Baraitser-Winter syndrome 1

Summary

Baraitser-Winter syndrome 1 (MONDO:0009470) is a disease caused by ACTB (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: ACTB (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 484

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Baraitser-Winter syndrome 1
Mondo ID	MONDO:0009470
OMIM	243310
DOID	DOID:0081112
UMLS	C1855722
MedGen	340943
GARD	0015189
Is cancer (heuristic)	no

Also known as: ACTB Baraitser-Winter cerebrofrontofacial syndrome · ACTB-related BAFopathy · Baraitser-Winter cerebrofrontofacial syndrome caused by mutation in ACTB · Baraitser-Winter syndrome 1 · Baraitser-Winter syndrome type 1 · BRWS1 · cerebrofrontofacial syndrome · Fryns-Aftimos syndrome · iris coloboma with ptosis, hypertelorism, and mental retardation · mental retardation with epilepsy and characteristic facies · pachygyria, mental retardation, epilepsy, and characteristic facies

Data availability: 484 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Baraitser-Winter cerebrofrontofacial syndrome › Baraitser-Winter syndrome 1

Related subtypes (1): Baraitser-winter syndrome 2

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

484 retrieved; paginated sample, class counts are floors:

264 likely benign, 99 uncertain significance, 30 likely pathogenic, 25 conflicting classifications of pathogenicity, 25 pathogenic, 19 benign/likely benign, 12 benign, 10 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1196724	NM_001101.5(ACTB):c.158A>G (p.Tyr53Cys)	ACTB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
127166	NM_001101.5(ACTB):c.34A>C (p.Asn12His)	ACTB	Pathogenic	no assertion criteria provided
127167	NM_001101.5(ACTB):c.356T>C (p.Met119Thr)	ACTB	Pathogenic	criteria provided, single submitter
127168	NM_001101.5(ACTB):c.359C>T (p.Thr120Ile)	ACTB	Pathogenic	no assertion criteria provided
127169	NM_001101.5(ACTB):c.446C>T (p.Thr149Ile)	ACTB	Pathogenic	no assertion criteria provided
127170	NM_001101.5(ACTB):c.586C>A (p.Arg196Ser)	ACTB	Pathogenic	no assertion criteria provided
127171	NM_001101.5(ACTB):c.611C>G (p.Ala204Gly)	ACTB	Pathogenic	criteria provided, single submitter
127172	NM_001101.5(ACTB):c.625G>A (p.Val209Met)	ACTB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1334712	NM_001101.5(ACTB):c.439C>T (p.Arg147Cys)	ACTB	Pathogenic	criteria provided, multiple submitters, no conflicts
1685500	NM_001101.5(ACTB):c.141G>A (p.Met47Ile)	ACTB	Pathogenic	criteria provided, single submitter
18275	NM_001101.5(ACTB):c.547C>T (p.Arg183Trp)	ACTB	Pathogenic	criteria provided, multiple submitters, no conflicts
203375	NM_001101.5(ACTB):c.123+1G>A	ACTB	Pathogenic	criteria provided, single submitter
2159436	NM_001101.5(ACTB):c.511C>T (p.Leu171Phe)	ACTB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2445203	NM_001101.5(ACTB):c.220G>T (p.Gly74Cys)	ACTB	Pathogenic	criteria provided, single submitter
264642	NM_001101.5(ACTB):c.802G>C (p.Gly268Arg)	ACTB	Pathogenic	no assertion criteria provided
265318	NM_001101.5(ACTB):c.617G>A (p.Arg206Gln)	ACTB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
279997	NM_001101.5(ACTB):c.1043C>T (p.Ser348Leu)	ACTB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
29599	NM_001101.5(ACTB):c.587G>A (p.Arg196His)	ACTB	Pathogenic	criteria provided, multiple submitters, no conflicts
29600	NM_001101.5(ACTB):c.586C>T (p.Arg196Cys)	ACTB	Pathogenic	criteria provided, multiple submitters, no conflicts
29601	NM_001101.5(ACTB):c.193C>G (p.Leu65Val)	ACTB	Pathogenic	no assertion criteria provided
29602	NM_001101.5(ACTB):c.34A>G (p.Asn12Asp)	ACTB	Pathogenic	no assertion criteria provided
3075716	NM_001101.5(ACTB):c.355A>G (p.Met119Val)	ACTB	Pathogenic	criteria provided, single submitter
418804	NM_001101.5(ACTB):c.629G>A (p.Arg210His)	ACTB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
431099	NM_001101.5(ACTB):c.351G>T (p.Glu117Asp)	ACTB	Pathogenic	criteria provided, single submitter
438274	NM_001101.5(ACTB):c.350A>T (p.Glu117Val)	ACTB	Pathogenic	no assertion criteria provided
449190	NM_001101.5(ACTB):c.826G>A (p.Glu276Lys)	ACTB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4685516	NM_001101.5(ACTB):c.901G>A (p.Gly301Ser)	ACTB	Pathogenic	criteria provided, single submitter
495294	NM_001101.5(ACTB):c.1097dup (p.Ser368fs)	ACTB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
495295	NM_001101.5(ACTB):c.1117A>T (p.Lys373Ter)	ACTB	Pathogenic	no assertion criteria provided
495296	NM_001101.5(ACTB):c.329del (p.Leu110fs)	ACTB	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 9 · 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
ACTB	Definitive	Autosomal dominant	Baraitser-Winter cerebrofrontofacial syndrome	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ACTB	Orphanet:2995	Baraitser-Winter cerebrofrontofacial syndrome
ACTB	Orphanet:64755	Becker nevus syndrome
ACTB	Orphanet:673556	Pseudomyogenic hemangioendothelioma
ACTB	Orphanet:674653	Actinomyopathy-associated syndromic thrombocytopenia
ACTB	Orphanet:79107	Developmental malformations-deafness-dystonia syndrome
ACTG1	Orphanet:2995	Baraitser-Winter cerebrofrontofacial syndrome
ACTG1	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
ACTG1	Orphanet:98942	Coloboma of choroid and retina
ACTG1	Orphanet:98944	Coloboma of iris

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ACTB	HGNC:132	ENSG00000075624	P60709	Actin, cytoplasmic 1	gencc,clinvar
ACTG1	HGNC:144	ENSG00000184009	P63261	Actin, cytoplasmic 2	clinvar
RADIL	HGNC:22226	ENSG00000157927	Q96JH8	Ras-associating and dilute domain-containing protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ACTB	Actin, cytoplasmic 1	Actin is a highly conserved protein that polymerizes to produce filaments that form cross-linked networks in the cytoplasm of cells.
ACTG1	Actin, cytoplasmic 2	Actins are highly conserved proteins that are involved in various types of cell motility and are ubiquitously expressed in all eukaryotic cells.
RADIL	Ras-associating and dilute domain-containing protein	Downstream effector of Rap required for cell adhesion and migration of neural crest precursors during development.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · 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
Scaffold/PPI	1	5.8×	0.327
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ACTB	Other/Unknown	no		Actin, Actin_CS, Actin/actin-like_CS
ACTG1	Other/Unknown	no		Actin, Actin_CS, Actin/actin-like_CS
RADIL	Scaffold/PPI	no		RA_dom, FHA_dom, PDZ

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
postcentral gyrus	1
saphenous vein	1
urethra	1
amniotic fluid	1
ileal mucosa	1
ventricular zone	1
cerebellar vermis	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ACTB	295	ubiquitous	marker	urethra, postcentral gyrus, saphenous vein
ACTG1	288	ubiquitous	marker	ileal mucosa, ventricular zone, amniotic fluid
RADIL	193	broad	yes	oocyte, secondary oocyte, cerebellar vermis

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RADIL	2,430
ACTB	2,212
ACTG1	1,017

Intra-cohort edges

A	B	Sources
ACTB	ACTG1	biogrid_interaction, intact

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ACTB	P60709	88
ACTG1	P63261	10
RADIL	Q96JH8	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 102. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Formation of annular gap junctions	2	1038.2×	3e-05	ACTB, ACTG1
GBP-mediated host defense	2	1038.2×	3e-05	ACTB, ACTG1
Gap junction degradation	2	951.7×	3e-05	ACTB, ACTG1
Regulation of CDH1 Function	2	951.7×	3e-05	ACTB, ACTG1
Cell-extracellular matrix interactions	2	671.8×	4e-05	ACTB, ACTG1
Gap junction trafficking and regulation	2	475.8×	6e-05	ACTB, ACTG1
Gap junction trafficking	2	475.8×	6e-05	ACTB, ACTG1
Signaling by RAS mutants	2	423.0×	6e-05	ACTB, ACTG1
Interaction between L1 and Ankyrins	2	368.4×	6e-05	ACTB, ACTG1
RHO GTPases activate IQGAPs	2	346.1×	6e-05	ACTB, ACTG1
Parasite infection	2	346.1×	6e-05	ACTB, ACTG1
Leishmania phagocytosis	2	346.1×	6e-05	ACTB, ACTG1
RHO GTPases Activate WASPs and WAVEs	2	317.2×	6e-05	ACTB, ACTG1
Signaling by high-kinase activity BRAF mutants	2	317.2×	6e-05	ACTB, ACTG1
Sensory processing of sound	2	308.6×	6e-05	ACTB, ACTG1
Formation of the dystrophin-glycoprotein complex (DGC)	2	308.6×	6e-05	ACTB, ACTG1
MAP2K and MAPK activation	2	285.5×	6e-05	ACTB, ACTG1
Fcgamma receptor (FCGR) dependent phagocytosis	2	278.5×	6e-05	ACTB, ACTG1
Signaling by RAF1 mutants	2	278.5×	6e-05	ACTB, ACTG1
EPHB-mediated forward signaling	2	265.6×	6e-05	ACTB, ACTG1
Signaling by moderate kinase activity BRAF mutants	2	253.8×	6e-05	ACTB, ACTG1
Paradoxical activation of RAF signaling by kinase inactive BRAF	2	253.8×	6e-05	ACTB, ACTG1
Signaling downstream of RAS mutants	2	253.8×	6e-05	ACTB, ACTG1
Adherens junctions interactions	2	248.3×	6e-05	ACTB, ACTG1
Cell-cell junction organization	2	248.3×	6e-05	ACTB, ACTG1
Oncogenic MAPK signaling	2	248.3×	6e-05	ACTB, ACTG1
Recycling pathway of L1	2	223.9×	7e-05	ACTB, ACTG1
Signaling by VEGF	2	219.6×	7e-05	ACTB, ACTG1
EPH-ephrin mediated repulsion of cells	2	219.6×	7e-05	ACTB, ACTG1
Sensory processing of sound by outer hair cells of the cochlea	2	203.9×	8e-05	ACTB, ACTG1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
morphogenesis of a polarized epithelium	2	2808.7×	3e-06	ACTB, ACTG1
regulation of transepithelial transport	2	2808.7×	3e-06	ACTB, ACTG1
regulation of synaptic vesicle endocytosis	2	591.3×	6e-05	ACTB, ACTG1
maintenance of blood-brain barrier	2	321.0×	2e-04	ACTB, ACTG1
cell motility	2	267.5×	2e-04	ACTB, ACTG1
platelet aggregation	2	224.7×	2e-04	ACTB, ACTG1
axonogenesis	2	107.0×	8e-04	ACTB, ACTG1
positive regulation of norepinephrine uptake	1	5617.3×	9e-04	ACTB
cellular response to cytochalasin B	1	5617.3×	9e-04	ACTB
regulation of norepinephrine uptake	1	2808.7×	0.002	ACTB
protein localization to adherens junction	1	1123.5×	0.004	ACTB
protein localization to bicellular tight junction	1	936.2×	0.004	ACTG1
tight junction assembly	1	802.5×	0.005	ACTG1
adherens junction assembly	1	432.1×	0.008	ACTB
apical protein localization	1	330.4×	0.009	ACTB
regulation of stress fiber assembly	1	330.4×	0.009	ACTG1
regulation of G0 to G1 transition	1	224.7×	0.012	ACTB
regulation of protein localization to plasma membrane	1	216.1×	0.012	ACTB
regulation of focal adhesion assembly	1	200.6×	0.012	ACTG1
regulation of nucleotide-excision repair	1	200.6×	0.012	ACTB
regulation of double-strand break repair	1	193.7×	0.012	ACTB
positive regulation of wound healing	1	175.5×	0.012	ACTG1
regulation of mitotic metaphase/anaphase transition	1	165.2×	0.013	ACTB
positive regulation of T cell differentiation	1	151.8×	0.013	ACTB
establishment or maintenance of cell polarity	1	133.8×	0.013	ACTB
sarcomere organization	1	127.7×	0.013	ACTG1
positive regulation of double-strand break repair via homologous recombination	1	127.7×	0.013	ACTB
substantia nigra development	1	122.1×	0.013	ACTB
positive regulation of myoblast differentiation	1	122.1×	0.013	ACTB
substrate adhesion-dependent cell spreading	1	114.6×	0.013	RADIL

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ACTB	1	2
ACTG1	0	0
RADIL	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	ACTB

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
ACTB	21	Binding:21

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	ACTB

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	1	ACTB
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	ACTG1, RADIL

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ACTG1	0	ACTB
RADIL	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.