GUCY2D-related recessive retinopathy

Summary

GUCY2D-related recessive retinopathy (MONDO:0100453) is a disease caused by GUCY2D (GenCC Strong), with 1 cohort gene and 3 clinical trials. Top therapeutic interventions include polymyxin b, trimethoprim, and zuretinol acetate.

At a glance

• Causal gene: GUCY2D (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 69
• Clinical trials: 3

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	GUCY2D-related recessive retinopathy
Mondo ID	MONDO:0100453
GARD	0026227
Is cancer (heuristic)	no

Also known as: amaurosis congenita of Leber 1 · amaurosis congenita of Leber I · amaurosis congenita of Leber, type 1 · cone-rod dystrophy 6 · cone-rod dystrophy caused by mutation in GUCY2D · cone-rod dystrophy type 6 · CORD6 · CRB · GUCY2D cone-rod dystrophy · GUCY2D Leber congenital amaurosis · LCA · LCA1 · Leber congenital amaurosis 1 · Leber congenital amaurosis caused by mutation in GUCY2D · Leber congenital amaurosis type 1 · night blindness, congenital stationary, type 1I · RCD2 · recessive GUCY2D retinopathy · retinal blindness, congenital · retinal cone dystrophy 2

Data availability: 69 ClinVar variants · 69 ClinGen variant curations · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › GUCY2D-related recessive retinopathy

Related subtypes (218): immunodeficiency-centromeric instability-facial anomalies syndrome, hypercalcemia, infantile, Ochoa syndrome, autosomal recessive Ehlers-Danlos syndrome, vascular type, hydrolethalus syndrome, 3-M syndrome, isolated hyperchlorhidrosis, dacryocystitis-osteopoikilosis syndrome, Hutchinson-Gilford progeria syndrome, achalasia microcephaly syndrome, acrorenal syndrome, autosomal recessive, beta-ketothiolase deficiency, autosomal recessive Alport syndrome, Alstrom syndrome, microphthalmia with limb anomalies, camptodactyly-arthropathy-coxa vara-pericarditis syndrome, Behr syndrome, bifid nose, autosomal recessive, Bloom syndrome, Bowen-Conradi syndrome, camptodactyly with fibrous tissue hyperplasia and skeletal dysplasia, heart defects-limb shortening syndrome, autosomal recessive palmoplantar keratoderma and congenital alopecia, COFS syndrome, craniometaphyseal dysplasia, autosomal recessive, Fraser syndrome, cystic fibrosis, polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly, persistent hyperplastic primary vitreous, autosomal recessive, Donnai-Barrow syndrome, Schöpf-Schulz-Passarge syndrome, cleft lip/palate-ectodermal dysplasia syndrome, Ellis-van Creveld syndrome, Wolcott-Rallison syndrome, autosomal recessive faciodigitogenital syndrome, acromesomelic dysplasia 2B, brittle cornea syndrome, triple-A syndrome, autosomal recessive humeroradial synostosis, multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome, hydrocephalus, nonsyndromic, autosomal recessive 1, autosomal recessive hydrocephalus due to congenital stenosis of aqueduct of Sylvius, hypertelorism, microtia, facial clefting syndrome, hypoparathyroidism-retardation-dysmorphism syndrome, Vici syndrome, Johanson-Blizzard syndrome, autosomal recessive Kenny-Caffey syndrome, Papillon-Lefevre disease, Haim-Munk syndrome, Laurence-Moon syndrome, Donohue syndrome, lipase deficiency, combined, autosomal recessive familial Mediterranean fever, thiamine-responsive megaloblastic anemia syndrome, cartilage-hair hypoplasia, Nijmegen breakage syndrome, pseudo-TORCH syndrome, Galloway-Mowat syndrome, mulibrey nanism, myotonia congenita, autosomal recessive, Schwartz-Jampel syndrome, proteosome-associated autoinflammatory syndrome, Netherton syndrome, Niemann-Pick disease type A, oculodentodigital dysplasia, autosomal recessive, odonto-onycho-dermal dysplasia, autosomal recessive omodysplasia, osteoporosis-pseudoglioma syndrome, Shwachman-Diamond syndrome, phenylketonuria, Bjornstad syndrome, Laron syndrome, autosomal recessive polycystic kidney disease, autosomal recessive inherited pseudoxanthoma elasticum, autosomal recessive multiple pterygium syndrome, rapadilino syndrome, short-rib thoracic dysplasia 9 with or without polydactyly, autosomal recessive Robinow syndrome, Sjogren-Larsson syndrome, scapuloperoneal spinal muscular atrophy, autosomal recessive, spondyloepiphyseal dysplasia tarda, autosomal recessive, inherited threoninemia, Pendred syndrome, autosomal recessive spondylocostal dysostosis, Werner syndrome, ABCD syndrome, Naxos disease, autosomal recessive amelia, human HOXA1 syndromes, sickle cell disease, autosomal recessive proximal renal tubular acidosis, hyper-IgM syndrome type 2, temtamy preaxial brachydactyly syndrome, TH-deficient dopa-responsive dystonia, craniosynostosis syndrome, autosomal recessive, Niemann-Pick disease type B, skin fragility-woolly hair-palmoplantar keratoderma syndrome, CoQ-responsive OXPHOS deficiency, familial adenomatous polyposis 2, Pierson syndrome, palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome, cardiomyopathy-hypotonia-lactic acidosis syndrome, PHARC syndrome, Kahrizi syndrome, cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies, congenital prothrombin deficiency, immunodeficiency 31B, dyskeratosis congenita, autosomal recessive 2, dyskeratosis congenita, autosomal recessive 3, Nestor-Guillermo progeria syndrome, leukoencephalopathy with calcifications and cysts, mitochondrial pyruvate carrier deficiency, branched-chain keto acid dehydrogenase kinase deficiency, dyskeratosis congenita, autosomal recessive 5, hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome, alacrima, achalasia, and intellectual disability syndrome, hyperlipoproteinemia, type 1D, microcephaly and chorioretinopathy 2, congenital stationary night blindness 1G, combined oxidative phosphorylation deficiency 29, hypermanganesemia with dystonia 2, growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy, gnb5-related intellectual disability-cardiac arrhythmia syndrome, autosomal recessive spastic paraplegia type 78, autosomal recessive limb-girdle muscular dystrophy, Bardet-Biedl syndrome, autosomal recessive cerebellar ataxia, neuronopathy, distal hereditary motor, autosomal recessive, UV-sensitive syndrome, Ehlers-Danlos syndrome, kyphoscoliotic type 1, Cockayne syndrome, hyperphenylalaninemia due to tetrahydrobiopterin deficiency, leukoencephalopathy-palmoplantar keratoderma syndrome, autosomal recessive hypohidrotic ectodermal dysplasia, Warburg micro syndrome, autosomal recessive primary microcephaly, autosomal recessive progressive external ophthalmoplegia, Meier-Gorlin syndrome, autosomal recessive sideroblastic anemia, autosomal recessive intermediate Charcot-Marie-Tooth disease, Perrault syndrome, autosomal recessive hypophosphatemic rickets, de Barsy syndrome, leukocyte adhesion deficiency, Senior-Loken syndrome, autosomal recessive spastic ataxia, childhood-onset autosomal recessive myopathy with external ophthalmoplegia, autosomal recessive cerebral atrophy, GM3 synthase deficiency, autosomal recessive distal renal tubular acidosis, pigmentation defects-palmoplantar keratoderma-skin carcinoma syndrome, autosomal recessive brachyolmia, Aicardi-Goutieres syndrome, homocystinuria without methylmalonic aciduria, Niemann-Pick disease type C, nephronophthisis, autosomal recessive osteopetrosis, peroxisome biogenesis disorder, congenital non-bullous ichthyosiform erythroderma, Seckel syndrome, Usher syndrome, autosomal recessive cutis laxa type 1, autosomal recessive cutis laxa type 2, hearing loss, autosomal recessive, microcephaly, growth restriction, and increased sister chromatid exchange 2, encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1, congenital vertebral-cardiac-renal anomalies syndrome, hair defect with photosensitivity and intellectual disability syndrome, autosomal recessive severe congenital neutropenia, severe combined immunodeficiency due to CARMIL2 deficiency, extraoral halitosis due to methanethiol oxidase deficiency, neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, mitochondrial complex 2 deficiency, nuclear type 3, mitochondrial complex 2 deficiency, nuclear type 4, mismatch repair cancer syndrome, spondyloepimetaphyseal dysplasia with joint laxity, type 3, Kilquist syndrome, Duane anomaly-myopathy-scoliosis syndrome, autosomal recessive axonal charcot-marie-tooth disease due to copper metabolism defect, immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome, optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome, congenital myopathy with reduced type 2 muscle fibers, NAD(P)HX dehydratase deficiency, autosomal recessive ocular albinism, ichthyosis linearis circumflexa, eosinophil peroxidase deficiency, hyperphenylalaninemia due to DNAJC12 deficiency, autosomal recessive epidermolytic ichthyosis, Ehlers-Danlos syndrome, classic-like, 2, joint laxity, short stature, and myopia, HELIX syndrome, auditory neuropathy-optic atrophy syndrome, glycosylphosphatidylinositol biosynthesis defect 15, neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, SCN4A-related myopathy, autosomal recessive, Uner Tan Syndrome, nephropathic cystinosis, Imerslund-Grasbeck syndrome type 1, Imerslund-Grasbeck syndrome type 2, permanent neonatal diabetes mellitus 1, growth hormone insensitivity with immune dysregulation 1, autosomal recessive, Rajab interstitial lung disease with brain calcifications 1, Roberts-SC phocomelia syndrome, neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, RPE65-related recessive retinopathy, autosomal recessive titinopathy, intellectual disability, autosomal recessive, ALPL-related autosomal recessive hypophosphatasia, spastic paraplegia 18b, autosomal recessive, CEP164-related ciliopathy, RP1-related recessive retinopathy, pseudohypoaldosteronism, type IB2, autosomal recessive, pseudohypoaldosteronism, type IB3, autosomal recessive, spastic paraplegia 30B, autosomal recessive, cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1, brain small vessel disease 2B, autosomal recessive, IMPG1-related recessive retinopathy, PROM1-related recessive retinopathy

Subtypes (2): Leber congenital amaurosis 1, night blindness, congenital stationary, type1i

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

69 retrieved; paginated sample, class counts are floors:

23 pathogenic, 16 likely pathogenic, 13 benign, 9 uncertain significance, 8 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2137915	NM_000180.4(GUCY2D):c.1762C>T (p.Arg588Trp)	GUCY2D	Pathogenic	reviewed by expert panel
3583120	NM_000180.4(GUCY2D):c.1956+1G>A	GUCY2D	Pathogenic	reviewed by expert panel
3602090	NM_000180.4(GUCY2D):c.722-1G>T	GUCY2D	Pathogenic	reviewed by expert panel
3602092	NM_000180.4(GUCY2D):c.726del (p.Ile243fs)	GUCY2D	Pathogenic	reviewed by expert panel
3602093	NM_000180.4(GUCY2D):c.2633_2636del (p.Gln878fs)	GUCY2D	Pathogenic	reviewed by expert panel
4538535	NM_000180.4(GUCY2D):c.-127_1566+2del	GUCY2D	Pathogenic	reviewed by expert panel
560463	NM_000180.4(GUCY2D):c.2303G>A (p.Arg768Gln)	GUCY2D	Pathogenic	reviewed by expert panel
581095	NM_000180.4(GUCY2D):c.3224+1G>C	GUCY2D	Pathogenic	reviewed by expert panel
587413	NM_000180.4(GUCY2D):c.2766C>G (p.Tyr922Ter)	GUCY2D	Pathogenic	reviewed by expert panel
638494	NM_000180.4(GUCY2D):c.1561C>T (p.Arg521Ter)	GUCY2D	Pathogenic	reviewed by expert panel
689384	NM_000180.4(GUCY2D):c.1633C>T (p.Gln545Ter)	GUCY2D	Pathogenic	reviewed by expert panel
803313	NM_000180.4(GUCY2D):c.1245del (p.Phe415fs)	GUCY2D	Pathogenic	reviewed by expert panel
861651	NM_000180.4(GUCY2D):c.2595del (p.Lys866fs)	GUCY2D	Pathogenic	reviewed by expert panel
866048	NM_000180.4(GUCY2D):c.3271C>T (p.Arg1091Ter)	GUCY2D	Pathogenic	reviewed by expert panel
9350	NM_000180.4(GUCY2D):c.1694T>C (p.Phe565Ser)	GUCY2D	Pathogenic	reviewed by expert panel
938393	NM_000180.4(GUCY2D):c.2516del (p.Thr839fs)	GUCY2D	Pathogenic	reviewed by expert panel
98540	NM_000180.4(GUCY2D):c.1343C>A (p.Ser448Ter)	GUCY2D	Pathogenic	reviewed by expert panel
98562	NM_000180.4(GUCY2D):c.226_239del (p.Ala76fs)	GUCY2D	Pathogenic	reviewed by expert panel
98563	NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp)	GUCY2D	Pathogenic	reviewed by expert panel
98582	NM_000180.4(GUCY2D):c.2944+1del	GUCY2D	Pathogenic	reviewed by expert panel
98602	NM_000180.3(GUCY2D):c.389del (p.Pro130Leufs)	GUCY2D	Pathogenic	reviewed by expert panel
98603	NM_000180.4(GUCY2D):c.3G>A (p.Met1Ile)	GUCY2D	Pathogenic	reviewed by expert panel
98609	NM_000180.4(GUCY2D):c.91dup (p.Arg31fs)	GUCY2D	Pathogenic	reviewed by expert panel
1445009	NM_000180.4(GUCY2D):c.743C>G (p.Ser248Trp)	GUCY2D	Likely pathogenic	reviewed by expert panel
3602089	NM_000180.4(GUCY2D):c.2833C>T (p.His945Tyr)	GUCY2D	Likely pathogenic	reviewed by expert panel
3602091	NM_000180.4(GUCY2D):c.2765A>G (p.Tyr922Cys)	GUCY2D	Likely pathogenic	reviewed by expert panel
3602094	NM_000180.4(GUCY2D):c.82dup (p.Arg28fs)	GUCY2D	Likely pathogenic	reviewed by expert panel
3602095	NM_000180.4(GUCY2D):c.3078_3083dup (p.Leu1028_Arg1029insIleLeu)	GUCY2D	Likely pathogenic	reviewed by expert panel
4538536	NM_000180.4(GUCY2D):c.3020C>A (p.Ser1007Ter)	GUCY2D	Likely pathogenic	reviewed by expert panel
596790	NM_000180.4(GUCY2D):c.2384G>A (p.Arg795Gln)	GUCY2D	Likely pathogenic	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · 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
GUCY2D	Strong	Autosomal dominant	GUCY2D-related dominant retinopathy	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GUCY2D	Orphanet:1872	Cone rod dystrophy
GUCY2D	Orphanet:65	Leber congenital amaurosis
GUCY2D	Orphanet:75377	Central areolar choroidal dystrophy

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GUCY2D	HGNC:4689	ENSG00000132518	Q02846	Retinal guanylyl cyclase 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GUCY2D	Retinal guanylyl cyclase 1	Catalyzes the synthesis of cyclic GMP (cGMP) in rods and cones of photoreceptors.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GUCY2D	Kinase	yes	4.6.1.2	Prot_kinase_dom, A/G_cyclase, Ser-Thr/Tyr_kinase_cat_dom

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
esophagus mucosa	1
lower esophagus mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GUCY2D	121	tissue_specific	marker	buccal mucosa cell, esophagus mucosa, lower esophagus mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GUCY2D	1,083

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GUCY2D	Q02846	82.37

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Inactivation, recovery and regulation of the phototransduction cascade	1	317.2×	0.003	GUCY2D

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 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 opsin-mediated signaling pathway	1	1685.2×	0.001	GUCY2D
cGMP biosynthetic process	1	1404.3×	0.001	GUCY2D
receptor guanylyl cyclase signaling pathway	1	1296.3×	0.001	GUCY2D
obsolete cGMP-mediated signaling	1	802.5×	0.002	GUCY2D
visual perception	1	79.5×	0.013	GUCY2D

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
GUCY2D	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GUCY2D	4.6.1.2	guanylate cyclase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	GUCY2D
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
GUCY2D	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1	2
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03920007	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Study of Subretinally Injected ATSN-101 Administered in Patients With Leber Congenital Amaurosis Caused by Biallelic Mutations in GUCY2D
NCT01014052	PHASE1	COMPLETED	Safety/Proof of Concept Study of Oral QLT091001 in Subjects With Leber Congenital Amaurosis (LCA) or Retinitis Pigmentosa (RP) Due to Retinal Pigment Epithelial 65 Protein (RPE65) or Lecithin:Retinol Acyltransferase (LRAT) Mutations
NCT01521793	PHASE1	COMPLETED	Repeated Treatments of QLT091001 in Subjects With Leber Congenital Amaurosis or Retinitis Pigmentosa (Extension of Study RET IRD 01)

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
POLYMYXIN B	4	1
TRIMETHOPRIM	4	1
ZURETINOL ACETATE	2	2
CHEMBL15720	0	1
CHEMBL2397513	0	1
CHEMBL373756	0	1
CHEMBL3989738	0	1
CHEMBL4636958	0	1
CHEMBL5281080	0	1