with Twist. This protein may inhibit osteoblast maturation and maintain cells in a preosteoblast phenotype during osteoblast development. This gene may be upregulated in certain cancers. Mutations in this gene cause focal facial dermal dysplasia 3, Setleis type. Two transcript variants encoding the same protein have been found. [provided by RefSeq, Apr 2014]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Ablepharon-macrostomia syndromeMIM #200110

Barber-Say syndromeMIM #209885

Focal facial dermal dysplasia 3, Setleis typeMIM #227260

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Ablepharon-macrostomia syndrome; Barber-Say syndrome (+1); no ClinGen or GenCC tier

Interpreting a novel variant

The dominant disease is caused by dominant-negative changes and the recessive disease by loss of function (Gene2Phenotype). A single heterozygous truncating variant therefore fits the recessive disease and does not by itself explain a dominant presentation; a novel missense has to be read against the dominant mechanism.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.15

LOEUF

Multiple*

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

1.15LOEUF

pLI 0.560

Z-score 1.46

OE 0.00 (0.00–1.15)

Moderately constrained

Highly tolerant — LoF variants common in population

Missense Constraint?

2.13Z-score

OE missense 0.37 (0.28–0.49)

33 obs / 89.9 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–1.15)

0≤0.351.4

Missense OE?0.37 (0.28–0.49)

0≤0.61.4

Synonymous OE?0.62

0≤1.21.6

LoF obs/exp: 0 / 2.5Missense obs/exp: 33 / 89.9Syn Z: 1.88

Background carrier burden — how many people carry a rare variant somewhere in TWIST2?

gnomAD v4 · ~720k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 800

178 rare PASS variants

Rare truncating (LoF)

1 in 34,000

7 rare PASS variants

Rare synonymous (reference)

1 in 1,200

94 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TWIST2. 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)	~552k	1 in 820	1 in 29,000
South Asian	~41k	1 in 540	none seen
Remaining (unassigned)	~30k	1 in 510	≈ 1 in 9,100
European (Finnish)	~25k	1 in 460	none seen
Admixed American	~21k	1 in 730	1 in 4,100
African / African American	~21k	1 in 760	none seen
East Asian	~19k	1 in 950	none seen
Ashkenazi Jewish	~13k	1 in 1,800	none seen
Middle Eastern	~2,877	≈ 1 in 940	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.

Exome coverage (gnomAD): All 1 coding exons well covered in gnomAD exomes and genomes.? see exons ↓