Megalocornea

Summary

Megalocornea (MONDO:0009576) is a disease with 3 cohort genes.

At a glance

• Cohort genes: 3
• ClinVar variants: 19

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	megalocornea
Mondo ID	MONDO:0009576
MeSH	C562829
OMIM	249300
DOID	DOID:0060305
ICD-11	58849242
SNOMED CT	268158009
UMLS	C5574682
MedGen	1807965
Is cancer (heuristic)	no

Also known as: megalocornea · megalocornea (disease)

Data availability: 19 ClinVar variants · 2 HPO phenotypes.

Disease family

An umbrella term covering 1 Mondo subtype.

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

Related subtypes (23): cornea plana, pseudopterygium, corneal deposit, Bowman’s membrane folds or rupture, corneal degeneration, corneal staphyloma, corneal argyrosis, corneal ectasia, keratopathy, keratitis, corneal edema, brittle cornea syndrome, X-linked corneal dermoid, Peters anomaly, pellucid marginal degeneration, keratoconus, corneal dystrophy, sclerocornea, cornea neoplasm, Arnold stickler bourne syndrome, limbal stem cell deficiency, thygeson superficial punctate keratopathy, Terrien marginal degeneration

Subtypes (1): isolated congenital megalocornea

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

19 retrieved; paginated sample, class counts are floors:

13 pathogenic, 3 likely pathogenic, 3 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
1065523	NM_001143981.2(CHRDL1):c.1123C>T (p.Gln375Ter)	CHRDL1	Pathogenic	no assertion criteria provided
1076999	NM_001143981.2(CHRDL1):c.976A>T (p.Lys326Ter)	CHRDL1	Pathogenic	criteria provided, single submitter
1077000	NM_001143981.2(CHRDL1):c.94+1G>A	CHRDL1	Pathogenic	criteria provided, single submitter
1077001	NM_001143981.2(CHRDL1):c.1156+1G>T	CHRDL1	Pathogenic	criteria provided, single submitter
1077004	NM_001143981.2(CHRDL1):c.483dup (p.Lys162fs)	CHRDL1	Pathogenic	criteria provided, single submitter
1077007	NM_001143981.2(CHRDL1):c.229C>T (p.Arg77Ter)	CHRDL1	Pathogenic	criteria provided, single submitter
218164	NM_001143981.2(CHRDL1):c.807_808del (p.His270fs)	CHRDL1	Pathogenic	no assertion criteria provided
29957	NM_001143981.2(CHRDL1):c.872del (p.Cys291fs)	CHRDL1	Pathogenic	no assertion criteria provided
29958	NM_001143981.2(CHRDL1):c.782G>T (p.Cys261Phe)	CHRDL1	Pathogenic	no assertion criteria provided
29959	NM_001143981.2(CHRDL1):c.301+2T>G	CHRDL1	Pathogenic	criteria provided, single submitter
29960	NM_001143981.2(CHRDL1):c.102_103del (p.Glu34fs)	CHRDL1	Pathogenic	no assertion criteria provided
29961	NM_001143981.2(CHRDL1):c.652C>T (p.Arg218Ter)	CHRDL1	Pathogenic	no assertion criteria provided
369678	NM_001143981.2(CHRDL1):c.520dup (p.Ser174fs)	CHRDL1	Pathogenic	criteria provided, single submitter
1077002	NM_001143981.2(CHRDL1):c.436T>G (p.Cys146Gly)	CHRDL1	Likely pathogenic	criteria provided, single submitter
523552	NM_001854.4(COL11A1):c.4048_4065del (p.Ser1350_Pro1355del)	COL11A1	Likely pathogenic	criteria provided, single submitter
627622	NM_001365902.3(NFIX):c.440G>A (p.Gly147Glu)	NFIX	Likely pathogenic	criteria provided, single submitter
267920	46;XY;t(6;20)(p12;q13.1)dn		Uncertain significance	criteria provided, single submitter
1077003	NM_001143981.2(CHRDL1):c.207G>C (p.Glu69Asp)	CHRDL1	Uncertain significance	criteria provided, single submitter
1077006	NM_001143981.2(CHRDL1):c.968G>T (p.Cys323Phe)	CHRDL1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 9 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
COL11A1	Orphanet:2021	Fibrochondrogenesis
COL11A1	Orphanet:440354	Autosomal dominant myopia-midfacial retrusion-sensorineural hearing loss-rhizomelic dysplasia syndrome
COL11A1	Orphanet:560	Marshall syndrome
COL11A1	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
COL11A1	Orphanet:90654	Stickler syndrome type 2
CHRDL1	Orphanet:91489	Isolated congenital megalocornea
NFIX	Orphanet:420179	Malan overgrowth syndrome
NFIX	Orphanet:447980	19p13.3 microduplication syndrome
NFIX	Orphanet:561	Marshall-Smith syndrome

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
COL11A1	HGNC:2186	ENSG00000060718	P12107	Collagen alpha-1(XI) chain	clinvar
CHRDL1	HGNC:29861	ENSG00000101938	Q9BU40	Chordin-like protein 1	clinvar
NFIX	HGNC:7788	ENSG00000008441	Q14938	Nuclear factor 1 X-type	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COL11A1	Collagen alpha-1(XI) chain	May play an important role in fibrillogenesis by controlling lateral growth of collagen II fibrils.
CHRDL1	Chordin-like protein 1	Antagonizes the function of BMP4 by binding to it and preventing its interaction with receptors.
NFIX	Nuclear factor 1 X-type	Recognizes and binds the palindromic sequence 5’-TTGGCNNNNNGCCAA-3’ present in viral and cellular promoters and in the origin of replication of adenovirus type 2.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COL11A1	Other/Unknown	no		Fib_collagen_C, Laminin_G, Collagen
CHRDL1	Other/Unknown	no		VWF_dom, CHRDL_1/2_C, CHRDL1/2
NFIX	Other/Unknown	no		CTF/NFI, MAD_homology1_Dwarfin-type, CTF/NFI_DNA-bd_N

Expression context

Cohort genes with no expression data: 0.

3 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
cartilage tissue	1
periodontal ligament	1
tibia	1
decidua	1
parietal pleura	1
vena cava	1
cortical plate	1
ganglionic eminence	1
nipple	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COL11A1	209	broad	marker	tibia, cartilage tissue, periodontal ligament
CHRDL1	255	broad	marker	decidua, vena cava, parietal pleura
NFIX	267	ubiquitous	marker	cortical plate, nipple, ganglionic eminence

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COL11A1	2,433
NFIX	2,162
CHRDL1	1,294

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NFIX	Q14938	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CHRDL1	Q9BU40	69.79
COL11A1	P12107	53.06

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
RNA Polymerase III Transcription Termination	1	165.5×	0.023	NFIX
MET activates PTK2 signaling	1	126.9×	0.023	COL11A1
Signaling by BMP	1	119.0×	0.023	CHRDL1
RNA Polymerase III Abortive And Retractive Initiation	1	92.8×	0.023	NFIX
Collagen chain trimerization	1	86.5×	0.023	COL11A1
Developmental Lineage of Pancreatic Ductal Cells	1	76.1×	0.023	COL11A1
Assembly of collagen fibrils and other multimeric structures	1	66.8×	0.023	COL11A1
Collagen degradation	1	58.6×	0.023	COL11A1
Collagen biosynthesis and modifying enzymes	1	56.8×	0.023	COL11A1
Non-integrin membrane-ECM interactions	1	51.4×	0.023	COL11A1
Post-translational protein phosphorylation	1	33.4×	0.032	CHRDL1
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	28.8×	0.034	CHRDL1

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
tendon development	1	1404.3×	0.011	COL11A1
AMPA glutamate receptor clustering	1	1123.5×	0.011	CHRDL1
embryonic axis specification	1	802.5×	0.011	CHRDL1
proteoglycan metabolic process	1	624.1×	0.011	COL11A1
excitatory chemical synaptic transmission	1	432.1×	0.011	CHRDL1
chondrocyte development	1	312.1×	0.011	COL11A1
detection of mechanical stimulus involved in sensory perception of sound	1	312.1×	0.011	COL11A1
synapse maturation	1	312.1×	0.011	CHRDL1
cartilage condensation	1	255.3×	0.012	COL11A1
ventricular cardiac muscle tissue morphogenesis	1	234.1×	0.012	COL11A1
endodermal cell differentiation	1	165.2×	0.015	COL11A1
embryonic skeletal system morphogenesis	1	130.6×	0.017	COL11A1
eye development	1	117.0×	0.018	CHRDL1
inner ear morphogenesis	1	100.3×	0.019	COL11A1
negative regulation of BMP signaling pathway	1	96.8×	0.019	CHRDL1
regulation of synaptic plasticity	1	86.4×	0.019	CHRDL1
ossification	1	75.9×	0.020	CHRDL1
collagen fibril organization	1	74.9×	0.020	COL11A1
BMP signaling pathway	1	66.9×	0.021	CHRDL1
DNA replication	1	55.1×	0.024	NFIX
sensory perception of sound	1	33.6×	0.038	COL11A1
visual perception	1	26.5×	0.046	COL11A1
transcription by RNA polymerase II	1	23.5×	0.049	NFIX
cell differentiation	1	9.7×	0.112	CHRDL1
negative regulation of transcription by RNA polymerase II	1	5.9×	0.173	NFIX
positive regulation of transcription by RNA polymerase II	1	5.0×	0.196	NFIX
regulation of transcription by RNA polymerase II	1	3.9×	0.236	NFIX

Therapeutics

Drug target analysis

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

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
COL11A1	0	0
CHRDL1	0	0
NFIX	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	3	COL11A1, CHRDL1, NFIX

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)
COL11A1	0	—
CHRDL1	0	—
NFIX	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.