Doyne honeycomb retinal dystrophy

Summary

Doyne honeycomb retinal dystrophy (MONDO:0007471) is a disease caused by EFEMP1 (GenCC Definitive), with 4 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: EFEMP1 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 55
• Phenotypes (HPO): 20

Clinical features

Signs & symptoms

Clinical features (HPO)

20 HPO clinical features (Orphanet curated; top 20 by frequency):

HPO ID	Term	Frequency
HP:0030499	Macular drusen	Obligate (100%)
HP:0030500	Yellow/white lesions of the macula	Obligate (100%)
HP:0000572	Visual loss	Very frequent (80-99%)
HP:0007754	Macular dystrophy	Very frequent (80-99%)
HP:0007937	Reticular pigmentary degeneration	Very frequent (80-99%)
HP:0007703	Abnormality of retinal pigmentation	Frequent (30-79%)
HP:0011509	Macular hyperpigmentation	Frequent (30-79%)
HP:0012508	Metamorphopsia	Frequent (30-79%)
HP:0030629	Perifoveal ring of hyperautofluorescence	Frequent (30-79%)
HP:0030631	Hyperautofluorescent macular lesion	Frequent (30-79%)
HP:0030632	Hypoautofluorescent macular lesion	Frequent (30-79%)
HP:0000613	Photophobia	Occasional (5-29%)
HP:0007401	Macular atrophy	Occasional (5-29%)
HP:0007793	Granular macular appearance	Occasional (5-29%)
HP:0007950	Peripapillary chorioretinal atrophy	Occasional (5-29%)
HP:0011506	Choroidal neovascularization	Occasional (5-29%)
HP:0012231	Exudative retinal detachment	Occasional (5-29%)
HP:0025574	Macular hemorrhage	Occasional (5-29%)
HP:0030528	Paracentral scotoma	Occasional (5-29%)
HP:0031526	Subretinal fluid	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Doyne honeycomb retinal dystrophy
Mondo ID	MONDO:0007471
OMIM	126600
Orphanet	75376
DOID	DOID:0060745
SNOMED CT	193411004
UMLS	C1832174
MedGen	321900
GARD	0001912
Is cancer (heuristic)	no

Also known as: DHD · DHRD · dominant drusen · dominant radial drusen · Doyne honeycomb degeneration of retina · Doyne honeycomb retinal dystrophy · Malattia leventinese

Data availability: 55 ClinVar variants · 10 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › retinal disorder › retinal degeneration › macular degeneration › degeneration of macula and posterior pole › retinal drusen › Doyne honeycomb retinal dystrophy

Related subtypes (2): basal laminar drusen, reticular pseudodrusen

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

55 retrieved; paginated sample, class counts are floors:

27 benign, 12 uncertain significance, 8 conflicting classifications of pathogenicity, 3 likely benign, 3 benign/likely benign, 1 pathogenic/likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
8072	NM_001039348.3(EFEMP1):c.1033C>T (p.Arg345Trp)	EFEMP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
98713	NM_000322.5(PRPH2):c.828+3A>T	PRPH2	Pathogenic	criteria provided, multiple submitters, no conflicts
194014	NM_001039348.3(EFEMP1):c.1413C>T (p.Ser471=)	EFEMP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1942561	NM_001039348.3(EFEMP1):c.525C>T (p.Asp175=)	EFEMP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
197709	NM_001039348.3(EFEMP1):c.418C>T (p.Arg140Trp)	EFEMP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
283832	NM_001039348.3(EFEMP1):c.146A>C (p.Asp49Ala)	EFEMP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
336632	NM_001039348.3(EFEMP1):c.134T>C (p.Ile45Thr)	EFEMP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
895242	NM_001039348.3(EFEMP1):c.1062T>C (p.His354=)	EFEMP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
896671	NM_001039348.3(EFEMP1):c.401G>A (p.Arg134Gln)	EFEMP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
896672	NM_001039348.3(EFEMP1):c.195T>C (p.Tyr65=)	EFEMP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1042759	NM_001039348.3(EFEMP1):c.389T>C (p.Met130Thr)	EFEMP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2441181	NM_001039348.3(EFEMP1):c.1339G>T (p.Ala447Ser)	EFEMP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
336605	NM_001039348.3(EFEMP1):c.*1088A>C	EFEMP1	Uncertain significance	criteria provided, single submitter
336610	NM_001039348.3(EFEMP1):c.*946T>C	EFEMP1	Uncertain significance	criteria provided, single submitter
336617	NM_001039348.3(EFEMP1):c.*182G>C	EFEMP1	Uncertain significance	criteria provided, single submitter
336619	NM_001039348.3(EFEMP1):c.*152G>A	EFEMP1	Uncertain significance	criteria provided, single submitter
336620	NM_001039348.3(EFEMP1):c.*146T>A	EFEMP1	Uncertain significance	criteria provided, single submitter
336623	NM_001039348.3(EFEMP1):c.963C>T (p.Pro321=)	EFEMP1	Uncertain significance	criteria provided, single submitter
849590	NM_001039348.3(EFEMP1):c.1118C>T (p.Pro373Leu)	EFEMP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
895241	NM_001039348.3(EFEMP1):c.1120G>C (p.Glu374Gln)	EFEMP1	Uncertain significance	criteria provided, single submitter
898223	NM_001039348.3(EFEMP1):c.*349A>T	EFEMP1	Uncertain significance	criteria provided, single submitter
899334	NM_001039348.3(EFEMP1):c.1353C>T (p.Leu451=)	EFEMP1	Uncertain significance	criteria provided, single submitter
1168191	NM_001039348.3(EFEMP1):c.81+20G>C	EFEMP1	Benign	criteria provided, multiple submitters, no conflicts
1168267	NM_001039348.3(EFEMP1):c.1000+19del	EFEMP1	Benign	criteria provided, multiple submitters, no conflicts
167031	NM_001039348.3(EFEMP1):c.518-13A>G	EFEMP1	Benign	criteria provided, multiple submitters, no conflicts
257227	NM_001039348.3(EFEMP1):c.1001-14C>T	EFEMP1	Benign	criteria provided, multiple submitters, no conflicts
336606	NM_001039348.3(EFEMP1):c.*1063G>A	EFEMP1	Benign	criteria provided, single submitter
336607	NM_001039348.3(EFEMP1):c.*1026C>T	EFEMP1	Benign	criteria provided, single submitter
336608	NM_001039348.3(EFEMP1):c.*1004C>G	EFEMP1	Benign	criteria provided, multiple submitters, no conflicts
336609	NM_001039348.3(EFEMP1):c.*962C>A	EFEMP1	Benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 31 · Orphanet: 23 · 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
EFEMP1	Definitive	Autosomal dominant	Doyne honeycomb retinal dystrophy	13
CFH	Supportive	Autosomal dominant	Doyne honeycomb retinal dystrophy	9
CFI	Supportive	Autosomal dominant	Doyne honeycomb retinal dystrophy	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EFEMP1	Orphanet:75376	Familial drusen
EFEMP1	Orphanet:98977	Juvenile glaucoma
CFH	Orphanet:200421	Immunodeficiency with factor H anomaly
CFH	Orphanet:244242	HELLP syndrome
CFH	Orphanet:244275	De novo thrombotic microangiopathy after kidney transplantation
CFH	Orphanet:329903	Immunoglobulin-mediated membranoproliferative glomerulonephritis
CFH	Orphanet:544472	Atypical hemolytic uremic syndrome with complement gene abnormality
CFH	Orphanet:75376	Familial drusen
CFH	Orphanet:93571	Dense deposit disease
CFI	Orphanet:200418	Immunodeficiency with factor I anomaly
CFI	Orphanet:244242	HELLP syndrome
CFI	Orphanet:244275	De novo thrombotic microangiopathy after kidney transplantation
CFI	Orphanet:544472	Atypical hemolytic uremic syndrome with complement gene abnormality
CFI	Orphanet:75376	Familial drusen
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

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
EFEMP1	HGNC:3218	ENSG00000115380	Q12805	EGF-containing fibulin-like extracellular matrix protein 1	gencc,clinvar
CFH	HGNC:4883	ENSG00000000971	P08603	Complement factor H	gencc
CFI	HGNC:5394	ENSG00000205403	P05156	Complement factor I	gencc
PRPH2	HGNC:9942	ENSG00000112619	P23942	Peripherin-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EFEMP1	EGF-containing fibulin-like extracellular matrix protein 1	Binds EGFR, the EGF receptor, inducing EGFR autophosphorylation and the activation of downstream signaling pathways.
CFH	Complement factor H	Glycoprotein that plays an essential role in maintaining a well-balanced immune response by modulating complement activation.
CFI	Complement factor I	Trypsin-like serine protease that plays an essential role in regulating the immune response by controlling all complement pathways.
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.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 2 · 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
Complement	1	67.0×	0.045
Protease	1	9.2×	0.157
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EFEMP1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom
CFH	Complement	yes		Sushi_SCR_CCP_dom, Sushi/SCR/CCP_sf, ComplSys_Reg/VirEntry_Med
CFI	Protease	yes	3.4.21.45	SRCR, Trypsin_dom, Peptidase_S1A
PRPH2	Other/Unknown	no		Peripherin/rom-1, Tetraspanin_EC2_sf, Peripherin/rom-1_CS

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right coronary artery	2
descending thoracic aorta	1
thoracic aorta	1
calcaneal tendon	1
urethra	1
germinal epithelium of ovary	1
parietal pleura	1
right lobe of liver	1
hindlimb stylopod muscle	1
quadriceps femoris	1
vastus lateralis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EFEMP1	286	ubiquitous	marker	right coronary artery, thoracic aorta, descending thoracic aorta
CFH	267	ubiquitous	marker	urethra, calcaneal tendon, right coronary artery
CFI	240	broad	marker	germinal epithelium of ovary, parietal pleura, right lobe of liver
PRPH2	176	tissue_specific	marker	quadriceps femoris, vastus lateralis, hindlimb stylopod muscle

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EFEMP1	2,988
CFH	1,844
PRPH2	1,234
CFI	1,120

Intra-cohort edges

A	B	Sources
CFH	CFI	intact, string_interaction
CFH	EFEMP1	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CFH	P08603	51
CFI	P05156	2
PRPH2	P23942	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
EFEMP1	Q12805	77.67

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 4 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
Regulation of Complement cascade	2	155.4×	1e-04	CFH, CFI
Molecules associated with elastic fibres	1	102.9×	0.010	EFEMP1

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to low light intensity stimulus	1	4213.0×	0.006	PRPH2
regulation of complement activation, alternative pathway	1	2106.5×	0.006	CFH
post-embryonic eye morphogenesis	1	1404.3×	0.006	EFEMP1
visual perception	2	39.8×	0.006	EFEMP1, PRPH2
regulation of complement-dependent cytotoxicity	1	842.6×	0.006	CFH
regulation of complement activation	1	526.6×	0.009	CFH
embryonic eye morphogenesis	1	383.0×	0.010	EFEMP1
photoreceptor cell outer segment organization	1	263.3×	0.010	PRPH2
protein heterooligomerization	1	263.3×	0.010	PRPH2
complement activation, alternative pathway	1	247.8×	0.010	CFH
central nervous system myelination	1	247.8×	0.010	CFH
proteolysis	2	17.1×	0.011	CFH, CFI
negative regulation of chondrocyte differentiation	1	168.5×	0.012	EFEMP1
detection of light stimulus involved in visual perception	1	162.0×	0.012	PRPH2
complement activation	1	156.0×	0.012	CFH
complement activation, classical pathway	1	135.9×	0.012	CFI
peptidyl-tyrosine phosphorylation	1	105.3×	0.015	EFEMP1
camera-type eye development	1	89.6×	0.017	EFEMP1
retina development in camera-type eye	1	63.8×	0.022	PRPH2
epidermal growth factor receptor signaling pathway	1	62.0×	0.022	EFEMP1
protein maturation	1	40.9×	0.031	PRPH2
protein homooligomerization	1	30.5×	0.040	PRPH2
protein localization to plasma membrane	1	27.2×	0.043	PRPH2
inflammatory response	1	9.4×	0.111	CFH
cell adhesion	1	9.4×	0.111	PRPH2
innate immune response	1	8.4×	0.118	CFI
regulation of DNA-templated transcription	1	7.9×	0.121	EFEMP1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
EFEMP1	0	0
CFH	0	0
CFI	0	0
PRPH2	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
CFH	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CFI	3.4.21.45	complement factor I

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	2	CFH, CFI
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	EFEMP1, PRPH2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
EFEMP1	0	—
CFH	1	—
CFI	0	—
PRPH2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.