Hereditary macular dystrophy

Summary

Hereditary macular dystrophy (MONDO:0020242) is a disease (an umbrella term covering 17 Mondo subtypes) caused by variants in CRB1, CRX, PRPH2, and 1 other genes, with 5 cohort genes.

At a glance

• Causal genes: CRB1 (GenCC Definitive), CRX (GenCC Definitive), PRPH2 (GenCC Definitive), GUCA1A (GenCC Strong)
• Umbrella term: 17 Mondo subtypes
• Cohort genes: 5
• ClinVar variants: 12

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary macular dystrophy
Mondo ID	MONDO:0020242
Orphanet	98664
NCIT	C140264
SNOMED CT	276436007
UMLS	C0339508
MedGen	137919
GARD	0025154
Is cancer (heuristic)	no

Also known as: genetic macular dystrophy · genetic macular dystrophy (disease)

Data availability: 12 ClinVar variants · 4 GenCC gene-disease records · 12 cell lines.

Disease family

An umbrella term covering 17 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › retinal disorder › retinal degeneration › inherited retinal dystrophy › hereditary macular dystrophy

Related subtypes (104): retinal dystrophies primarily involving Bruch’s membrane, vitreoretinal dystrophy, dystrophies primarily involving the retinal pigment epithelium, retinal dystrophy in systemic or cerebroretinal lipidoses, age-related macular degeneration, helicoid peripapillary chorioretinal degeneration, Sorsby fundus dystrophy, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, pigmented paravenous retinochoroidal atrophy, retinoschisis, autosomal dominant, retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations, amaurosis-hypertrichosis syndrome, familial benign flecked retina, microcephaly and chorioretinopathy 1, ornithine aminotransferase deficiency, retinal degeneration-nanophthalmos-glaucoma syndrome, retinoschisis of fovea, Revesz syndrome, choroideremia, choroideremia-deafness-obesity syndrome, X-linked retinal dysplasia, X-linked retinoschisis, progressive bifocal chorioretinal atrophy, aceruloplasminemia, late-onset retinal degeneration, infantile cerebellar-retinal degeneration, progressive retinal dystrophy due to retinol transport defect, microcornea-myopic chorioretinal atrophy, retinal dystrophy with inner retinal dysfunction and ganglion cell anomalies, macular degeneration, early-onset, cone-rod dystrophy, ectopia lentis-chorioretinal dystrophy-myopia syndrome, foveal hypoplasia-presenile cataract syndrome, MRCS syndrome, X-linked intellectual disability-limb spasticity-retinal dystrophy-diabetes insipidus syndrome, Leber congenital amaurosis, oligocone trichromacy, Oguchi disease, retinitis pigmentosa, RPE65-related recessive retinopathy, RPGR-related retinopathy, AIPL1-related retinopathy, RP2-related retinopathy, RDH5-related retinopathy, RLBP1-related retinopathy, LCA5-related retinopathy, ATF6-related retinopathy, RAB28-related retinopathy, FLVCR1-related retinopathy with or without ataxia, RPE65-related dominant retinopathy, GUCY2D retinopathy, PDE6A-related retinopathy, ELOVL4-related maculopathy, MAK-related retinopathy, KIZ-related retinopathy, TOPORS-related retinopathy, PRPF8-related retinopathy, RD3-related retinopathy, BEST1-related dominant retinopathy, BEST1-related recessive retinopathy, IMPG2-related recessive retinopathy, IMPG2-related dominant retinopathy, CACNA1F-related retinopathy, CACNA2D4-related retinopathy, CDHR1-related retinopathy, GUCA1A-related retinopathy, RHO-related retinopathy, SNRNP200-related dominant retinopathy, RDH12-related recessive retinopathy, RDH12-related dominant retinopathy, NMNAT1-related retinopathy, CNGA3-related retinopathy, EYS-related retinopathy, GNAT2-related retinopathy, IDH3B-related retinopathy, MERTK-related retinopathy, PRPF31-related retinopathy, GPR179-related retinopathy, GRM6-related retinopathy, ADAM9-related retinopathy, RP1-related recessive retinopathy, RP1-related dominant retinopathy, CERKL-related retinopathy, TRPM1-related retinopathy, CNGB1-related retinopathy, PCARE-related retinopathy, CNGA1-related retinopathy, ABCA4-related retinopathy, NYX-related retinopathy, retinal dystrophy, X-linked, Gardner-Hardcastle type, PDE6C-related retinopathy, PDE6G-related retinopathy, LRIT3-related retinopathy, IMPG1-related dominant retinopathy, IMPG1-related recessive retinopathy, TTLL5-related retinopathy, HGSNAT-related retinopathy, IMPDH1-related retinopathy, PRPH2-related retinopathy, PROM1-related retinopathy, KCNV2-related retinopathy, CRX-related retinopathy, REEP6-related retinopathy, SPATA7-related retinopathy

Subtypes (17): vitelliform macular dystrophy, cone dystrophy, coloboma of macula, coloboma of macula-brachydactyly type B syndrome, benign concentric annular macular dystrophy, macular dystrophy, fenestrated sheen type, macular coloboma-cleft palate-hallux valgus syndrome, macular corneal dystrophy, EEM syndrome, renal hypomagnesemia 5 with ocular involvement, macular dystrophy, X-linked, AICA-ribosiduria, occult macular dystrophy, familial flecked retinopathy, patterned dystrophy of the retinal pigment epithelium, macular dystrophy, retinal, macular dystrophy with or without cone dysfunction

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

12 retrieved; paginated sample, class counts are floors:

7 conflicting classifications of pathogenicity, 3 uncertain significance, 1 pathogenic/likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
372352	NM_201253.3(CRB1):c.2506C>A (p.Pro836Thr)	CRB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
39614	NM_201253.3(CRB1):c.2843G>A (p.Cys948Tyr)	CRB1	Pathogenic	criteria provided, multiple submitters, no conflicts
294687	NM_201253.3(CRB1):c.3397G>A (p.Val1133Met)	CRB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
294688	NM_201253.3(CRB1):c.3695A>G (p.His1232Arg)	CRB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3028405	NM_201253.3(CRB1):c.2209A>G (p.Ile737Val)	CRB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
783191	NM_201253.3(CRB1):c.161G>T (p.Cys54Phe)	CRB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
847770	NM_201253.3(CRB1):c.4148G>A (p.Arg1383His)	CRB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
99887	NM_201253.3(CRB1):c.2681A>G (p.Asn894Ser)	CRB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1094039	NM_001252024.2(TRPM1):c.1484G>A (p.Arg495His)	TRPM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3779171	NM_201253.3(CRB1):c.5_7del (p.Ala2_Leu3delinsVal)	CRB1	Uncertain significance	criteria provided, single submitter
971732	NM_201253.3(CRB1):c.4060G>A (p.Ala1354Thr)	CRB1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1496774	NM_001252024.2(TRPM1):c.4469C>T (p.Thr1490Met)	TRPM1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 50 · Orphanet: 20 · 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
CRB1	Definitive	Autosomal recessive	hereditary macular dystrophy	11
CRX	Definitive	Autosomal dominant	cone-rod dystrophy 2	10
GUCA1A	Definitive	Autosomal dominant	cone-rod dystrophy 14	8
PRPH2	Definitive	Autosomal dominant	hereditary macular dystrophy	21

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CRB1	Orphanet:251295	Pigmented paravenous retinochoroidal atrophy
CRB1	Orphanet:35612	Nanophthalmos
CRB1	Orphanet:65	Leber congenital amaurosis
CRB1	Orphanet:791	Retinitis pigmentosa
CRX	Orphanet:1872	Cone rod dystrophy
CRX	Orphanet:65	Leber congenital amaurosis
CRX	Orphanet:791	Retinitis pigmentosa
GUCA1A	Orphanet:1871	Progressive cone dystrophy
GUCA1A	Orphanet:1872	Cone rod dystrophy
GUCA1A	Orphanet:75377	Central areolar choroidal dystrophy
PRPH2	Orphanet:1872	Cone rod dystrophy
PRPH2	Orphanet:227796	Fundus albipunctatus
PRPH2	Orphanet:52427	Retinitis punctata albescens
PRPH2	Orphanet:75377	Central areolar choroidal dystrophy
PRPH2	Orphanet:791	Retinitis pigmentosa
PRPH2	Orphanet:827	Stargardt disease
PRPH2	Orphanet:99000	Adult-onset foveomacular vitelliform dystrophy
PRPH2	Orphanet:99001	Butterfly-shaped pigment dystrophy
PRPH2	Orphanet:99003	Multifocal pattern dystrophy simulating fundus flavimaculatus
TRPM1	Orphanet:714079	Complete congenital stationary night blindness, Schubert-Bornschein type

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
CRB1	HGNC:2343	ENSG00000134376	P82279	Protein crumbs homolog 1	gencc,clinvar
CRX	HGNC:2383	ENSG00000105392	O43186	Cone-rod homeobox protein	gencc
GUCA1A	HGNC:4678	ENSG00000048545	P43080	Guanylyl cyclase-activating protein 1	gencc
PRPH2	HGNC:9942	ENSG00000112619	P23942	Peripherin-2	gencc
TRPM1	HGNC:7146	ENSG00000134160	Q7Z4N2	Transient receptor potential cation channel subfamily M member 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CRB1	Protein crumbs homolog 1	Plays a role in photoreceptor morphogenesis in the retina.
CRX	Cone-rod homeobox protein	Transcription factor that binds and transactivates the sequence 5’-TAATC[CA]-3’ which is found upstream of several photoreceptor-specific genes, including the opsin genes.
GUCA1A	Guanylyl cyclase-activating protein 1	Stimulates retinal guanylyl cyclase when free calcium ions concentration is low and inhibits guanylyl cyclase when free calcium ions concentration is elevated.
PRPH2	Peripherin-2	Essential for retina photoreceptor outer segment disk morphogenesis, may also play a role with ROM1 in the maintenance of outer segment disk structure.
TRPM1	Transient receptor potential cation channel subfamily M member 1	Constitutively open nonselective divalent cation-conducting channels which mediate the influx of Ca(2+), Mg(2+), Mn(2+), Ba(2+), and Ni(2+) into the cytoplasm, leading to membrane depolarization.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 3 · Druggable fraction: 0.2

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
Ion channel	1	22.3×	0.132
Transcription factor	1	1.6×	0.608
Other/Unknown	3	1.1×	0.608

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CRB1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Laminin_G
CRX	Transcription factor	no		HD, Homeodomain-like_sf, Otx_TF_C
GUCA1A	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS
PRPH2	Other/Unknown	no		Peripherin/rom-1, Tetraspanin_EC2_sf, Peripherin/rom-1_CS
TRPM1	Ion channel	yes		Ion_trans_dom, TRPM_tetra, TRPM_tetra_sf

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
pigmented layer of retina	2
retina	2
endothelial cell	1
ganglionic eminence	1
ventricular zone	1
primordial germ cell in gonad	1
hypothalamus	1
nucleus accumbens	1
putamen	1
hindlimb stylopod muscle	1
quadriceps femoris	1
vastus lateralis	1
nipple	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CRB1	163	broad	marker	ganglionic eminence, ventricular zone, endothelial cell
CRX	54	tissue_specific	marker	pigmented layer of retina, retina, primordial germ cell in gonad
GUCA1A	52	broad	marker	nucleus accumbens, putamen, hypothalamus
PRPH2	176	tissue_specific	marker	quadriceps femoris, vastus lateralis, hindlimb stylopod muscle
TRPM1	119	tissue_specific	marker	pigmented layer of retina, retina, nipple

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CRX	2,076
GUCA1A	1,434
PRPH2	1,234
TRPM1	1,190
CRB1	1,075

Intra-cohort edges

A	B	Sources
CRX	GUCA1A	string_interaction
CRX	PRPH2	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CRB1	P82279	1
CRX	O43186	1
PRPH2	P23942	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GUCA1A	P43080	71.28
TRPM1	Q7Z4N2	66.74

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 5 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
Regulation of MITF-M-dependent genes involved in apoptosis	1	317.2×	0.006	TRPM1
TRP channels	1	203.9×	0.006	TRPM1
Inactivation, recovery and regulation of the phototransduction cascade	1	158.6×	0.006	GUCA1A

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
visual perception	4	63.6×	5e-06	CRX, GUCA1A, TRPM1, PRPH2
photoreceptor cell outer segment organization	2	421.3×	1e-04	CRB1, PRPH2
cellular response to light stimulus	2	421.3×	1e-04	CRB1, TRPM1
detection of light stimulus involved in visual perception	2	259.3×	2e-04	CRB1, PRPH2
retina development in camera-type eye	2	102.1×	0.001	CRX, PRPH2
response to low light intensity stimulus	1	3370.4×	0.002	PRPH2
positive regulation of guanylate cyclase activity	1	3370.4×	0.002	GUCA1A
camera-type eye photoreceptor cell development	1	3370.4×	0.002	CRB1
post-embryonic retina morphogenesis in camera-type eye	1	1685.2×	0.003	CRB1
establishment of bipolar cell polarity involved in cell morphogenesis	1	1123.5×	0.004	CRB1
obsolete positive regulation of cGMP-mediated signaling	1	481.5×	0.008	GUCA1A
G protein-coupled glutamate receptor signaling pathway	1	210.7×	0.016	TRPM1
protein heterooligomerization	1	210.7×	0.016	PRPH2
plasma membrane organization	1	177.4×	0.016	CRB1
glial cell differentiation	1	177.4×	0.016	CRB1
retina layer formation	1	129.6×	0.019	CRB1
protein tetramerization	1	124.8×	0.019	TRPM1
monoatomic cation transmembrane transport	1	124.8×	0.019	TRPM1
establishment or maintenance of epithelial cell apical/basal polarity	1	116.2×	0.019	CRB1
calcium ion import across plasma membrane	1	108.7×	0.020	TRPM1
phototransduction	1	99.1×	0.021	GUCA1A
establishment or maintenance of cell polarity	1	80.2×	0.024	CRB1
blood vessel remodeling	1	76.6×	0.024	CRB1
photoreceptor cell maintenance	1	71.7×	0.025	CRB1
heterophilic cell-cell adhesion	1	67.4×	0.025	CRB1
regulation of signal transduction	1	53.5×	0.031	GUCA1A
calcium ion transmembrane transport	1	42.1×	0.037	TRPM1
cellular response to calcium ion	1	40.1×	0.038	GUCA1A
animal organ morphogenesis	1	38.3×	0.038	CRX
calcium ion transport	1	36.2×	0.039	TRPM1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 0 of 5 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CRB1	0	0
CRX	0	0
GUCA1A	0	0
PRPH2	0	0
TRPM1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	TRPM1
E	Difficult family or no structure, no drug	4	CRB1, CRX, GUCA1A, PRPH2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CRB1	0	—
CRX	0	—
GUCA1A	0	—
PRPH2	0	—
TRPM1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.