Barber-Say syndrome

Summary

Barber-Say syndrome (MONDO:0008853) is a disease caused by TWIST2 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TWIST2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 3
• Phenotypes (HPO): 23

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		16	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

23 HPO clinical features (Orphanet curated; top 23 by frequency):

HPO ID	Term	Frequency
HP:0000154	Wide mouth	Very frequent (80-99%)
HP:0000271	Abnormality of the face	Very frequent (80-99%)
HP:0000316	Hypertelorism	Very frequent (80-99%)
HP:0000365	Hearing impairment	Very frequent (80-99%)
HP:0000414	Bulbous nose	Very frequent (80-99%)
HP:0000431	Wide nasal bridge	Very frequent (80-99%)
HP:0000463	Anteverted nares	Very frequent (80-99%)
HP:0000506	Telecanthus	Very frequent (80-99%)
HP:0000656	Ectropion	Very frequent (80-99%)
HP:0000684	Delayed eruption of teeth	Very frequent (80-99%)
HP:0001508	Failure to thrive	Very frequent (80-99%)
HP:0001582	Redundant skin	Very frequent (80-99%)
HP:0002230	Generalized hirsutism	Very frequent (80-99%)
HP:0008065	Aplasia/Hypoplasia of the skin	Very frequent (80-99%)
HP:0100840	Aplasia/Hypoplasia of the eyebrow	Very frequent (80-99%)
HP:0200102	Sparse or absent eyelashes	Very frequent (80-99%)
HP:0000974	Hyperextensible skin	Frequent (30-79%)
HP:0002557	Hypoplastic nipples	Frequent (30-79%)
HP:0100783	Breast aplasia	Frequent (30-79%)
HP:0000049	Shawl scrotum	Occasional (5-29%)
HP:0000377	Abnormal pinna morphology	Occasional (5-29%)
HP:0000413	Atresia of the external auditory canal	Occasional (5-29%)
HP:0011224	Ablepharon	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Barber-Say syndrome
Mondo ID	MONDO:0008853
MeSH	C537908
OMIM	209885
Orphanet	1231
DOID	DOID:0060549
ICD-11	37248895
SNOMED CT	408537003
UMLS	C1319466
MedGen	230818
GARD	0000819
NORD	875
Is cancer (heuristic)	no

Also known as: Barber Say syndrome · Barber-Say syndrome · BBRSAY · Brown Séquard Syndrome · hypertrichosis atrophic skin ectropion macrostomia · hypertrichosis, atrophic skin, ectropion, and macrostomia · hypertrichosis-atrophic skin-ectropion-macrostomia syndrome

Data availability: 3 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye adnexa disorder › eyelid disorder › hypertrichosis of eyelid › Barber-Say syndrome

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

3 retrieved; paginated sample, class counts are floors:

3 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
208076	NM_001271893.4(TWIST2):c.224A>C (p.Glu75Ala)	TWIST2	Pathogenic	no assertion criteria provided
208078	NM_001271893.4(TWIST2):c.223G>C (p.Glu75Gln)	TWIST2	Pathogenic	criteria provided, multiple submitters, no conflicts
208079	NM_001271893.4(TWIST2):c.229_234dup (p.Gln77_Arg78dup)	TWIST2	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
TWIST2	Strong	Autosomal dominant	Barber-Say syndrome	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TWIST2	Orphanet:1231	Barber-Say syndrome
TWIST2	Orphanet:1807	Focal facial dermal dysplasia type III
TWIST2	Orphanet:920	Ablepharon macrostomia syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TWIST2	HGNC:20670	ENSG00000233608	Q8WVJ9	Twist-related protein 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TWIST2	Twist-related protein 2	Binds to the E-box consensus sequence 5’-CANNTG-3’ as a heterodimer and inhibits transcriptional activation by MYOD1, MYOG, MEF2A and MEF2C.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TWIST2	Transcription factor	no		bHLH_dom, HLH_DNA-bd_sf, Twist2_bHLH

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ectocervix	1
endocervix	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TWIST2	126	broad	marker	stromal cell of endometrium, endocervix, ectocervix

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TWIST2	1,730

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TWIST2	Q8WVJ9	73.94

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Transcriptional regulation by RUNX2	1	253.8×	0.008	TWIST2
Negative Regulation of CDH1 Gene Transcription	1	120.2×	0.008	TWIST2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
developmental process	1	674.1×	0.009	TWIST2
negative regulation of osteoblast differentiation	1	295.6×	0.010	TWIST2
positive regulation of cell migration	1	61.7×	0.032	TWIST2
negative regulation of DNA-templated transcription	1	31.6×	0.041	TWIST2
cell differentiation	1	29.1×	0.041	TWIST2
regulation of transcription by RNA polymerase II	1	11.7×	0.086	TWIST2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TWIST2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	TWIST2

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
TWIST2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.