Congenital ptosis

Summary

Congenital ptosis (MONDO:0008340) is a disease with 5 cohort genes and 5 clinical trials.

At a glance

• Prevalence: Unknown (Worldwide)
• Cohort genes: 5
• ClinVar variants: 3
• Clinical trials: 5

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital ptosis
Mondo ID	MONDO:0008340
MeSH	C566737
Orphanet	91411
DOID	DOID:0060261
NCIT	C27049
SNOMED CT	268163008
UMLS	C1867438
MedGen	357987
GARD	0016798
MedDRA	10015996
Is cancer (heuristic)	no

Also known as: congenital eyelid ptosis · congenital ptosis (disease) · ptosis, hereditary congenital 1

Data availability: 3 ClinVar variants · 2 GenCC gene-disease records · 1 HPO phenotype · 2 cell lines.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › ptosis › congenital ptosis

Related subtypes (2): mcpherson robertson cammarano syndrome, mehta lewis patton syndrome

Subtypes (3): ptosis, hereditary congenital 2, fibrosis of extraocular muscles, congenital, 5, ptosis, hereditary congenital, 1

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:

2 pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
625873	NM_001256012.3(MYH10):c.4505G>C (p.Arg1502Pro)	MYH10	Pathogenic	criteria provided, single submitter
996741	NM_012233.3(RAB3GAP1):c.151-5T>G	RAB3GAP1	Pathogenic	no assertion criteria provided
870572	NM_001170629.2(CHD8):c.1732C>T (p.Arg578Cys)	CHD8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 8 · 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
COL25A1	Strong	Autosomal recessive	fibrosis of extraocular muscles, congenital, 5	5
ZFHX4	No Known Disease Relationship	Autosomal dominant	congenital ptosis	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
COL25A1	Orphanet:1143	Neurogenic arthrogryposis multiplex congenita
COL25A1	Orphanet:45358	Congenital fibrosis of extraocular muscles
COL25A1	Orphanet:91411	Congenital ptosis
ZFHX4	Orphanet:91411	Congenital ptosis
RAB3GAP1	Orphanet:1387	Cataract-intellectual disability-hypogonadism syndrome
RAB3GAP1	Orphanet:2510	Micro syndrome
CHD8	Orphanet:261229	14q11.2 microduplication syndrome
CHD8	Orphanet:642675	CHD8 overgrowth syndrome

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
COL25A1	HGNC:18603	ENSG00000188517	Q9BXS0	Collagen alpha-1(XXV) chain	gencc
ZFHX4	HGNC:30939	ENSG00000091656	Q86UP3	Zinc finger homeobox protein 4	gencc
RAB3GAP1	HGNC:17063	ENSG00000115839	Q15042	Rab3 GTPase-activating protein catalytic subunit	clinvar
CHD8	HGNC:20153	ENSG00000100888	Q9HCK8	ATP-dependent chromatin remodeler CHD8	clinvar
MYH10	HGNC:7568	ENSG00000133026	P35580	Myosin-10	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COL25A1	Collagen alpha-1(XXV) chain	Inhibits fibrillization of amyloid-beta peptide during the elongation phase.
ZFHX4	Zinc finger homeobox protein 4	May play a role in neural and muscle differentiation.
RAB3GAP1	Rab3 GTPase-activating protein catalytic subunit	Catalytic subunit of the Rab3 GTPase-activating (Rab3GAP) complex composed of RAB3GAP1 and RAB3GAP2, which accelerates the otherwise slow GTP hydrolysis catalyzed by Rab proteins.
CHD8	ATP-dependent chromatin remodeler CHD8	ATP-dependent chromatin-remodeling factor, it slides nucleosomes along DNA; nucleosome sliding requires ATP.
MYH10	Myosin-10	Cellular myosin that appears to play a role in cytokinesis, cell shape, and specialized functions such as secretion and capping.

Protein-family classification

Druggable: 0 · Difficult: 2 · Unknown: 3 · 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	3.5×	0.608
Transcription factor	1	1.6×	0.608
Other/Unknown	3	1.1×	0.608

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COL25A1	Other/Unknown	no		Collagen, Collagen_Structural_Proteins
ZFHX4	Transcription factor	no		HD, Matrin/U1-like-C_Znf_C2H2, Homeodomain-like_sf
RAB3GAP1	Other/Unknown	no		Rab3GAP1_conserved, Rab3GAP1_C, Rab3GAP1
CHD8	Other/Unknown	no		SNF2_N, Chromo/chromo_shadow_dom, Helicase_C-like
MYH10	Scaffold/PPI	no		IQ_motif_EF-hand-BS, Myosin_head_motor_dom-like, Myosin_tail

Expression context

Cohort genes with no expression data: 0.

5 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left testis	1
right testis	1
sperm	1
adrenal tissue	1
calcaneal tendon	1
tendon	1
Brodmann (1909) area 23	1
hair follicle	1
secondary oocyte	1
cortical plate	1
sural nerve	1
ventricular zone	1
blood vessel layer	1
right coronary artery	1
saphenous vein	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COL25A1	163	broad	marker	sperm, left testis, right testis
ZFHX4	230	ubiquitous	marker	calcaneal tendon, tendon, adrenal tissue
RAB3GAP1	300	ubiquitous	marker	hair follicle, Brodmann (1909) area 23, secondary oocyte
CHD8	283	ubiquitous	marker	sural nerve, ventricular zone, cortical plate
MYH10	300	ubiquitous	marker	blood vessel layer, saphenous vein, right coronary artery

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CHD8	4,791
MYH10	3,368
RAB3GAP1	2,039
ZFHX4	1,255
COL25A1	1,104

Structural data

PDB: 3 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CHD8	Q9HCK8	2
RAB3GAP1	Q15042	1
MYH10	P35580	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
COL25A1	Q9BXS0	57.23
ZFHX4	Q86UP3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 23. Enrichment computed across 5 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Sema4D in semaphorin signaling	1	167.9×	0.034	MYH10
RHO GTPases activate CIT	1	150.3×	0.034	MYH10
RHO GTPases Activate ROCKs	1	150.3×	0.034	MYH10
Sema4D induced cell migration and growth-cone collapse	1	142.8×	0.034	MYH10
RHO GTPases activate PAKs	1	135.9×	0.034	MYH10
Semaphorin interactions	1	98.5×	0.034	MYH10
EPHA-mediated growth cone collapse	1	95.2×	0.034	MYH10
RHO GTPases activate PKNs	1	79.3×	0.036	MYH10
Collagen chain trimerization	1	64.9×	0.039	COL25A1
Deactivation of the beta-catenin transactivating complex	1	58.3×	0.039	CHD8
COPI-independent Golgi-to-ER retrograde traffic	1	51.9×	0.039	RAB3GAP1
Collagen degradation	1	43.9×	0.039	COL25A1
Collagen biosynthesis and modifying enzymes	1	42.6×	0.039	COL25A1
EPH-Ephrin signaling	1	41.4×	0.039	MYH10
CHD6, CHD7, CHD8, CHD9 subfamily	1	37.1×	0.041	CHD8
RAB GEFs exchange GTP for GDP on RABs	1	31.0×	0.046	RAB3GAP1
RHO GTPase Effectors	1	17.0×	0.078	MYH10
Axon guidance	1	11.3×	0.109	MYH10
Nervous system development	1	10.7×	0.109	MYH10
Signaling by Rho GTPases	1	8.6×	0.125	MYH10
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	8.4×	0.125	MYH10
Developmental Biology	1	3.6×	0.261	MYH10
Signal Transduction	1	2.5×	0.339	MYH10

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
fourth ventricle development	1	1685.2×	0.011	MYH10
positive regulation of glutamate neurotransmitter secretion in response to membrane depolarization	1	1685.2×	0.011	RAB3GAP1
regulation of calcium ion-dependent exocytosis of neurotransmitter	1	1685.2×	0.011	RAB3GAP1
establishment of protein localization to endoplasmic reticulum membrane	1	1123.5×	0.011	RAB3GAP1
positive regulation of protein lipidation	1	842.6×	0.011	RAB3GAP1
positive regulation of endoplasmic reticulum tubular network organization	1	842.6×	0.011	RAB3GAP1
third ventricle development	1	674.1×	0.011	MYH10
brain development	2	31.8×	0.011	RAB3GAP1, CHD8
negative regulation of fibroblast apoptotic process	1	481.5×	0.012	CHD8
postsynaptic actin cytoskeleton organization	1	374.5×	0.012	MYH10
cardiac septum development	1	337.0×	0.012	MYH10
axonogenesis involved in innervation	1	337.0×	0.012	COL25A1
substrate-dependent cell migration, cell extension	1	306.4×	0.012	MYH10
cerebellar Purkinje cell layer development	1	306.4×	0.012	MYH10
ventricular cardiac muscle cell development	1	306.4×	0.012	MYH10
in utero embryonic development	2	28.8×	0.012	CHD8, MYH10
lateral ventricle development	1	259.3×	0.012	MYH10
cardiac myofibril assembly	1	259.3×	0.012	MYH10
adult heart development	1	240.7×	0.012	MYH10
regulation of short-term neuronal synaptic plasticity	1	224.7×	0.012	RAB3GAP1
prepulse inhibition	1	224.7×	0.012	CHD8
hypothalamus development	1	210.7×	0.012	RAB3GAP1
Rab protein signal transduction	1	198.3×	0.012	RAB3GAP1
lipid droplet organization	1	187.2×	0.012	RAB3GAP1
positive regulation of transcription by RNA polymerase III	1	187.2×	0.012	CHD8
actin filament-based movement	1	160.5×	0.013	MYH10
positive regulation of autophagosome assembly	1	160.5×	0.013	RAB3GAP1
nuclear migration	1	146.5×	0.014	MYH10
coronary vasculature development	1	124.8×	0.015	MYH10
plasma membrane repair	1	116.2×	0.015	MYH10

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 5 evidence-associated genes (40%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
MYH10	QUIZARTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MYH10	2	4
CHD8	1	2
COL25A1	0	0
ZFHX4	0	0
RAB3GAP1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
QUIZARTINIB	4	MYH10
MOLIBRESIB	2	CHD8
R-406	2	MYH10

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CHD8	7	Binding:7
MYH10	3	Binding:3

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

3 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)
QUIZARTINIB	4	MYH10
MOLIBRESIB	2	CHD8
R-406	2	MYH10

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	MYH10
B	Phased (≥1) drug, not yet approved	1	CHD8
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	COL25A1, ZFHX4, RAB3GAP1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
COL25A1	0	—
ZFHX4	0	—
RAB3GAP1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 5.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	5

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07466706	Not specified	NOT_YET_RECRUITING	Levator Muscle and Its Aponeurotic Maldevelopment in Congenital Ptosis
NCT03240107	Not specified	COMPLETED	Levator Resection with3 Point Fixation Versus 2 Point Fixation Tucking for Congenital Ptosis
NCT04537169	Not specified	UNKNOWN	Clinical Significance of Whitnall Ligament Structure
NCT05895695	Not specified	UNKNOWN	Levator Muscle Reaction for Unilateral Congenital Ptosis Repair as Compared to Levator Plication
NCT07078552	Not specified	COMPLETED	Research on Precision Diagnosis and Treatment Decision of Common Eye Diseases Based on Artificial Intelligence