Macular corneal dystrophy

Summary

Macular corneal dystrophy (MONDO:0009020) is a disease caused by CHST6 (GenCC Definitive), with 2 cohort genes and 7 clinical trials. Top therapeutic interventions include adalimumab, fomepizole, and atacicept.

At a glance

• Prevalence: 1-9 / 100 000 (Europe)
• Causal gene: CHST6 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 292
• Phenotypes (HPO): 11
• Clinical trials: 7

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000		Europe	Not yet validated
Point prevalence	1-9 / 100 000	1	United States	Not yet validated

Signs & symptoms

Clinical features (HPO)

11 HPO clinical features (Orphanet curated; top 11 by frequency):

HPO ID	Term	Frequency
HP:0000531	Corneal crystals	Very frequent (80-99%)
HP:0001939	Abnormality of metabolism/homeostasis	Very frequent (80-99%)
HP:0007759	Opacification of the corneal stroma	Very frequent (80-99%)
HP:0007856	Punctate opacification of the cornea	Very frequent (80-99%)
HP:0000495	Recurrent corneal erosions	Frequent (30-79%)
HP:0001141	Severely reduced visual acuity	Frequent (30-79%)
HP:0100689	Decreased corneal thickness	Frequent (30-79%)
HP:0000484	Hyperopic astigmatism	Occasional (5-29%)
HP:0000613	Photophobia	Occasional (5-29%)
HP:0012155	Decreased corneal sensation	Occasional (5-29%)
HP:0200026	Ocular pain	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	macular corneal dystrophy
Mondo ID	MONDO:0009020
MeSH	C537834
OMIM	217800
Orphanet	98969
DOID	DOID:2565
ICD-10-CM	H18.55
ICD-11	791344343
NCIT	C34793
SNOMED CT	60258001
UMLS	C1636149
MedGen	351514
GARD	0006953
MedDRA	10025406
Is cancer (heuristic)	no

Also known as: corneal dystrophy Groenouw type II · Fehr corneal dystrophy · Groenouw type II corneal dystrophy · macular corneal dystrophy · macular corneal dystrophy type 1 · macular dystrophy, corneal · macular dystrophy, corneal type 1 · MCD · Mcdc1

Data availability: 292 ClinVar variants · 3 GenCC gene-disease records · 2 cell lines.

Disease family

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

Related subtypes (9): lattice corneal dystrophy, Schnyder corneal dystrophy, fleck corneal dystrophy, granular corneal dystrophy type I, central cloudy dystrophy of François, granular corneal dystrophy type II, congenital stromal corneal dystrophy, posterior amorphous corneal dystrophy, pre-descemet corneal dystrophy

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

292 retrieved; paginated sample, class counts are floors:

141 uncertain significance, 42 likely benign, 42 benign, 26 pathogenic, 23 likely pathogenic, 11 conflicting classifications of pathogenicity, 4 pathogenic/likely pathogenic, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1300205	NM_021615.5(CHST6):c.847_848delinsTG (p.Glu283Ter)	CHST6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2026508	NM_021615.5(CHST6):c.290_293dup (p.Val99fs)	CHST6	Pathogenic	criteria provided, single submitter
2114380	NM_021615.5(CHST6):c.601_621del (p.Val201_Val207del)	CHST6	Pathogenic	criteria provided, single submitter
2506044	NM_021615.5(CHST6):c.573dup (p.Ala192fs)	CHST6	Pathogenic	criteria provided, single submitter
2577141	NM_021615.5(CHST6):c.379C>T (p.Arg127Cys)	CHST6	Pathogenic	criteria provided, multiple submitters, no conflicts
2581187	NM_021615.5(CHST6):c.418C>T (p.Arg140Ter)	CHST6	Pathogenic	criteria provided, multiple submitters, no conflicts
2637472	NM_021615.5(CHST6):c.631C>T (p.Arg211Trp)	CHST6	Pathogenic	criteria provided, single submitter
2736373	NM_021615.5(CHST6):c.632G>A (p.Arg211Gln)	CHST6	Pathogenic	criteria provided, multiple submitters, no conflicts
2736374	NM_021615.5(CHST6):c.6_7delinsAA (p.Trp2_Leu3delinsTer)	CHST6	Pathogenic	criteria provided, single submitter
320606	NM_021615.5(CHST6):c.892C>T (p.Gln298Ter)	CHST6	Pathogenic	criteria provided, single submitter
3335959	NM_021615.5(CHST6):c.158C>T (p.Ser53Leu)	CHST6	Pathogenic	criteria provided, multiple submitters, no conflicts
3375062	NM_021615.5(CHST6):c.820G>A (p.Glu274Lys)	CHST6	Pathogenic	criteria provided, single submitter
3385288	NM_021615.5(CHST6):c.894dup (p.Leu299fs)	CHST6	Pathogenic	criteria provided, single submitter
3581252	NM_021615.5(CHST6):c.805del (p.Arg269fs)	CHST6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3629653	NM_021615.5(CHST6):c.463_464del (p.Arg155fs)	CHST6	Pathogenic	criteria provided, single submitter
3722066	NM_021615.5(CHST6):c.680del (p.Gly227fs)	CHST6	Pathogenic	criteria provided, single submitter
3768560	NM_021615.5(CHST6):c.124C>T (p.His42Tyr)	CHST6	Pathogenic	criteria provided, single submitter
4525911	NM_021615.5(CHST6):c.613C>T (p.Arg205Trp)	CHST6	Pathogenic	criteria provided, single submitter
4710277	NM_021615.5(CHST6):c.614G>A (p.Arg205Gln)	CHST6	Pathogenic	criteria provided, single submitter
4710278	NM_021615.5(CHST6):c.231G>A (p.Trp77Ter)	CHST6	Pathogenic	criteria provided, single submitter
4710279	NM_021615.5(CHST6):c.51del (p.Gln18fs)	CHST6	Pathogenic	criteria provided, single submitter
4710280	NM_021615.5(CHST6):c.15_16insATGCTGTGCG (p.Val6fs)	CHST6	Pathogenic	criteria provided, single submitter
497526	NM_021615.5(CHST6):c.172C>T (p.Gln58Ter)	CHST6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5071	NM_021615.5(CHST6):c.521A>G (p.Lys174Arg)	CHST6	Pathogenic	criteria provided, single submitter
5072	NM_021615.5(CHST6):c.609C>A (p.Asp203Glu)	CHST6	Pathogenic	no assertion criteria provided
5075	NM_021615.5(CHST6):c.599T>G (p.Leu200Arg)	CHST6	Pathogenic	criteria provided, multiple submitters, no conflicts
5076	NM_021615.5(CHST6):c.304T>G (p.Cys102Gly)	CHST6	Pathogenic	criteria provided, multiple submitters, no conflicts
5077	NM_021615.5(CHST6):c.329A>G (p.Tyr110Cys)	CHST6	Pathogenic	criteria provided, single submitter
871665	NM_021615.5(CHST6):c.1A>T (p.Met1Leu)	CHST6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1459206	NC_000016.9:g.(?74748068)(75513746_?)del	FA2H	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
CHST6	Definitive	Autosomal recessive	macular corneal dystrophy	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CHST6	Orphanet:98969	Macular corneal dystrophy
FA2H	Orphanet:171629	Autosomal recessive spastic paraplegia type 35
FA2H	Orphanet:329308	Fatty acid hydroxylase-associated neurodegeneration

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CHST6	HGNC:6938	ENSG00000183196	Q9GZX3	Carbohydrate sulfotransferase 6	gencc,clinvar
FA2H	HGNC:21197	ENSG00000103089	Q7L5A8	Fatty acid 2-hydroxylase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CHST6	Carbohydrate sulfotransferase 6	Sulfotransferase that utilizes 3’-phospho-5’-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the transfer of sulfate to position 6 of non-reducing N-acetylglucosamine (GlcNAc) residues of keratan.
FA2H	Fatty acid 2-hydroxylase	Catalyzes the hydroxylation of free fatty acids at the C-2 position to produce 2-hydroxy fatty acids, which are building blocks of sphingolipids and glycosphingolipids common in neural tissue and epidermis.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CHST6	Other/Unknown	no		Sulfotransferase_dom, Carbohydrate_sulfotransferase, P-loop_NTPase
FA2H	Enzyme (other)	yes	1.14.18.6	Cyt_B5-like_heme/steroid-bd, Fatty_acid_hydroxylase, Scs7

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bronchial epithelial cell	1
bronchus	1
nasal cavity epithelium	1
C1 segment of cervical spinal cord	1
corpus callosum	1
spinal cord	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CHST6	162	broad	marker	bronchial epithelial cell, bronchus, nasal cavity epithelium
FA2H	213	broad	marker	C1 segment of cervical spinal cord, spinal cord, corpus callosum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FA2H	2,099
CHST6	523

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CHST6	Q9GZX3	90.66
FA2H	Q7L5A8	85.53

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 2 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
Defective CHST6 causes MCDC1	1	713.8×	0.004	CHST6
Keratan sulfate biosynthesis	1	190.3×	0.007	CHST6
Sphingolipid de novo biosynthesis	1	142.8×	0.007	FA2H

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of sebum secreting cell proliferation	1	4213.0×	0.002	FA2H
regulation of acinar cell proliferation	1	4213.0×	0.002	FA2H
sebaceous gland cell differentiation	1	2808.7×	0.002	FA2H
glucosylceramide biosynthetic process	1	2808.7×	0.002	FA2H
galactosylceramide biosynthetic process	1	1685.2×	0.002	FA2H
central nervous system myelin maintenance	1	1404.3×	0.002	FA2H
plasma membrane raft organization	1	1404.3×	0.002	FA2H
regulation of hair cycle	1	1203.7×	0.002	FA2H
lipid modification	1	936.2×	0.002	FA2H
peripheral nervous system myelin maintenance	1	766.0×	0.002	FA2H
N-acetylglucosamine metabolic process	1	601.9×	0.003	CHST6
sulfur compound metabolic process	1	561.7×	0.003	CHST6
keratan sulfate proteoglycan biosynthetic process	1	495.6×	0.003	CHST6
establishment of skin barrier	1	227.7×	0.006	FA2H
ceramide biosynthetic process	1	210.7×	0.006	FA2H
sphingolipid biosynthetic process	1	179.3×	0.006	FA2H
fatty acid biosynthetic process	1	175.5×	0.006	FA2H
fatty acid metabolic process	1	96.8×	0.011	FA2H
carbohydrate metabolic process	1	68.0×	0.015	CHST6

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 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
CHST6	0	0
FA2H	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
FA2H	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
FA2H	1.14.18.6	4-hydroxysphinganine ceramide fatty acyl 2-hydroxylase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	1	FA2H
E	Difficult family or no structure, no drug	1	CHST6

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)
CHST6	0	—
FA2H	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 7.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3
PHASE2	2
PHASE1	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06983028	PHASE2	RECRUITING	Atacicept in Multiple Glomerular Diseases
NCT04009668	PHASE2	COMPLETED	Tumor Necrosis Factor Inhibition in Focal Segmental Glomerulosclerosis and Treatment Resistant Minimal Change Disease
NCT07267026	PHASE1	RECRUITING	A Study to Evaluate the Safety, Tolerability and PK of SK-09
NCT00346853	PHASE1	COMPLETED	Phase 1 Pilot Study of 4-MP to Treat Stargardt Macular Dystrophy
NCT04571658	Not specified	RECRUITING	NEPTUNE Match Study
NCT05650619	Not specified	RECRUITING	Recurrence Post-transplant Observational Study in Focal Segmental Glomerulosclerosis and Minimal Change Disease
NCT04642729	Not specified	UNKNOWN	Fresh Corneal Lenticule Implantation in Macular Corneal Distrophy With Relex Smile Surgery

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ADALIMUMAB	4	1
FOMEPIZOLE	4	1
ATACICEPT	3	1