Blepharophimosis

Summary

Blepharophimosis (MONDO:0001008) is a disease with 8 cohort genes and 1 clinical trial.

At a glance

• Cohort genes: 8
• ClinVar variants: 13
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	blepharophimosis
Mondo ID	MONDO:0001008
MeSH	D016569
DOID	DOID:10348
ICD-10-CM	H02.52
UMLS	C0005744
MedGen	2670
Is cancer (heuristic)	no

Also known as: blepharophimosis · blepharophimosis (disease)

Data availability: 13 ClinVar variants · 1 HPO phenotype.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye adnexa disorder › eyelid disorder › blepharophimosis

Related subtypes (19): eyelid degenerative disorder, hypertrichosis of eyelid, hypotrichosis of eyelid, entropion, lagophthalmos, stenosis of lacrimal punctum, stenosis of lacrimal passage, ectropion, eyelid neoplasm, blepharochalasis, blepharitis, eyelid hypopigmentation, telecanthus, cryptophthalmia, epiblepharon, congenital eyelid retraction, herpes zoster with dermatitis of eyelid, eyelid seborrheic keratosis, dermatosis of eyelid

Subtypes (2): Krauss Herman Holmes syndrome, Krieble Bixler 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

13 retrieved; paginated sample, class counts are floors:

7 pathogenic, 4 uncertain significance, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
268016	46;XY;inv(1)(p22.3p34.1)dn		Pathogenic	criteria provided, single submitter
242863	Single allele	ARID1B	Pathogenic	criteria provided, single submitter
242864	NM_001374828.1(ARID1B):c.3577_3578del (p.Lys1193fs)	ARID1B	Pathogenic	criteria provided, single submitter
242865	NM_001374828.1(ARID1B):c.2516_2518delinsTCCGCAGCCACTCC (p.Pro839fs)	ARID1B	Pathogenic	criteria provided, single submitter
242866	NM_001374828.1(ARID1B):c.4642dup (p.Tyr1548fs)	ARID1B	Pathogenic	criteria provided, multiple submitters, no conflicts
242867	NM_001374828.1(ARID1B):c.3151C>T (p.Gln1051Ter)	ARID1B	Pathogenic	criteria provided, multiple submitters, no conflicts
3384077	NM_023067.4(FOXL2):c.926del (p.Pro309fs)	FOXL2	Pathogenic	criteria provided, single submitter
523499	NM_012330.4(KAT6B):c.3399_3402del (p.Arg1133fs)	KAT6B	Likely pathogenic	criteria provided, single submitter
979174	NM_003070.5(SMARCA2):c.1538G>A (p.Gly513Asp)	SMARCA2	Likely pathogenic	criteria provided, single submitter
635772	GRCh37/hg19 14q24.1(chr14:68126321-68269053)x3	ARG2	Uncertain significance	no assertion criteria provided
523539	NM_031407.7(HUWE1):c.6485G>C (p.Arg2162Pro)	HUWE1	Uncertain significance	criteria provided, single submitter
559504	GRCh37/hg19 5q31.1(chr5:131484039-132998360)x3	IRF1	Uncertain significance	no assertion criteria provided
1252000	NM_152381.6(XIRP2):c.3085T>A (p.Phe1029Ile)	XIRP2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 12 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FOXL2	Orphanet:572333	Blepharophimosis-ptosis-epicanthus inversus syndrome plus
FOXL2	Orphanet:572354	Blepharophimosis-ptosis-epicanthus inversus syndrome type 1
FOXL2	Orphanet:572361	Blepharophimosis-ptosis-epicanthus inversus syndrome type 2
FOXL2	Orphanet:99915	Malignant granulosa cell tumor of the ovary
SMARCA2	Orphanet:3051	Nicolaides-Baraitser syndrome
SMARCA2	Orphanet:637013	SMARCA2-related blepharophimosis-intellectual disability syndrome
KAT6B	Orphanet:3047	Blepharophimosis-intellectual disability syndrome, SBBYS type
KAT6B	Orphanet:85201	Genitopatellar syndrome
ARID1B	Orphanet:1465	Coffin-Siris syndrome
ARID1B	Orphanet:251056	6q25.2q25.3 microdeletion syndrome
HUWE1	Orphanet:528084	Non-specific syndromic intellectual disability
IRF1	Orphanet:699615	Severe mendelian susceptibility to mycobacterial diseases due to complete IRF1 deficiency

Cohort genes → proteins

8 cohort genes, 8 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	8

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FOXL2	HGNC:1092	ENSG00000183770	P58012	Forkhead box protein L2	clinvar
SMARCA2	HGNC:11098	ENSG00000080503	P51531	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 2	clinvar
XIRP2	HGNC:14303	ENSG00000163092	A4UGR9	Xin actin-binding repeat-containing protein 2	clinvar
KAT6B	HGNC:17582	ENSG00000156650	Q8WYB5	Histone acetyltransferase KAT6B	clinvar
ARID1B	HGNC:18040	ENSG00000049618	Q8NFD5	AT-rich interactive domain-containing protein 1B	clinvar
HUWE1	HGNC:30892	ENSG00000086758	Q7Z6Z7	E3 ubiquitin-protein ligase HUWE1	clinvar
IRF1	HGNC:6116	ENSG00000125347	P10914	Interferon regulatory factor 1	clinvar
ARG2	HGNC:664	ENSG00000081181	P78540	Arginase-2, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FOXL2	Forkhead box protein L2	Transcriptional regulator.
SMARCA2	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 2	ATPase involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).
XIRP2	Xin actin-binding repeat-containing protein 2	Protects actin filaments from depolymerization.
KAT6B	Histone acetyltransferase KAT6B	Histone acetyltransferase which may be involved in both positive and negative regulation of transcription.
ARID1B	AT-rich interactive domain-containing protein 1B	Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).
HUWE1	E3 ubiquitin-protein ligase HUWE1	E3 ubiquitin-protein ligase which mediates ubiquitination and subsequent proteasomal degradation of target proteins.
IRF1	Interferon regulatory factor 1	Transcriptional regulator which displays a remarkable functional diversity in the regulation of cellular responses.
ARG2	Arginase-2, mitochondrial	May play a role in the regulation of extra-urea cycle arginine metabolism and also in down-regulation of nitric oxide synthesis.

Protein-family classification

Druggable: 2 · Difficult: 2 · Unknown: 4 · Druggable fraction: 0.25

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
Enzyme (other)	2	3.0×	0.377
Transcription factor	2	2.1×	0.377
Other/Unknown	4	0.9×	0.755

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FOXL2	Transcription factor	no		Fork_head_dom, TF_fork_head_CS_1, TF_fork_head_CS_2
SMARCA2	Other/Unknown	no		SNF2_N, Bromodomain, Helicase_C-like
XIRP2	Other/Unknown	no		Actin-binding_Xin_repeat, XIRP1/XIRP2
KAT6B	Transcription factor	no	2.3.1.48	Znf_PHD, HAT_MYST-type, Histone_H1/H5_H15
ARID1B	Other/Unknown	no		ARID_dom, BAF250/Osa, BAF250_C
HUWE1	Enzyme (other)	yes	2.3.2.26	HECT_dom, WWE_dom, UBA-like_sf
IRF1	Other/Unknown	no		Interferon_reg_fact_DNA-bd_dom, IRF1/IRF2, Interferon_reg_fac_CS
ARG2	Enzyme (other)	yes	3.5.3.1	Ureohydrolase, Arginase, Ureohydrolase_Mn_BS

Expression context

Cohort genes with no expression data: 0.

7 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)	8
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	3
colonic epithelium	2
sural nerve	2
left ovary	1
ovary	1
stromal cell of endometrium	1
calcaneal tendon	1
biceps brachii	1
deltoid	1
quadriceps femoris	1
ventricular zone	1
bone marrow cell	1
right lobe of thyroid gland	1
skin of abdomen	1
skin of leg	1
granulocyte	1
leukocyte	1
monocyte	1
oocyte	1
tendon of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FOXL2	84	broad	marker	left ovary, stromal cell of endometrium, ovary
SMARCA2	301	ubiquitous	marker	calcaneal tendon, colonic epithelium, cortical plate
XIRP2	150	tissue_specific	marker	deltoid, biceps brachii, quadriceps femoris
KAT6B	140	ubiquitous	yes	cortical plate, ventricular zone, sural nerve
ARID1B	256	ubiquitous	marker	bone marrow cell, colonic epithelium, sural nerve
HUWE1	300	ubiquitous	marker	skin of leg, skin of abdomen, right lobe of thyroid gland
IRF1	265	ubiquitous	marker	granulocyte, monocyte, leukocyte
ARG2	269	ubiquitous	marker	tendon of biceps brachii, oocyte, cortical plate

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HUWE1	5,793
SMARCA2	4,237
IRF1	4,076
ARG2	3,757
KAT6B	2,214
ARID1B	2,131
XIRP2	1,735
FOXL2	1,727

Intra-cohort edges

A	B	Sources
ARID1B	SMARCA2	biogrid_interaction, string_interaction

Structural data

PDB: 7 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SMARCA2	P51531	32
HUWE1	Q7Z6Z7	19
ARG2	P78540	18
KAT6B	Q8WYB5	3
FOXL2	P58012	2
ARID1B	Q8NFD5	2
XIRP2	A4UGR9	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
IRF1	P10914	66.65

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 42. Enrichment computed across 8 evidence-associated genes (8 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 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Formation of the canonical BAF (cBAF) complex	2	158.6×	0.001	SMARCA2, ARID1B
Formation of neuronal progenitor and neuronal BAF (npBAF and nBAF)	2	114.2×	0.001	SMARCA2, ARID1B
Chromatin organization	3	30.6×	0.001	SMARCA2, KAT6B, ARID1B
Chromatin modifying enzymes	3	27.1×	0.001	SMARCA2, KAT6B, ARID1B
Regulation of endogenous retroelements	2	92.1×	0.002	SMARCA2, ARID1B
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	2	75.1×	0.002	SMARCA2, ARID1B
Regulation of MITF-M-dependent genes involved in pigmentation	2	66.4×	0.002	SMARCA2, ARID1B
MITF-M-dependent gene expression	2	45.3×	0.004	SMARCA2, ARID1B
RMTs methylate histone arginines	2	36.6×	0.005	SMARCA2, ARID1B
Transcriptional regulation by RUNX1	2	36.6×	0.005	SMARCA2, ARID1B
Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs)	2	29.4×	0.007	SMARCA2, ARID1B
MITF-M-regulated melanocyte development	2	28.6×	0.007	SMARCA2, ARID1B
Epigenetic regulation of gene expression	2	17.8×	0.017	SMARCA2, ARID1B
Urea cycle	1	109.8×	0.027	ARG2
Regulated Necrosis	1	89.2×	0.029	IRF1
Transcriptional regulation of testis differentiation	1	89.2×	0.029	FOXL2
Formation of the non-canonical BAF (ncBAF) complex	1	84.0×	0.029	SMARCA2
Formation of the polybromo-BAF (pBAF) complex	1	79.3×	0.029	SMARCA2
SUMOylation of transcription factors	1	71.4×	0.031	FOXL2
Pyroptosis	1	52.9×	0.039	IRF1
Sensory processing of sound by outer hair cells of the cochlea	1	25.5×	0.077	XIRP2
Sensory processing of sound by inner hair cells of the cochlea	1	20.4×	0.088	XIRP2
RNA Polymerase II Transcription	2	5.6×	0.088	SMARCA2, ARID1B
Interferon alpha/beta signaling	1	19.0×	0.090	IRF1
Programmed Cell Death	1	18.3×	0.090	IRF1
Interferon gamma signaling	1	15.7×	0.100	IRF1
Interferon Signaling	1	15.0×	0.100	IRF1
Mitochondrial protein degradation	1	14.3×	0.100	ARG2
Regulation of PD-L1(CD274) transcription	1	13.6×	0.100	IRF1
Gene expression (Transcription)	2	4.5×	0.100	SMARCA2, ARID1B

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of DNA-templated transcription	5	17.5×	3e-04	FOXL2, SMARCA2, KAT6B, ARID1B, IRF1
regulation of G0 to G1 transition	2	168.5×	0.002	SMARCA2, ARID1B
regulation of nucleotide-excision repair	2	150.5×	0.002	SMARCA2, ARID1B
negative regulation of DNA-templated transcription	4	15.8×	0.002	FOXL2, SMARCA2, KAT6B, IRF1
regulation of mitotic metaphase/anaphase transition	2	123.9×	0.002	SMARCA2, ARID1B
positive regulation of T cell differentiation	2	113.9×	0.002	SMARCA2, ARID1B
positive regulation of myoblast differentiation	2	91.6×	0.003	SMARCA2, ARID1B
positive regulation of double-strand break repair	2	86.0×	0.003	SMARCA2, ARID1B
regulation of transcription by RNA polymerase II	5	7.3×	0.003	FOXL2, SMARCA2, KAT6B, ARID1B, IRF1
regulation of G1/S transition of mitotic cell cycle	2	76.6×	0.003	SMARCA2, ARID1B
female somatic sex determination	1	2106.5×	0.003	FOXL2
granulosa cell differentiation	1	2106.5×	0.003	FOXL2
negative regulation of chemokine (C-C motif) ligand 4 production	1	2106.5×	0.003	ARG2
positive regulation of cell differentiation	2	66.9×	0.003	SMARCA2, ARID1B
regulation of MyD88-dependent toll-like receptor signaling pathway	1	1053.2×	0.006	IRF1
negative regulation of activated CD8-positive, alpha-beta T cell apoptotic process	1	1053.2×	0.006	ARG2
CD8-positive, alpha-beta T cell differentiation	1	702.2×	0.007	IRF1
negative regulation of macrophage inflammatory protein 1 alpha production	1	702.2×	0.007	ARG2
negative regulation of defense response to bacterium	1	702.2×	0.007	ARG2
regulation of CD8-positive, alpha-beta T cell proliferation	1	702.2×	0.007	IRF1
oocyte growth	1	526.6×	0.009	FOXL2
positive regulation of luteinizing hormone secretion	1	421.3×	0.010	FOXL2
negative regulation of regulatory T cell differentiation	1	421.3×	0.010	IRF1
extraocular skeletal muscle development	1	351.1×	0.010	FOXL2
negative regulation of type 2 immune response	1	351.1×	0.010	ARG2
negative regulation of peroxisome proliferator activated receptor signaling pathway	1	351.1×	0.010	HUWE1
positive regulation of follicle-stimulating hormone secretion	1	351.1×	0.010	FOXL2
negative regulation of chemokine (C-C motif) ligand 5 production	1	351.1×	0.010	ARG2
arginine metabolic process	1	300.9×	0.010	ARG2
negative regulation of interleukin-13 production	1	300.9×	0.010	ARG2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 2 · Undrugged: 6

Druggability breadth: 4 of 8 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SMARCA2	2	2
ARG2	2	2
FOXL2	0	0
XIRP2	0	0
KAT6B	0	0
ARID1B	0	0
HUWE1	0	0
IRF1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	SMARCA2
CAMIBIRSTAT	2	SMARCA2
NUMIDARGISTAT	2	ARG2
NOR-NOHA	1	ARG2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
SMARCA2	311	Binding:274, Functional:25, ADMET:12
ARG2	37	Binding:34, Functional:3
KAT6B	22	Binding:20, Functional:2
HUWE1	4	Binding:3, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
KAT6B	2.3.1.48	histone acetyltransferase
HUWE1	2.3.2.26	HECT-type E3 ubiquitin transferase
ARG2	3.5.3.1	arginase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
SMARCA2	311

Pharmacogenomics

Cohort genes with a PharmGKB record: 8; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

4 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	SMARCA2
CAMIBIRSTAT	2	SMARCA2
NUMIDARGISTAT	2	ARG2
NOR-NOHA	1	ARG2

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	2	SMARCA2, ARG2
C	Druggable family + PDB, no drug	1	HUWE1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	5	FOXL2, XIRP2, KAT6B, ARID1B, IRF1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
FOXL2	0	—
XIRP2	0	—
KAT6B	22	—
ARID1B	0	—
HUWE1	4	—
IRF1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06514612	PHASE3	RECRUITING	LIDRISE Study: A Phase 3 Study on the Efficacy and Safety of STN1013800 (Oxymetazoline HCl 0.1% Eye Drops, Single Dose) in the Treatment of Acquired Blepharoptosis.