PDE6C-Related Retinopathy

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Classifications

Harrison's Part

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Inheritance

1

Autosomal recessive HP:0000007

PDE6C-related retinopathy is caused by biallelic (homozygous or compound heterozygous) pathogenic variants in PDE6C.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:19615668 SUPPORT Human clinical

"Sequence analysis of 104 probands with arCD and 10 probands with ACHM revealed compound heterozygous PDE6C mutations in three complete ACHM patients from two families."

Identifies biallelic (homozygous and compound heterozygous) PDE6C variants in affected individuals, establishing recessive inheritance.

PMID:20301591 SUPPORT Other

"At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier."

GeneReviews states the autosomal recessive recurrence risks that underlie genetic counseling for this disease.

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Subtypes

2

Achromatopsia 5 (PDE6C) MONDO:0800196

Complete or incomplete achromatopsia from biallelic PDE6C variants: a congenital, largely stationary loss of cone function with severe colour vision defect, reduced acuity, photophobia and nystagmus.

Show evidence (1 reference)

PMID:19615668 SUPPORT Human clinical

"Sequence analysis of 104 probands with arCD and 10 probands with ACHM revealed compound heterozygous PDE6C mutations in three complete ACHM patients from two families."

Establishes the complete-achromatopsia pole of the PDE6C spectrum.

Cone Dystrophy 4 (PDE6C) MONDO:0013129

Progressive early-onset autosomal recessive cone (or cone-rod) dystrophy from biallelic PDE6C variants, with loss of visual acuity over decades and structural cone loss on imaging, representing the degenerative pole of the same PDE6C spectrum.

Show evidence (1 reference)

PMID:19615668 SUPPORT Human clinical

"Our findings identify PDE6C as a gene for cone photoreceptor disorders and show that arCD and ACHM constitute genetically and clinically overlapping phenotypes."

Establishes autosomal recessive cone dystrophy as the second, overlapping pole of the PDE6C phenotypic spectrum.

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Pathophysiology

4

PDE6C Catalytic Deficiency

Biallelic PDE6C variants abolish or reduce the catalytic activity of the cone-specific alpha-prime subunit of cGMP phosphodiesterase 6. PDE6 is the effector that hydrolyses cGMP to 5'-GMP during the cone light response, so a catalytic-subunit lesion is the initiating, cone-autonomous defect in the phototransduction cascade.

retinal cone cell CL:0000573

PDE6C hgnc:8787

phototransduction, visible light GO:0007603 ↓ DECREASED

3',5'-cyclic-GMP phosphodiesterase activity GO:0047555 ↓ DECREASED

photoreceptor outer segment GO:0001750

Downstream

Elevated Cone cGMP and Calcium Overload Loss of cGMP hydrolysis leaves cone cGMP and Ca2+ chronically elevated.

Show evidence (3 references)

PMID:19615668 SUPPORT BACKGROUND Human clinical

"The PDE6C gene encodes the cone alpha subunit of cyclic guanosine monophosphate (cGMP) phosphodiesterase, which converts cGMP to 5'-GMP, and thereby plays an essential role in cone phototransduction."

Defines PDE6C as the cone PDE6 catalytic subunit and its essential role in cone phototransduction (stated as established background in the gene-discovery paper).

CGGV:assertion_73ed48ac-bdd6-4608-953d-773da6ade759-2023-11-02T160000.000Z SUPPORT Other

"The mechanism of pathogenicity appears to be loss of function in PDE6C"

ClinGen Retina GCEP records loss of function as the disease mechanism.

PMID:21127010 SUPPORT In vitro / ex vivo

"Four of the six PDE6C missense mutations led to baseline PDE activities and most likely represent functional null alleles."

Recombinant expression shows disease-associated PDE6C missense alleles abolish catalytic activity, confirming the loss-of-function mechanism biochemically.

Elevated Cone cGMP and Calcium Overload

Without PDE6C-mediated hydrolysis, cone outer-segment cGMP stays elevated and the cyclic nucleotide-gated channels stay open, sustaining depolarising Na+/Ca2+ influx. The outer segment loses the cGMP and Ca2+ set point that the light response normally modulates.

retinal cone cell CL:0000573

cGMP catabolic process GO:0046069 ↓ DECREASED

Downstream

Failure of the Cone Light Response With cGMP held high the CNG channels cannot close on illumination, so the cone generates no light-evoked hyperpolarisation.

Progressive Cone Photoreceptor Degeneration Chronically elevated cGMP and Ca2+ are cytotoxic to cones.

Failure of the Cone Light Response

With the cascade unable to lower cGMP, the cone cannot translate absorbed photons into the graded hyperpolarisation that signals light. Cone-driven (photopic) light responses are reduced or abolished while rod-driven (scotopic) responses are preserved, the electrophysiological signature of a cone-autonomous cascade defect.

retinal cone cell CL:0000573

detection of light stimulus involved in visual perception GO:0050908 ↓ DECREASED

Animal models

Rhesus macaque PDE6C R565Q Rhesus macaque recapitulates Homozygotes have absent cone ERG responses from infancy.

Downstream

Color vision defect

Reduced visual acuity

Photophobia

Nystagmus

Abnormal cone electroretinogram

Show evidence (1 reference)

CGGV:assertion_73ed48ac-bdd6-4608-953d-773da6ade759-2023-11-02T160000.000Z SUPPORT Other

"reduced or absent cone/photopic ERG responses, normal rod/scotopic ERG responses"

Documents the selective loss of cone-driven light responses with preserved rod responses that defines this cone-cascade failure.

Progressive Cone Photoreceptor Degeneration

In the degenerative pole of the spectrum, chronically elevated cGMP and Ca2+ drive progressive death of cone photoreceptors, with thinning of the outer nuclear layer and loss of outer-segment structure most marked in the macula. This is the cone-dystrophy (cone dystrophy 4) end of the PDE6C spectrum, and is more pronounced in complete achromatopsia than in early-onset cone dystrophy.

retinal cone cell CL:0000573

photoreceptor cell maintenance GO:0045494 ↓ DECREASED

Animal models

Rhesus macaque PDE6C R565Q Rhesus macaque recapitulates Reduced foveal ONL thickness from infancy with slow progression and macular atrophy.

cpfl1 mouse (Pde6c) Mouse recapitulates Cone death is associated with cGMP accumulation, calpain activity and VASP phosphorylation, grounding the cGMP/Ca2+-overload degeneration edge in primary data.

pde6c(w59) zebrafish Zebrafish partially recapitulates Cone death proceeds through RIP1/RIP3-dependent necroptosis, rescuable by rip3 knockdown.

Downstream

Macular dystrophy

Central scotoma Macular cone loss produces a central scotoma.

Cone/cone-rod dystrophy

Constriction of peripheral visual field In the cone-rod end of the spectrum, rod involvement constricts the visual field.

Nyctalopia Rod involvement in PDE6C-related cone-rod dystrophy produces night blindness.

Show evidence (2 references)

PMID:19615668 SUPPORT Human clinical

"Cross-sectional retinal imaging via optical coherence tomography revealed a more pronounced absence of cone photoreceptors in patients with ACHM compared to patients with early-onset arCD."

Documents structural cone loss on OCT and its gradient across the PDE6C phenotypic spectrum.

PMID:39641747 SUPPORT Model organism

"Cone photoreceptors probably degenerate over time and macular atrophy can occur."

A naturally occurring PDE6C-mutant rhesus macaque model shows progressive cone degeneration with macular atrophy, supporting the degenerative pole.

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Pathograph

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Phenotypes

11

Color vision defect VERY_FREQUENT HP:0000551

Show evidence (3 references)

PMID:31826238 SUPPORT Human clinical

"All subjects presented with early-onset nystagmus, decreased best-corrected visual acuity, light sensitivity, and severe color vision loss, and five of them had high myopia."

Deep-phenotyping series (n=8) reports severe colour vision loss in all subjects.

PMID:33001157 SUPPORT Human clinical

"All cases shared decreased best-corrected visual acuity and poor color discrimination."

A PDE6C-patient cohort reports poor colour discrimination in all cases.

CGGV:assertion_73ed48ac-bdd6-4608-953d-773da6ade759-2023-11-02T160000.000Z SUPPORT Other

"Phenotypes generally occur with congenital or early childhood onset and include severe color vision defects, progressive loss of visual acuity over the course of decades, reduced or absent cone/photopic ERG responses, normal rod/scotopic ERG responses, photophobia, myopia, and/or nystagmus."

ClinGen records severe colour vision defect as a core PDE6C phenotype.

Reduced visual acuity VERY_FREQUENT HP:0007663

Show evidence (3 references)

PMID:31826238 SUPPORT Human clinical

"All subjects presented with early-onset nystagmus, decreased best-corrected visual acuity, light sensitivity, and severe color vision loss, and five of them had high myopia."

Deep-phenotyping series (n=8) reports decreased best-corrected visual acuity in all subjects.

PMID:33001157 SUPPORT Human clinical

"All cases shared decreased best-corrected visual acuity and poor color discrimination."

A PDE6C-patient cohort reports decreased best-corrected visual acuity in all cases.

CGGV:assertion_73ed48ac-bdd6-4608-953d-773da6ade759-2023-11-02T160000.000Z SUPPORT Other

"progressive loss of visual acuity over the course of decades"

ClinGen records progressive loss of visual acuity in PDE6C-related retinopathy.

Photophobia VERY_FREQUENT HP:0000613

Show evidence (2 references)

PMID:31826238 SUPPORT Human clinical

"All subjects presented with early-onset nystagmus, decreased best-corrected visual acuity, light sensitivity, and severe color vision loss, and five of them had high myopia."

Deep-phenotyping series (n=8) reports light sensitivity (photophobia) in all subjects.

CGGV:assertion_73ed48ac-bdd6-4608-953d-773da6ade759-2023-11-02T160000.000Z SUPPORT Other

"reduced or absent cone/photopic ERG responses, normal rod/scotopic ERG responses, photophobia, myopia, and/or nystagmus"

ClinGen records photophobia as a PDE6C phenotype.

Nystagmus VERY_FREQUENT HP:0000639

Show evidence (2 references)

PMID:31826238 SUPPORT Human clinical

"All subjects presented with early-onset nystagmus, decreased best-corrected visual acuity, light sensitivity, and severe color vision loss, and five of them had high myopia."

Deep-phenotyping series (n=8) reports early-onset nystagmus in all subjects.

CGGV:assertion_73ed48ac-bdd6-4608-953d-773da6ade759-2023-11-02T160000.000Z SUPPORT Other

"reduced or absent cone/photopic ERG responses, normal rod/scotopic ERG responses, photophobia, myopia, and/or nystagmus"

ClinGen records nystagmus as a PDE6C phenotype.

High myopia FREQUENT HP:0011003

Show evidence (2 references)

PMID:31826238 SUPPORT Human clinical

"All subjects presented with early-onset nystagmus, decreased best-corrected visual acuity, light sensitivity, and severe color vision loss, and five of them had high myopia."

Deep-phenotyping series reports high myopia in five of eight subjects.

CGGV:assertion_73ed48ac-bdd6-4608-953d-773da6ade759-2023-11-02T160000.000Z SUPPORT Other

"reduced or absent cone/photopic ERG responses, normal rod/scotopic ERG responses, photophobia, myopia, and/or nystagmus"

ClinGen also records myopia among the recurrent PDE6C features.

Abnormal cone electroretinogram HP:0000512

Show evidence (1 reference)

CGGV:assertion_73ed48ac-bdd6-4608-953d-773da6ade759-2023-11-02T160000.000Z SUPPORT Other

"reduced or absent cone/photopic ERG responses, normal rod/scotopic ERG responses"

ClinGen records reduced or absent cone (photopic) ERG responses with preserved rod responses.

Macular dystrophy HP:0007754

Show evidence (1 reference)

CGGV:assertion_73ed48ac-bdd6-4608-953d-773da6ade759-2023-11-02T160000.000Z SUPPORT Other

"At least one patient has been reported with central scotoma and macular retinal pigment epithelium atrophy"

ClinGen records macular RPE atrophy in a PDE6C patient.

Central scotoma HP:0000603

Show evidence (2 references)

CGGV:assertion_73ed48ac-bdd6-4608-953d-773da6ade759-2023-11-02T160000.000Z SUPPORT Other

"At least one patient has been reported with central scotoma and macular retinal pigment epithelium atrophy"

ClinGen records central scotoma in a PDE6C patient.

PMID:20301591 SUPPORT Other

"Achromatopsia is characterized by reduced visual acuity, pendular nystagmus, increased sensitivity to light (photophobia), a small central scotoma, eccentric fixation, and reduced or complete loss of color discrimination."

GeneReviews lists a small central scotoma among the cardinal achromatopsia features.

Cone/cone-rod dystrophy HP:0000548

Show evidence (1 reference)

PMID:33001157 SUPPORT Human clinical

"Three of the four patients had a cone-rod dystrophy, presenting with an ERG showing decreased amplitude on both photopic and scotopic waveforms and a mild to moderately constricted visual field."

Documents cone-rod dystrophy with mixed photopic/scotopic ERG loss in PDE6C patients.

Constriction of peripheral visual field HP:0001133

Show evidence (1 reference)

PMID:33001157 SUPPORT Human clinical

"progressive constriction of the visual field, and night blindness"

Reports progressive visual-field constriction in PDE6C-related cone-rod dystrophy.

Nyctalopia HP:0000662

Show evidence (1 reference)

PMID:33001157 SUPPORT Human clinical

"progressive constriction of the visual field, and night blindness"

Reports night blindness in the cone-rod end of the PDE6C spectrum.

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Genetic Associations

1

PDE6C

Gene: PDE6C hgnc:8787 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:19615668 SUPPORT Human clinical

"Our findings identify PDE6C as a gene for cone photoreceptor disorders and show that arCD and ACHM constitute genetically and clinically overlapping phenotypes."

Gene-discovery paper establishing PDE6C as causative across the cone-disorder spectrum.

Variants (3)

p.R29W

Homozygous missense allele reported in one of two sibling pairs (early-onset arCD and incomplete ACHM) in the gene-discovery study.

Show evidence (1 reference)

PMID:19615668 SUPPORT Human clinical

"Sequence analysis of the coding region of PDE6C revealed homozygous missense mutations (p.R29W, p.Y323N) in both sibling pairs."

Reports the p.R29W homozygous missense allele.

p.Y323N

Homozygous missense allele reported in one of two sibling pairs (early-onset arCD and incomplete ACHM); recombinant p.Y323N retains only ~20% of wild-type PDE activity.

Show evidence (2 references)

PMID:19615668 SUPPORT Human clinical

"Sequence analysis of the coding region of PDE6C revealed homozygous missense mutations (p.R29W, p.Y323N) in both sibling pairs."

Reports the p.Y323N homozygous missense allele.

PMID:21127010 SUPPORT In vitro / ex vivo

"For two mutations, p.E790K and p.Y323N, we observed reduction in PDE activity of approximately 60% and 80%, respectively."

Quantifies the residual catalytic activity of the p.Y323N allele.

p.M455V

Compound-heterozygous missense allele reported with a splice defect in a complete-achromatopsia patient.

Show evidence (1 reference)

PMID:19615668 SUPPORT Human clinical

"the other two had a splice defect and a missense variant (p.M455V)."

Reports the p.M455V missense allele in complete-achromatopsia patients.

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Medical Actions

3

Low vision aids and tinted filters

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Platform: Device

Management is supportive. Tinted or filtering lenses reduce photophobia and improve comfort, and low-vision aids support residual acuity; there is no approved disease-modifying therapy.

Show evidence (1 reference)

PMID:20301591 SUPPORT Other

"Dark or special filter glasses or red-tinted contact lenses to reduce photophobia and potentially improve visual acuity; low vision aids"

GeneReviews management of achromatopsia (which includes PDE6C-related ACHM5) directly supports tinted/filter lenses and low-vision aids.

Genetic counseling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

Autosomal recessive inheritance warrants genetic counseling and molecular confirmation of both alleles.

Show evidence (1 reference)

PMID:19615668 SUPPORT Human clinical

"Sequence analysis of 104 probands with arCD and 10 probands with ACHM revealed compound heterozygous PDE6C mutations in three complete ACHM patients from two families."

Confirms biallelic recessive inheritance underlying genetic counseling.

Ophthalmologic surveillance

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Platform: Other

Periodic ophthalmologic examination monitors for macular and structural change; GeneReviews recommends examination every six to 12 months for children and every two to three years for adults in achromatopsia.

Show evidence (1 reference)

PMID:20301591 SUPPORT Other

"Ophthalmologic examination every six to 12 months for children and every two to three years for adults."

GeneReviews surveillance schedule for achromatopsia, which includes PDE6C-related (ACHM5) disease.

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Diagnosis

3

Molecular genetic testing

Sequencing of PDE6C to identify biallelic pathogenic variants confirms the diagnosis and places the patient on the achromatopsia-to-cone-dystrophy spectrum.

diagnostic procedure NCIT:C18020

Results: Identification of biallelic pathogenic PDE6C variants confirms the diagnosis.

Show evidence (2 references)

PMID:20301591 SUPPORT Other

"Identification of biallelic pathogenic (or likely pathogenic) variants in ATF6, CNGA3, CNGB3, GNAT2, PDE6C, or PDE6H confirms the clinical diagnosis."

GeneReviews states biallelic PDE6C variants confirm the clinical diagnosis of achromatopsia.

PMID:19615668 SUPPORT Human clinical

"Sequence analysis of 104 probands with arCD and 10 probands with ACHM revealed compound heterozygous PDE6C mutations in three complete ACHM patients from two families."

Molecular sequencing identifies the biallelic PDE6C variants that confirm the diagnosis.

Full-field electroretinography

Photopic (cone and flicker) and scotopic (rod) full-field ERG distinguishes the cone-selective dysfunction of PDE6C-related retinopathy.

diagnostic procedure NCIT:C18020

Results: Reduced or absent cone/photopic ERG responses with preserved rod/scotopic responses.

Show evidence (1 reference)

CGGV:assertion_73ed48ac-bdd6-4608-953d-773da6ade759-2023-11-02T160000.000Z SUPPORT Other

"reduced or absent cone/photopic ERG responses, normal rod/scotopic ERG responses"

ERG shows the cone-selective response loss characteristic of PDE6C disease.

Optical coherence tomography

OCT images outer-retinal and cone-photoreceptor structure, which is more severely disrupted in complete achromatopsia than in early-onset cone dystrophy.

diagnostic procedure NCIT:C18020

Results: More pronounced absence of cone photoreceptors in ACHM than in early-onset cone dystrophy. Unlike ATF6-related achromatopsia, PDE6C retinopathy presents without foveal hypoplasia, a useful distinguishing feature.

Show evidence (2 references)

PMID:19615668 SUPPORT Human clinical

"Cross-sectional retinal imaging via optical coherence tomography revealed a more pronounced absence of cone photoreceptors in patients with ACHM compared to patients with early-onset arCD."

OCT resolves the structural cone-loss gradient across the spectrum.

PMID:31826238 SUPPORT Human clinical

"PDE6C retinopathy is a severe cone dysfunction syndrome often presenting as typical achromatopsia but without foveal hypoplasia."

Absence of foveal hypoplasia on OCT distinguishes PDE6C retinopathy from ATF6-related achromatopsia.

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Epidemiology

1

Contribution to achromatopsia and cone dysfunction

PDE6C is a rare cause of achromatopsia and cone dysfunction. In one large screen, twelve affected patients from seven independent families carried PDE6C mutations within a cohort of 492 independent families.

Show evidence (1 reference)

PMID:21127010 SUPPORT Human clinical

"Twelve affected patients from seven independent families segregating PDE6C mutations were identified in our total patient cohort of 492 independent families."

Quantifies the rarity of PDE6C among achromatopsia/cone-dysfunction families.

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Animal Models

3

Rhesus macaque PDE6C R565Q

A naturally occurring homozygous PDE6C missense colony; the only PDE6C model with a true fovea, making it the most translationally relevant for human cone-dystrophy structure.

Species

Rhesus macaque

Genotype

PDE6C c.1694G>A (p.R565Q) homozygous

Publication

PMID:39641747

Pathograph links

Failure of the Cone Light Response recapitulates fidelity: high observes: tissue Homozygotes have absent cone ERG responses from infancy.

Limitations: ERG is a tissue-level summation; the cone-intrinsic signalling step is inferred rather than directly recorded.

Readouts

Light-adapted (cone) electroretinogram

Direction: DECREASED

Interpretation: Absent cone ERG from infancy indicates loss of the cone light response.

Show evidence (1 reference)

PMID:39641747 SUPPORT Model organism

"Homozygotes as young as 3 months postnatal showed absent cone responses on electroretinogram."

Reports absent cone ERG responses in homozygous macaques from infancy.

Progressive Cone Photoreceptor Degeneration recapitulates fidelity: high observes: tissue Reduced foveal ONL thickness from infancy with slow progression and macular atrophy.

Limitations: Progression within adults over four years was modest; degeneration is slow.

Show evidence (1 reference)

PMID:39641747 SUPPORT Model organism

"Cone photoreceptors probably degenerate over time and macular atrophy can occur."

Documents progressive cone degeneration with macular atrophy in the foveate macaque model.

cpfl1 mouse (Pde6c)

The spontaneous cpfl1 mouse carries a Pde6c loss-of-function mutation and is the homologous mouse model of PDE6C achromatopsia; it directly evidences the cGMP-driven cone-death branch.

Species

Mouse

Genotype

Pde6c cpfl1 (cone photoreceptor function loss 1), homozygous

Publication

PMID:20593360

Pathograph links

Progressive Cone Photoreceptor Degeneration recapitulates fidelity: moderate observes: cellular Cone death is associated with cGMP accumulation, calpain activity and VASP phosphorylation, grounding the cGMP/Ca2+-overload degeneration edge in primary data.

Limitations: The mouse is rod-dominant and lacks a fovea, and cone death is far more rapid than in human PDE6C disease.

Readouts

Cone cGMP accumulation

Direction: INCREASED

Interpretation: cGMP accumulation precedes and accompanies cone death, the module's toxic-second-messenger route.

Show evidence (1 reference)

PMID:20593360 SUPPORT Model organism

"cpfl1 cone photoreceptor cell death was associated with an accumulation of cyclic guanosine monophosphate (cGMP), activity of calpains, and phosphorylation of vasodilator-stimulated protein (VASP)."

Directly ties cGMP accumulation to cone photoreceptor death in the PDE6C mouse.

pde6c(w59) zebrafish

The pde6c(w59) zebrafish shows early cone loss; it localises cone death to a necroptotic (RIP1/RIP3) pathway distinct from the rod caspase route.

Species

Zebrafish

Genotype

pde6c(w59) homozygous

Publication

PMID:24413151

Pathograph links

Progressive Cone Photoreceptor Degeneration partially recapitulates fidelity: moderate observes: cellular Cone death proceeds through RIP1/RIP3-dependent necroptosis, rescuable by rip3 knockdown.

Limitations: Zebrafish retinal architecture and regenerative capacity differ markedly from human; the necroptosis mechanism is not confirmed in human PDE6C disease.

Show evidence (1 reference)

PMID:24413151 SUPPORT Model organism

"In pde6c(w59) mutant zebrafish, cone photoreceptors expressed high levels of receptor-interacting protein kinase 1 (RIP1) and receptor-interacting protein kinase 3 (RIP3) kinases, key regulators of necroptotic cell death."

Identifies the necroptotic cone-death mechanism in the PDE6C zebrafish model.

{ }

Source YAML

click to show

name: PDE6C-Related Retinopathy
creation_date: "2026-11-02T00:00:00Z"
category: Mendelian
description: >-
  PDE6C-related retinopathy is an autosomal recessive cone photoreceptor
  disorder caused by biallelic pathogenic variants in PDE6C, which encodes the
  catalytic alpha-prime subunit of the cone-specific cGMP phosphodiesterase 6.
  In the light response, activated cone transducin stimulates PDE6 to hydrolyse
  cGMP to 5'-GMP, lowering outer-segment cGMP and closing the cyclic
  nucleotide-gated channels. Loss of PDE6C catalytic activity leaves cone cGMP
  (and, through the open CNG channels, Ca2+) chronically elevated, so the cone
  cannot generate a normal light response and the same second messengers become
  cytotoxic. The phenotype is a clinical spectrum from complete/incomplete
  achromatopsia (ACHM5) to progressive early-onset cone and cone-rod dystrophy
  (cone dystrophy 4), distinguished largely by the rate of structural cone loss.
  This entry captures the PDE6C-specific gene-disease mechanism and spectrum;
  Achromatopsia.yaml models the ACHM5 subtype within the broader achromatopsia
  umbrella and should be consulted for cross-gene comparison within that
  phenotype.
synonyms:
- achromatopsia 5
- cone dystrophy 4
- PDE6C-related cone dystrophy
- PDE6C-related cone-rod dystrophy
parents:
- Ophthalmological Disease
- Retinal Dystrophy
- Inherited retinal dystrophy
notes: >-
  PDE6C is the cone-specific catalytic subunit of PDE6; it is the direct cone
  counterpart of the rod catalytic subunits PDE6A and PDE6B. Because loss of
  PDE6C catalytic activity parks cone cGMP high rather than merely silencing the
  response, this gene sits on the degenerative side of the phototransduction
  spectrum, which is why its phenotype spans stationary achromatopsia through
  progressive cone/cone-rod dystrophy depending on residual activity. The
  PDE6C-specific phenotype statements below are restricted to gene-specific
  sources (the ClinGen Retina GCEP curation and the PDE6C gene-discovery cohort)
  rather than generic achromatopsia descriptions.
disease_term:
  preferred_term: PDE6C-related retinopathy
  term:
    id: MONDO:1040028
    label: PDE6C-related retinopathy
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    PDE6C-related retinopathy is caused by biallelic (homozygous or compound
    heterozygous) pathogenic variants in PDE6C.
  evidence:
  - reference: PMID:19615668
    reference_title: "Homozygosity mapping reveals PDE6C mutations in patients with early-onset cone photoreceptor disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sequence analysis of 104 probands with arCD and 10 probands with ACHM revealed compound heterozygous PDE6C mutations in three complete ACHM patients from two families."
    explanation: >-
      Identifies biallelic (homozygous and compound heterozygous) PDE6C variants
      in affected individuals, establishing recessive inheritance.
  - reference: PMID:20301591
    reference_title: "Achromatopsia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier."
    explanation: >-
      GeneReviews states the autosomal recessive recurrence risks that underlie
      genetic counseling for this disease.
has_subtypes:
- name: ACHM5
  display_name: Achromatopsia 5 (PDE6C)
  description: >-
    Complete or incomplete achromatopsia from biallelic PDE6C variants: a
    congenital, largely stationary loss of cone function with severe colour
    vision defect, reduced acuity, photophobia and nystagmus.
  subtype_term:
    preferred_term: achromatopsia 5
    term:
      id: MONDO:0800196
      label: achromatopsia 5
  evidence:
  - reference: PMID:19615668
    reference_title: "Homozygosity mapping reveals PDE6C mutations in patients with early-onset cone photoreceptor disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sequence analysis of 104 probands with arCD and 10 probands with ACHM revealed compound heterozygous PDE6C mutations in three complete ACHM patients from two families."
    explanation: Establishes the complete-achromatopsia pole of the PDE6C spectrum.
- name: Cone Dystrophy 4
  display_name: Cone Dystrophy 4 (PDE6C)
  description: >-
    Progressive early-onset autosomal recessive cone (or cone-rod) dystrophy
    from biallelic PDE6C variants, with loss of visual acuity over decades and
    structural cone loss on imaging, representing the degenerative pole of the
    same PDE6C spectrum.
  subtype_term:
    preferred_term: cone dystrophy 4
    term:
      id: MONDO:0013129
      label: cone dystrophy 4
  evidence:
  - reference: PMID:19615668
    reference_title: "Homozygosity mapping reveals PDE6C mutations in patients with early-onset cone photoreceptor disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings identify PDE6C as a gene for cone photoreceptor disorders and show that arCD and ACHM constitute genetically and clinically overlapping phenotypes."
    explanation: >-
      Establishes autosomal recessive cone dystrophy as the second, overlapping
      pole of the PDE6C phenotypic spectrum.
pathophysiology:
- name: PDE6C Catalytic Deficiency
  conforms_to: "phototransduction_cascade_dysfunction#Phototransduction Cascade Component Defect"
  description: >-
    Biallelic PDE6C variants abolish or reduce the catalytic activity of the
    cone-specific alpha-prime subunit of cGMP phosphodiesterase 6. PDE6 is the
    effector that hydrolyses cGMP to 5'-GMP during the cone light response, so a
    catalytic-subunit lesion is the initiating, cone-autonomous defect in the
    phototransduction cascade.
  role: trigger
  biological_scale: MOLECULAR
  genes:
  - preferred_term: PDE6C
    term:
      id: hgnc:8787
      label: PDE6C
  cell_types:
  - preferred_term: retinal cone cell
    term:
      id: CL:0000573
      label: retinal cone cell
  cellular_components:
  - preferred_term: photoreceptor outer segment
    term:
      id: GO:0001750
      label: photoreceptor outer segment
  molecular_functions:
  - preferred_term: 3',5'-cyclic-GMP phosphodiesterase activity
    term:
      id: GO:0047555
      label: 3',5'-cyclic-GMP phosphodiesterase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: phototransduction, visible light
    term:
      id: GO:0007603
      label: phototransduction, visible light
    modifier: DECREASED
  downstream:
  - target: Elevated Cone cGMP and Calcium Overload
    causal_link_type: DIRECT
    description: Loss of cGMP hydrolysis leaves cone cGMP and Ca2+ chronically elevated.
    evidence:
    - reference: PMID:19615668
      reference_title: "Homozygosity mapping reveals PDE6C mutations in patients with early-onset cone photoreceptor disorders."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The PDE6C gene encodes the cone alpha subunit of cyclic guanosine monophosphate (cGMP) phosphodiesterase, which converts cGMP to 5'-GMP, and thereby plays an essential role in cone phototransduction."
      explanation: >-
        Establishes the catalytic reaction PDE6C performs, so loss of that
        activity directly leaves cGMP un-hydrolysed.
  evidence:
  - reference: PMID:19615668
    reference_title: "Homozygosity mapping reveals PDE6C mutations in patients with early-onset cone photoreceptor disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "The PDE6C gene encodes the cone alpha subunit of cyclic guanosine monophosphate (cGMP) phosphodiesterase, which converts cGMP to 5'-GMP, and thereby plays an essential role in cone phototransduction."
    explanation: Defines PDE6C as the cone PDE6 catalytic subunit and its essential role in cone phototransduction (stated as established background in the gene-discovery paper).
  - reference: CGGV:assertion_73ed48ac-bdd6-4608-953d-773da6ade759-2023-11-02T160000.000Z
    reference_title: "PDE6C / PDE6C-related retinopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The mechanism of pathogenicity appears to be loss of function in PDE6C"
    explanation: ClinGen Retina GCEP records loss of function as the disease mechanism.
  - reference: PMID:21127010
    reference_title: "Decreased catalytic activity and altered activation properties of PDE6C mutants associated with autosomal recessive achromatopsia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Four of the six PDE6C missense mutations led to baseline PDE activities and most likely represent functional null alleles."
    explanation: >-
      Recombinant expression shows disease-associated PDE6C missense alleles
      abolish catalytic activity, confirming the loss-of-function mechanism
      biochemically.
- name: Elevated Cone cGMP and Calcium Overload
  conforms_to: "phototransduction_cascade_dysfunction#Loss of Outer-Segment cGMP and Calcium Set-Point Control"
  description: >-
    Without PDE6C-mediated hydrolysis, cone outer-segment cGMP stays elevated and
    the cyclic nucleotide-gated channels stay open, sustaining depolarising
    Na+/Ca2+ influx. The outer segment loses the cGMP and Ca2+ set point that the
    light response normally modulates.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: retinal cone cell
    term:
      id: CL:0000573
      label: retinal cone cell
  biological_processes:
  - preferred_term: cGMP catabolic process
    term:
      id: GO:0046069
      label: cGMP catabolic process
    modifier: DECREASED
  downstream:
  - target: Failure of the Cone Light Response
    causal_link_type: DIRECT
    description: >-
      With cGMP held high the CNG channels cannot close on illumination, so the
      cone generates no light-evoked hyperpolarisation.
  - target: Progressive Cone Photoreceptor Degeneration
    causal_link_type: DIRECT
    description: Chronically elevated cGMP and Ca2+ are cytotoxic to cones.
    evidence:
    - reference: PMID:20593360
      reference_title: "cGMP-dependent cone photoreceptor degeneration in the cpfl1 mouse retina."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "cpfl1 cone photoreceptor cell death was associated with an accumulation of cyclic guanosine monophosphate (cGMP), activity of calpains, and phosphorylation of vasodilator-stimulated protein (VASP)."
      explanation: >-
        The PDE6C (cpfl1) mouse directly ties cone cGMP accumulation to cone
        photoreceptor death, grounding this edge in primary data.
    - reference: CGGV:assertion_73ed48ac-bdd6-4608-953d-773da6ade759-2023-11-02T160000.000Z
      reference_title: "PDE6C / PDE6C-related retinopathy (Definitive)"
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These models also collectively exhibit progressive thinning of the outer nuclear layer and photoreceptor outer segments within the macula, caused by rapid and progressive loss of cone photoreceptors"
      explanation: >-
        Animal models of PDE6C loss show the chronic cGMP/Ca2+ state proceeds to
        progressive cone death.
- name: Failure of the Cone Light Response
  conforms_to: "phototransduction_cascade_dysfunction#Failure of Photoreceptor Light-Response Generation or Timely Recovery"
  description: >-
    With the cascade unable to lower cGMP, the cone cannot translate absorbed
    photons into the graded hyperpolarisation that signals light. Cone-driven
    (photopic) light responses are reduced or abolished while rod-driven
    (scotopic) responses are preserved, the electrophysiological signature of a
    cone-autonomous cascade defect.
  role: central_effector
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: retinal cone cell
    term:
      id: CL:0000573
      label: retinal cone cell
  biological_processes:
  - preferred_term: detection of light stimulus involved in visual perception
    term:
      id: GO:0050908
      label: detection of light stimulus involved in visual perception
    modifier: DECREASED
  downstream:
  - target: Color vision defect
    causal_link_type: DIRECT
  - target: Reduced visual acuity
    causal_link_type: DIRECT
  - target: Photophobia
    causal_link_type: DIRECT
  - target: Nystagmus
    causal_link_type: DIRECT
  - target: Abnormal cone electroretinogram
    causal_link_type: DIRECT
  evidence:
  - reference: CGGV:assertion_73ed48ac-bdd6-4608-953d-773da6ade759-2023-11-02T160000.000Z
    reference_title: "PDE6C / PDE6C-related retinopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "reduced or absent cone/photopic ERG responses, normal rod/scotopic ERG responses"
    explanation: >-
      Documents the selective loss of cone-driven light responses with preserved
      rod responses that defines this cone-cascade failure.
- name: Progressive Cone Photoreceptor Degeneration
  conforms_to: "phototransduction_cascade_dysfunction#cGMP and Calcium Overload Handoff to Photoreceptor Degeneration"
  description: >-
    In the degenerative pole of the spectrum, chronically elevated cGMP and Ca2+
    drive progressive death of cone photoreceptors, with thinning of the outer
    nuclear layer and loss of outer-segment structure most marked in the macula.
    This is the cone-dystrophy (cone dystrophy 4) end of the PDE6C spectrum, and
    is more pronounced in complete achromatopsia than in early-onset cone
    dystrophy.
  role: consequence
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: retinal cone cell
    term:
      id: CL:0000573
      label: retinal cone cell
  biological_processes:
  - preferred_term: photoreceptor cell maintenance
    term:
      id: GO:0045494
      label: photoreceptor cell maintenance
    modifier: DECREASED
  downstream:
  - target: Macular dystrophy
    causal_link_type: DIRECT
  - target: Central scotoma
    causal_link_type: DIRECT
    description: Macular cone loss produces a central scotoma.
  - target: Cone/cone-rod dystrophy
    causal_link_type: DIRECT
  - target: Constriction of peripheral visual field
    causal_link_type: DIRECT
    description: In the cone-rod end of the spectrum, rod involvement constricts the visual field.
  - target: Nyctalopia
    causal_link_type: DIRECT
    description: Rod involvement in PDE6C-related cone-rod dystrophy produces night blindness.
  evidence:
  - reference: PMID:19615668
    reference_title: "Homozygosity mapping reveals PDE6C mutations in patients with early-onset cone photoreceptor disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cross-sectional retinal imaging via optical coherence tomography revealed a more pronounced absence of cone photoreceptors in patients with ACHM compared to patients with early-onset arCD."
    explanation: >-
      Documents structural cone loss on OCT and its gradient across the PDE6C
      phenotypic spectrum.
  - reference: PMID:39641747
    reference_title: "Onset and Progression of Disease in Nonhuman Primates With PDE6C Cone Disorder."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Cone photoreceptors probably degenerate over time and macular atrophy can occur."
    explanation: >-
      A naturally occurring PDE6C-mutant rhesus macaque model shows progressive
      cone degeneration with macular atrophy, supporting the degenerative pole.
phenotypes:
- name: Color vision defect
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Color vision defect
    term:
      id: HP:0000551
      label: Color vision defect
  evidence:
  - reference: PMID:31826238
    reference_title: "Deep Phenotyping of PDE6C-Associated Achromatopsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All subjects presented with early-onset nystagmus, decreased best-corrected visual acuity, light sensitivity, and severe color vision loss, and five of them had high myopia."
    explanation: Deep-phenotyping series (n=8) reports severe colour vision loss in all subjects.
  - reference: PMID:33001157
    reference_title: "PDE6C: Novel Mutations, Atypical Phenotype, and Differences Among Children and Adults."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All cases shared decreased best-corrected visual acuity and poor color discrimination."
    explanation: A PDE6C-patient cohort reports poor colour discrimination in all cases.
  - reference: CGGV:assertion_73ed48ac-bdd6-4608-953d-773da6ade759-2023-11-02T160000.000Z
    reference_title: "PDE6C / PDE6C-related retinopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Phenotypes generally occur with congenital or early childhood onset and include severe color vision defects, progressive loss of visual acuity over the course of decades, reduced or absent cone/photopic ERG responses, normal rod/scotopic ERG responses, photophobia, myopia, and/or nystagmus."
    explanation: ClinGen records severe colour vision defect as a core PDE6C phenotype.
- name: Reduced visual acuity
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Reduced visual acuity
    term:
      id: HP:0007663
      label: Reduced visual acuity
  evidence:
  - reference: PMID:31826238
    reference_title: "Deep Phenotyping of PDE6C-Associated Achromatopsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All subjects presented with early-onset nystagmus, decreased best-corrected visual acuity, light sensitivity, and severe color vision loss, and five of them had high myopia."
    explanation: Deep-phenotyping series (n=8) reports decreased best-corrected visual acuity in all subjects.
  - reference: PMID:33001157
    reference_title: "PDE6C: Novel Mutations, Atypical Phenotype, and Differences Among Children and Adults."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All cases shared decreased best-corrected visual acuity and poor color discrimination."
    explanation: A PDE6C-patient cohort reports decreased best-corrected visual acuity in all cases.
  - reference: CGGV:assertion_73ed48ac-bdd6-4608-953d-773da6ade759-2023-11-02T160000.000Z
    reference_title: "PDE6C / PDE6C-related retinopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "progressive loss of visual acuity over the course of decades"
    explanation: ClinGen records progressive loss of visual acuity in PDE6C-related retinopathy.
- name: Photophobia
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Photophobia
    term:
      id: HP:0000613
      label: Photophobia
  evidence:
  - reference: PMID:31826238
    reference_title: "Deep Phenotyping of PDE6C-Associated Achromatopsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All subjects presented with early-onset nystagmus, decreased best-corrected visual acuity, light sensitivity, and severe color vision loss, and five of them had high myopia."
    explanation: Deep-phenotyping series (n=8) reports light sensitivity (photophobia) in all subjects.
  - reference: CGGV:assertion_73ed48ac-bdd6-4608-953d-773da6ade759-2023-11-02T160000.000Z
    reference_title: "PDE6C / PDE6C-related retinopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "reduced or absent cone/photopic ERG responses, normal rod/scotopic ERG responses, photophobia, myopia, and/or nystagmus"
    explanation: ClinGen records photophobia as a PDE6C phenotype.
- name: Nystagmus
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:31826238
    reference_title: "Deep Phenotyping of PDE6C-Associated Achromatopsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All subjects presented with early-onset nystagmus, decreased best-corrected visual acuity, light sensitivity, and severe color vision loss, and five of them had high myopia."
    explanation: Deep-phenotyping series (n=8) reports early-onset nystagmus in all subjects.
  - reference: CGGV:assertion_73ed48ac-bdd6-4608-953d-773da6ade759-2023-11-02T160000.000Z
    reference_title: "PDE6C / PDE6C-related retinopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "reduced or absent cone/photopic ERG responses, normal rod/scotopic ERG responses, photophobia, myopia, and/or nystagmus"
    explanation: ClinGen records nystagmus as a PDE6C phenotype.
- name: High myopia
  frequency: FREQUENT
  description: >-
    High myopia was present in five of eight subjects in the deep-phenotyping
    series; ClinGen also records myopia among the recurrent features.
  phenotype_term:
    preferred_term: High myopia
    term:
      id: HP:0011003
      label: High myopia
  evidence:
  - reference: PMID:31826238
    reference_title: "Deep Phenotyping of PDE6C-Associated Achromatopsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All subjects presented with early-onset nystagmus, decreased best-corrected visual acuity, light sensitivity, and severe color vision loss, and five of them had high myopia."
    explanation: Deep-phenotyping series reports high myopia in five of eight subjects.
  - reference: CGGV:assertion_73ed48ac-bdd6-4608-953d-773da6ade759-2023-11-02T160000.000Z
    reference_title: "PDE6C / PDE6C-related retinopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "reduced or absent cone/photopic ERG responses, normal rod/scotopic ERG responses, photophobia, myopia, and/or nystagmus"
    explanation: ClinGen also records myopia among the recurrent PDE6C features.
- name: Abnormal cone electroretinogram
  phenotype_term:
    preferred_term: Abnormal electroretinogram
    term:
      id: HP:0000512
      label: Abnormal electroretinogram
  evidence:
  - reference: CGGV:assertion_73ed48ac-bdd6-4608-953d-773da6ade759-2023-11-02T160000.000Z
    reference_title: "PDE6C / PDE6C-related retinopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "reduced or absent cone/photopic ERG responses, normal rod/scotopic ERG responses"
    explanation: >-
      ClinGen records reduced or absent cone (photopic) ERG responses with
      preserved rod responses.
- name: Macular dystrophy
  description: >-
    Macular retinal pigment epithelium atrophy and outer-retinal thinning have
    been reported, consistent with the degenerative (cone dystrophy) pole.
  phenotype_term:
    preferred_term: Macular dystrophy
    term:
      id: HP:0007754
      label: Macular dystrophy
  evidence:
  - reference: CGGV:assertion_73ed48ac-bdd6-4608-953d-773da6ade759-2023-11-02T160000.000Z
    reference_title: "PDE6C / PDE6C-related retinopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "At least one patient has been reported with central scotoma and macular retinal pigment epithelium atrophy"
    explanation: ClinGen records macular RPE atrophy in a PDE6C patient.
- name: Central scotoma
  phenotype_term:
    preferred_term: Central scotoma
    term:
      id: HP:0000603
      label: Central scotoma
  evidence:
  - reference: CGGV:assertion_73ed48ac-bdd6-4608-953d-773da6ade759-2023-11-02T160000.000Z
    reference_title: "PDE6C / PDE6C-related retinopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "At least one patient has been reported with central scotoma and macular retinal pigment epithelium atrophy"
    explanation: ClinGen records central scotoma in a PDE6C patient.
  - reference: PMID:20301591
    reference_title: "Achromatopsia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Achromatopsia is characterized by reduced visual acuity, pendular nystagmus, increased sensitivity to light (photophobia), a small central scotoma, eccentric fixation, and reduced or complete loss of color discrimination."
    explanation: GeneReviews lists a small central scotoma among the cardinal achromatopsia features.
- name: Cone/cone-rod dystrophy
  description: >-
    Biallelic PDE6C variants cause cone dystrophy and, in a subset, cone-rod
    dystrophy, the degenerative pole of the spectrum (cone dystrophy 4).
  phenotype_term:
    preferred_term: Cone/cone-rod dystrophy
    term:
      id: HP:0000548
      label: Cone/cone-rod dystrophy
  evidence:
  - reference: PMID:33001157
    reference_title: "PDE6C: Novel Mutations, Atypical Phenotype, and Differences Among Children and Adults."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three of the four patients had a cone-rod dystrophy, presenting with an ERG showing decreased amplitude on both photopic and scotopic waveforms and a mild to moderately constricted visual field."
    explanation: Documents cone-rod dystrophy with mixed photopic/scotopic ERG loss in PDE6C patients.
- name: Constriction of peripheral visual field
  phenotype_term:
    preferred_term: Constriction of peripheral visual field
    term:
      id: HP:0001133
      label: Constriction of peripheral visual field
  evidence:
  - reference: PMID:33001157
    reference_title: "PDE6C: Novel Mutations, Atypical Phenotype, and Differences Among Children and Adults."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "progressive constriction of the visual field, and night blindness"
    explanation: Reports progressive visual-field constriction in PDE6C-related cone-rod dystrophy.
- name: Nyctalopia
  phenotype_term:
    preferred_term: Nyctalopia
    term:
      id: HP:0000662
      label: Nyctalopia
  evidence:
  - reference: PMID:33001157
    reference_title: "PDE6C: Novel Mutations, Atypical Phenotype, and Differences Among Children and Adults."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "progressive constriction of the visual field, and night blindness"
    explanation: Reports night blindness in the cone-rod end of the PDE6C spectrum.
genetic:
- name: PDE6C
  gene_term:
    preferred_term: PDE6C
    term:
      id: hgnc:8787
      label: PDE6C
  relationship_type: CAUSATIVE
  features: >-
    Biallelic PDE6C variants reported to date include missense, nonsense,
    frameshift and splice-site changes; the gene-discovery cohort reported the
    homozygous missense alleles p.R29W and p.Y323N and a compound-heterozygous
    missense allele p.M455V. The mechanism of pathogenicity is loss of PDE6C
    catalytic function.
  case_fractions:
  - population: ACHM cohort (1074 independent families; Weisschuh et al., cited by Georgiou 2019)
    case_fraction_percent: 2.4
    notes: PDE6C is a low-prevalence achromatopsia genotype.
    evidence:
    - reference: PMID:31826238
      reference_title: "Deep Phenotyping of PDE6C-Associated Achromatopsia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A recent study by Weisschuh et al.11 estimated the prevalence of the PDE6C genotype to be 2.4% in a cohort of 1074 independent ACHM families."
      explanation: Gives the PDE6C share of a large achromatopsia cohort.
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_73ed48ac-bdd6-4608-953d-773da6ade759-2023-11-02T160000.000Z
    evidence:
    - reference: CGGV:assertion_73ed48ac-bdd6-4608-953d-773da6ade759-2023-11-02T160000.000Z
      reference_title: "PDE6C / PDE6C-related retinopathy (Definitive)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "PDE6C | HGNC:8787 | PDE6C-related retinopathy | MONDO:1040028 | AR | Definitive | SOP10 | Retina Gene Curation Expert Panel | 2023-11-02T16:00:00.000Z"
      explanation: ClinGen Retina GCEP classifies the PDE6C-retinopathy relationship as Definitive (AR).
  variants:
  - name: p.R29W
    description: Homozygous missense allele reported in one of two sibling pairs (early-onset arCD and incomplete ACHM) in the gene-discovery study.
    evidence:
    - reference: PMID:19615668
      reference_title: "Homozygosity mapping reveals PDE6C mutations in patients with early-onset cone photoreceptor disorders."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Sequence analysis of the coding region of PDE6C revealed homozygous missense mutations (p.R29W, p.Y323N) in both sibling pairs."
      explanation: Reports the p.R29W homozygous missense allele.
  - name: p.Y323N
    description: Homozygous missense allele reported in one of two sibling pairs (early-onset arCD and incomplete ACHM); recombinant p.Y323N retains only ~20% of wild-type PDE activity.
    evidence:
    - reference: PMID:19615668
      reference_title: "Homozygosity mapping reveals PDE6C mutations in patients with early-onset cone photoreceptor disorders."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Sequence analysis of the coding region of PDE6C revealed homozygous missense mutations (p.R29W, p.Y323N) in both sibling pairs."
      explanation: Reports the p.Y323N homozygous missense allele.
    - reference: PMID:21127010
      reference_title: "Decreased catalytic activity and altered activation properties of PDE6C mutants associated with autosomal recessive achromatopsia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "For two mutations, p.E790K and p.Y323N, we observed reduction in PDE activity of approximately 60% and 80%, respectively."
      explanation: Quantifies the residual catalytic activity of the p.Y323N allele.
  - name: p.M455V
    description: Compound-heterozygous missense allele reported with a splice defect in a complete-achromatopsia patient.
    evidence:
    - reference: PMID:19615668
      reference_title: "Homozygosity mapping reveals PDE6C mutations in patients with early-onset cone photoreceptor disorders."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the other two had a splice defect and a missense variant (p.M455V)."
      explanation: Reports the p.M455V missense allele in complete-achromatopsia patients.
  evidence:
  - reference: PMID:19615668
    reference_title: "Homozygosity mapping reveals PDE6C mutations in patients with early-onset cone photoreceptor disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings identify PDE6C as a gene for cone photoreceptor disorders and show that arCD and ACHM constitute genetically and clinically overlapping phenotypes."
    explanation: Gene-discovery paper establishing PDE6C as causative across the cone-disorder spectrum.
animal_models:
- name: Rhesus macaque PDE6C R565Q
  species: Rhesus macaque
  genotype: PDE6C c.1694G>A (p.R565Q) homozygous
  publication: PMID:39641747
  description: >-
    A naturally occurring homozygous PDE6C missense colony; the only PDE6C model
    with a true fovea, making it the most translationally relevant for human
    cone-dystrophy structure.
  modeled_mechanisms:
  - target: Failure of the Cone Light Response
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: TISSUE
    description: Homozygotes have absent cone ERG responses from infancy.
    limitations: >-
      ERG is a tissue-level summation; the cone-intrinsic signalling step is
      inferred rather than directly recorded.
    readouts:
    - name: Light-adapted (cone) electroretinogram
      target: Failure of the Cone Light Response
      direction: DECREASED
      interpretation: Absent cone ERG from infancy indicates loss of the cone light response.
      evidence:
      - reference: PMID:39641747
        reference_title: "Onset and Progression of Disease in Nonhuman Primates With PDE6C Cone Disorder."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Homozygotes as young as 3 months postnatal showed absent cone responses on electroretinogram."
        explanation: Reports absent cone ERG responses in homozygous macaques from infancy.
  - target: Progressive Cone Photoreceptor Degeneration
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: TISSUE
    description: Reduced foveal ONL thickness from infancy with slow progression and macular atrophy.
    limitations: Progression within adults over four years was modest; degeneration is slow.
    evidence:
    - reference: PMID:39641747
      reference_title: "Onset and Progression of Disease in Nonhuman Primates With PDE6C Cone Disorder."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Cone photoreceptors probably degenerate over time and macular atrophy can occur."
      explanation: Documents progressive cone degeneration with macular atrophy in the foveate macaque model.
- name: cpfl1 mouse (Pde6c)
  species: Mouse
  genotype: Pde6c cpfl1 (cone photoreceptor function loss 1), homozygous
  publication: PMID:20593360
  description: >-
    The spontaneous cpfl1 mouse carries a Pde6c loss-of-function mutation and is
    the homologous mouse model of PDE6C achromatopsia; it directly evidences the
    cGMP-driven cone-death branch.
  modeled_mechanisms:
  - target: Progressive Cone Photoreceptor Degeneration
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Cone death is associated with cGMP accumulation, calpain activity and VASP
      phosphorylation, grounding the cGMP/Ca2+-overload degeneration edge in
      primary data.
    limitations: >-
      The mouse is rod-dominant and lacks a fovea, and cone death is far more
      rapid than in human PDE6C disease.
    readouts:
    - name: Cone cGMP accumulation
      target: Progressive Cone Photoreceptor Degeneration
      direction: INCREASED
      interpretation: cGMP accumulation precedes and accompanies cone death, the module's toxic-second-messenger route.
      evidence:
      - reference: PMID:20593360
        reference_title: "cGMP-dependent cone photoreceptor degeneration in the cpfl1 mouse retina."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "cpfl1 cone photoreceptor cell death was associated with an accumulation of cyclic guanosine monophosphate (cGMP), activity of calpains, and phosphorylation of vasodilator-stimulated protein (VASP)."
        explanation: Directly ties cGMP accumulation to cone photoreceptor death in the PDE6C mouse.
- name: pde6c(w59) zebrafish
  species: Zebrafish
  genotype: pde6c(w59) homozygous
  publication: PMID:24413151
  description: >-
    The pde6c(w59) zebrafish shows early cone loss; it localises cone death to a
    necroptotic (RIP1/RIP3) pathway distinct from the rod caspase route.
  modeled_mechanisms:
  - target: Progressive Cone Photoreceptor Degeneration
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Cone death proceeds through RIP1/RIP3-dependent necroptosis, rescuable by rip3 knockdown.
    limitations: >-
      Zebrafish retinal architecture and regenerative capacity differ markedly
      from human; the necroptosis mechanism is not confirmed in human PDE6C disease.
    evidence:
    - reference: PMID:24413151
      reference_title: "Rip3 knockdown rescues photoreceptor cell death in blind pde6c zebrafish."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In pde6c(w59) mutant zebrafish, cone photoreceptors expressed high levels of receptor-interacting protein kinase 1 (RIP1) and receptor-interacting protein kinase 3 (RIP3) kinases, key regulators of necroptotic cell death."
      explanation: Identifies the necroptotic cone-death mechanism in the PDE6C zebrafish model.
treatments:
- name: Low vision aids and tinted filters
  therapeutic_modality: DEVICE
  description: >-
    Management is supportive. Tinted or filtering lenses reduce photophobia and
    improve comfort, and low-vision aids support residual acuity; there is no
    approved disease-modifying therapy.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301591
    reference_title: "Achromatopsia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Dark or special filter glasses or red-tinted contact lenses to reduce photophobia and potentially improve visual acuity; low vision aids"
    explanation: >-
      GeneReviews management of achromatopsia (which includes PDE6C-related
      ACHM5) directly supports tinted/filter lenses and low-vision aids.
- name: Genetic counseling
  therapeutic_modality: BEHAVIORAL
  description: >-
    Autosomal recessive inheritance warrants genetic counseling and molecular
    confirmation of both alleles.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:19615668
    reference_title: "Homozygosity mapping reveals PDE6C mutations in patients with early-onset cone photoreceptor disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sequence analysis of 104 probands with arCD and 10 probands with ACHM revealed compound heterozygous PDE6C mutations in three complete ACHM patients from two families."
    explanation: Confirms biallelic recessive inheritance underlying genetic counseling.
- name: Ophthalmologic surveillance
  therapeutic_modality: OTHER
  description: >-
    Periodic ophthalmologic examination monitors for macular and structural
    change; GeneReviews recommends examination every six to 12 months for
    children and every two to three years for adults in achromatopsia.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301591
    reference_title: "Achromatopsia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Ophthalmologic examination every six to 12 months for children and every two to three years for adults."
    explanation: GeneReviews surveillance schedule for achromatopsia, which includes PDE6C-related (ACHM5) disease.
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
  - classification_value: NEUROLOGIC
diagnosis:
- name: Molecular genetic testing
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  description: >-
    Sequencing of PDE6C to identify biallelic pathogenic variants confirms the
    diagnosis and places the patient on the achromatopsia-to-cone-dystrophy
    spectrum.
  results: >-
    Identification of biallelic pathogenic PDE6C variants confirms the diagnosis.
  evidence:
  - reference: PMID:20301591
    reference_title: "Achromatopsia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Identification of biallelic pathogenic (or likely pathogenic) variants in ATF6, CNGA3, CNGB3, GNAT2, PDE6C, or PDE6H confirms the clinical diagnosis."
    explanation: GeneReviews states biallelic PDE6C variants confirm the clinical diagnosis of achromatopsia.
  - reference: PMID:19615668
    reference_title: "Homozygosity mapping reveals PDE6C mutations in patients with early-onset cone photoreceptor disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sequence analysis of 104 probands with arCD and 10 probands with ACHM revealed compound heterozygous PDE6C mutations in three complete ACHM patients from two families."
    explanation: Molecular sequencing identifies the biallelic PDE6C variants that confirm the diagnosis.
- name: Full-field electroretinography
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  description: >-
    Photopic (cone and flicker) and scotopic (rod) full-field ERG distinguishes
    the cone-selective dysfunction of PDE6C-related retinopathy.
  results: >-
    Reduced or absent cone/photopic ERG responses with preserved rod/scotopic
    responses.
  evidence:
  - reference: CGGV:assertion_73ed48ac-bdd6-4608-953d-773da6ade759-2023-11-02T160000.000Z
    reference_title: "PDE6C / PDE6C-related retinopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "reduced or absent cone/photopic ERG responses, normal rod/scotopic ERG responses"
    explanation: ERG shows the cone-selective response loss characteristic of PDE6C disease.
- name: Optical coherence tomography
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  description: >-
    OCT images outer-retinal and cone-photoreceptor structure, which is more
    severely disrupted in complete achromatopsia than in early-onset cone
    dystrophy.
  results: >-
    More pronounced absence of cone photoreceptors in ACHM than in early-onset
    cone dystrophy. Unlike ATF6-related achromatopsia, PDE6C retinopathy presents
    without foveal hypoplasia, a useful distinguishing feature.
  evidence:
  - reference: PMID:19615668
    reference_title: "Homozygosity mapping reveals PDE6C mutations in patients with early-onset cone photoreceptor disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cross-sectional retinal imaging via optical coherence tomography revealed a more pronounced absence of cone photoreceptors in patients with ACHM compared to patients with early-onset arCD."
    explanation: OCT resolves the structural cone-loss gradient across the spectrum.
  - reference: PMID:31826238
    reference_title: "Deep Phenotyping of PDE6C-Associated Achromatopsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PDE6C retinopathy is a severe cone dysfunction syndrome often presenting as typical achromatopsia but without foveal hypoplasia."
    explanation: Absence of foveal hypoplasia on OCT distinguishes PDE6C retinopathy from ATF6-related achromatopsia.
epidemiology:
- name: Contribution to achromatopsia and cone dysfunction
  description: >-
    PDE6C is a rare cause of achromatopsia and cone dysfunction. In one large
    screen, twelve affected patients from seven independent families carried
    PDE6C mutations within a cohort of 492 independent families.
  evidence:
  - reference: PMID:21127010
    reference_title: "Decreased catalytic activity and altered activation properties of PDE6C mutants associated with autosomal recessive achromatopsia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Twelve affected patients from seven independent families segregating PDE6C mutations were identified in our total patient cohort of 492 independent families."
    explanation: Quantifies the rarity of PDE6C among achromatopsia/cone-dysfunction families.
references:
- reference: PMID:20301591
  title: "Achromatopsia."
  tags:
  - GeneReviews

📚

References & Deep Research

References

1

PMID:20301591

Achromatopsia.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: PDE6C-Related Retinopathy · 2026-11-02T00:24:02Z · View source

New autosomal recessive cone photoreceptor disorder entry (MONDO:1040028, PDE6C). Deep research via claude_code provider (preflight-dr PASS, 55 PDE6C mentions). Pathophysiology built as a chain conforming to phototransduction_cascade_dysfunction (trigger, cGMP/Ca set-point loss, light-response failure, cGMP/Ca overload degeneration handoff). Evidence from the PDE6C gene-discovery cohort (PMID:19615668), a PDE6C patient cohort (PMID:33001157), biochemical null-allele characterization (PMID:21127010), a PDE6C rhesus macaque model (PMID:39641747), the ClinGen Retina GCEP Definitive validity curation (CGGV assertion), and the GeneReviews Achromatopsia chapter (PMID:20301591, tagged GeneReviews). Validated with validate-disorders (0 issues), 35/35 snippets verified, gene-validity clean, conformance registered. Closes #16296.

Claude Code ▸

1. Disease Information

claude-haiku-5-5, claude-opus-5-5 15 citations 2026-11-02T00:10:03.507013

1. Disease Information

Overview. PDE6C-related retinopathy is an autosomal recessive disorder of the cone photoreceptors. It is caused by biallelic pathogenic variants in PDE6C (phosphodiesterase 6C; hgnc:8787; OMIM *600827; 10q23.33; UniProt P51160; Ensembl ENSG00000095464; MANE transcript NM_006204.4). PDE6C encodes the catalytic α′ subunit of the cone-specific cGMP phosphodiesterase. The clinical picture spans:

complete and incomplete achromatopsia (ACHM5);
early-onset cone dystrophy (COD4);
cone-rod dystrophy in some patients.

"The PDE6C gene encodes the cone alpha subunit of cyclic guanosine monophosphate (cGMP) phosphodiesterase, which converts cGMP to 5'-GMP, and thereby plays an essential role in cone phototransduction." (PMID:19615668, verified)

"Our findings identify PDE6C as a gene for cone photoreceptor disorders and show that arCD and ACHM constitute genetically and clinically overlapping phenotypes." (PMID:19615668, verified)

Identifiers

System	ID	Notes
MONDO	MONDO:1040028 PDE6C-related retinopathy	the entry's anchor
MONDO subtypes	MONDO:0800196 achromatopsia 5 ✓; MONDO:0013129 cone dystrophy 4	both already in the KB entry
OMIM (phenotype)	#613093 Cone dystrophy 4; COD4	OMIM files ACHM5 inside this entry; it has no separate phenotype number (OMIM mirror)
OMIM (gene)	*600827 PDE6C
MedGen	416518	lists COD4, achromatopsia 5, cone dystrophy 4, PDE6C cone dystrophy
ClinGen	Definitive, AR, PDE6C ↔ MONDO:1040028; Retina GCEP; 2023-11-02	`CGGV:assertion_73ed48ac-bdd6-4608-953d-773da6ade759-2023-11-02T160000.000Z` (from `kb/genes/ingest/clingen_gene_validity.tsv`)
Orphanet	not confirmed	the disease likely sits under ORPHA:49382 (achromatopsia) and the cone/cone-rod dystrophy groups. Not verified.
ICD-10-CM / ICD-11	H53.51 (achromatopsia); H35.5 (hereditary retinal dystrophy)	general codes only; nothing specific to PDE6C. Not verified in the repo.
MeSH	Color Vision Defects; Cone-Rod Dystrophies	general headings
OMIA (animal)	OMIA:002163-9544 Cone dystrophy 4, PDE6C-related in rhesus macaque (OMIA)

Synonyms: achromatopsia 5 (ACHM5); cone dystrophy 4 (COD4); PDE6C-related cone dystrophy; PDE6C-related cone-rod dystrophy; PDE6C-associated achromatopsia; rod monochromacy (PDE6C).

Source of information: Aggregated disease-level resources (OMIM, ClinGen, GeneReviews) plus small case series and individual case reports. No EHR-derived data were found.

2. Etiology

Cause: Monogenic, autosomal recessive. Patients carry biallelic loss-of-function variants in PDE6C, either homozygous or compound heterozygous.
Genetic risk factors: Only the biallelic causal variants are known. Consanguinity raises the chance of homozygosity. In the original study, homozygous regions were found by homozygosity mapping: "identified large homozygous regions spanning the PDE6C gene in one sibling pair with early-onset arCD and one sibling pair with incomplete ACHM" (PMID:19615668, verified).
Modifier genes: None established in humans. Possible molecular modifiers:
Correct maturation of PDE6C depends on the chaperone AIPL1 and the inhibitory γ′ subunit (PDE6H) (PMID:38110033; PMID:28378769, mouse).
Mouse data show that the γ′ subunit stabilises the cone PDE6 holoenzyme (PMID:30038560).
Environmental risk factors: None known. Light exposure causes photophobia but has not been shown to change the course of the disease.
Protective factors and gene–environment interactions: None documented in humans.

3. Phenotypes

The best human data are two deep-phenotyping series: Georgiou et al. 2019 (n=8; PMID:31826238) and Daich Varela et al. 2020 (n=4; PMID:33001157). Larger genetic cohorts are Grau 2011 (12 patients from 7 families; PMID:21127010) and Weisschuh 2018 (15 index cases; PMID:30080950).

Phenotype	HPO term	Onset	Frequency	Course	Key evidence
Colour vision loss (severe; often total)	HP:0000551 Color vision defect ✓; HP:0011516 Achromatopsia ✓	congenital or infancy	8/8 (Georgiou)	stable or slowly progressive	"severe color vision loss" ‡ (PMID:31826238)
Nystagmus, early onset	HP:0000639 Nystagmus ✓	first months of life	8/8; also present in the Daich Varela series	may lessen with age	"early-onset nystagmus" ‡ (PMID:31826238; PMID:33001157)
Photophobia / day blindness	HP:0000613 Photophobia ✓	infancy	8/8	lifelong	PMID:31826238
Reduced visual acuity, usually about 20/200	HP:0007663 Reduced visual acuity ✓; HP:0001141 Severely reduced visual acuity ✓	infancy	8/8	slowly worsens in adults	PMID:31826238
High myopia	HP:0011003 High myopia ✓	childhood	5/8	—	"five of them had high myopia" ‡ (PMID:31826238)
Absent or severely reduced cone ERG; rod ERG normal or later reduced	HP:0008275 Abnormal light-adapted electroretinogram ✓; HP:0000512 Abnormal electroretinogram ✓	infancy	universal	rod responses may decline (cone-rod pattern)	PMID:33001157; PMID:42525358
Foveal outer retinal disruption (absent EZ, hyporeflective zone, or atrophy); no foveal hypoplasia	HP:0030613 Abnormal foveal morphology on macular OCT ✓; HP:0000493 Abnormal foveal morphology ✓	childhood onward	8/8 abnormal; 0/8 foveal hypoplasia	progressive: EZ lesion grows a mean of 48.3 µm per year	"No subjects had foveal hypoplasia" ‡ (PMID:31826238)
Maculopathy / macular atrophy (adults)	HP:0007754 Macular dystrophy ✓; HP:0007401 Macular atrophy ✓	adulthood	adults in both series	slowly progressive; hypoautofluorescent area grows about 0.13 mm² per year	"the adults had clear macular dystrophy" ‡ (PMID:33001157)
Cone-rod dystrophy phenotype	HP:0000548 Cone/cone-rod dystrophy ✓	childhood to adult	3/4 (Daich Varela)	progressive	"Three of the four patients had a cone-rod dystrophy" ‡ (PMID:33001157)
Central scotoma	HP:0000603 Central scotoma ✓	—	frequency not reported	—	inferred from maculopathy

Quality of life: No PDE6C-specific quality-of-life studies were found. Achromatopsia generally impairs reading, outdoor and daylight activities, and driving eligibility. Validated instruments exist (for example the NEI-VFQ-25 and achromatopsia-specific instruments used in CNGA3/CNGB3 trials), but none have been applied to PDE6C cohorts.

4. Genetic / Molecular Information

Gene: PDE6C. It encodes PDE6α′, the cone-specific catalytic subunit (HGNC previous symbols: PDEA2, ACHM5, COD4). Cone PDE6 is a homodimer of α′ subunits bound to two inhibitory γ′ subunits (PDE6H).
Variant spectrum:
Original discovery (PMID:19615668, verified):
- homozygous missense p.R29W and p.Y323N;
- compound heterozygous frameshift + splice variant;
- splice variant + p.M455V.
Grau 2011: "Eleven different PDE6C mutations were found" ‡, comprising nonsense, splice (shown by minigene assay), a 1-bp insertion, and missense variants (PMID:21127010).
Weisschuh 2018: "The mutation spectrum comprises 18 different alleles, 15 of which are novel" ‡ (PMID:30080950).
Georgiou 2019: three further novel variants (PMID:31826238).
Later reports: novel variants from Iran, China and Saudi Arabia (PMID:32306724, PMID:32787476, PMID:34720973, PMID:35422133).
Nonhuman primate: macaque p.R565Q in the catalytic domain (PMID:30667376).
Classification: ClinGen rates the gene–disease relationship Definitive (AR). For individual variants, use ClinVar: most protein-truncating and splice alleles are Pathogenic or Likely Pathogenic, and many missense alleles are VUS. One recent report describes a likely-pathogenic frameshift in trans with a VUS (PMID:42525358).
Functional consequence: Loss of function. Most missense variants act as functional nulls: "Four of the six PDE6C missense mutations led to baseline PDE activities" ‡. Two other missense variants showed about 60% and 80% loss of activity together with altered activation properties (PMID:21127010). These partial-loss alleles may underlie the milder, incomplete ACHM or cone dystrophy end of the spectrum. This genotype–phenotype link is inferred, not formally shown.
Variant origin: Germline. No somatic or mosaic reports were found.
Allele frequency: Every allele is rare (check gnomAD per variant). No founder allele has been established.
Epigenetics: None reported in humans. In cpfl1 mice, H3K27 trimethylation and HDAC activity influence cone survival: "Increased H3K27 trimethylation contributes to cone survival" (title of PMID:35810394; mouse); HDAC inhibition protects cones (PMID:28172811).
Chromosomal abnormalities: None characteristic.

5. Environmental Information

There are no environmental, lifestyle or infectious causes. Bright light provokes photophobia; tinted or filter lenses manage it but do not change the course of disease. Not applicable otherwise.

6. Mechanism / Pathophysiology

Causal chain

Biallelic PDE6C loss-of-function variants (truncating, splice, or catalytically dead missense) lead to absent or severely reduced cone PDE6α′ catalytic activity (PMID:21127010; PMID:30667376 shows a stable but catalytically dead protein: "is unable to hydrolyze cyclic GMP (cGMP)" ‡).
Loss of cone PDE6 results in failure of light-activated cGMP hydrolysis in cone outer segments. Transducin (GNAT2) activates nothing, so the CNG channels (CNGA3/CNGB3) stay open after light: cone phototransduction fails.
Branch A (function). Absent cone light responses lead to absent photopic ERG, day blindness, photophobia, loss of colour vision and poor acuity. Without foveal fixation, nystagmus develops. This is congenital or infantile.
Branch B (degeneration). Unhydrolysed cGMP accumulates in cones (shown in mouse: "cpfl1 cone photoreceptor cell death was associated with an accumulation of cyclic guanosine monophosphate (cGMP)" ‡, PMID:20593360). This leads to excess Ca²⁺ entry through CNG channels and activation of cGMP-dependent protein kinase (PKG), calpain and HDAC activity (PMID:27402880; PMID:25392995; PMID:28172811), and then to non-apoptotic cone death. In zebrafish the death is RIP3-dependent necroptosis (PMID:24413151). Whether this happens in human cones is inferred from animal models.
Progressive cone loss leads to expanding foveal ellipsoid-zone loss and outer retinal atrophy, which appears clinically as progressive maculopathy (PMID:31826238).
Secondary rod involvement (a subset of patients) leads to a cone-rod dystrophy pattern (PMID:33001157). In macaques, rod responses fall late: "The oldest homozygote (11 years) had reduced rod responses" ‡ (PMID:39641747). In zebrafish, rods die as bystanders through a caspase-dependent pathway (PMID:24413151). The mechanism in humans is unproven.
Myopia is common (5/8 patients). Its mechanism is unknown; a link to abnormal cone signalling during eye growth is speculative.

Other mechanistic detail

Protein maturation: Folding of PDE6C needs the chaperones HSP90 and AIPL1 together with the γ′ subunit. Without Pγ, PDE6C mostly misassembles (PMID:38110033, in vitro). Structural work: "the dynamic nature of PDE6C association with its regulatory γ-subunit" ‡ (cryo-EM; PMID:39739818). Prenylation targets cone PDE6 to the outer segment (PMID:37384398).
Trafficking: In mouse, "functional PDE6 is required for trafficking of M-opsin to cone outer segments" ‡ (PMID:21799013).
Immune / inflammatory involvement: Microglia change state during degeneration and regeneration in zebrafish pde6c mutants (PMID:41995141). STAT3-related genes are induced in cpfl1 cones (PMID:20467778). Neither has been studied in humans.
Transcriptomics: Whole-retina RNA-seq of zebrafish pde6c at 5 dpf (PMID:29231925; check GEO for the accession). No human omics data were found.

Suggested terms

GO:
GO:0007602 phototransduction ✓ (DECREASED)
GO:0047555 3',5'-cyclic-GMP phosphodiesterase activity ✓ (DECREASED / LOSS_OF_FUNCTION)
GO:0046068 cGMP metabolic process ✓
GO:0050908 detection of light stimulus involved in visual perception ✓
GO:0070266 necroptotic process ✓ (zebrafish evidence)
GO:0097190 apoptotic signaling pathway ✓ (rod bystander death)
GO:0001750 photoreceptor outer segment ✓ (cellular component); also GO:0120199 "cone photoreceptor outer segment" — not verified
CHEBI: CHEBI:16356 3',5'-cyclic GMP ✓ (accumulates)
CL: CL:0000573 retinal cone cell ✓ (primary); CL:0000604 retinal rod cell ✓ (secondary)

7. Anatomical Structures Affected

Organ: Eye, bilateral and symmetric. Visual system only. No extra-ocular involvement has been reported.
The one reported co-occurrence with hearing loss came from a separate PDZD7 variant segregating in the same family (PMID:38956522). It is not part of PDE6C disease.
UBERON: UBERON:0000970 eye ✓; UBERON:0000966 retina ✓; UBERON:0001787 photoreceptor layer of retina ✓; UBERON:0000053 macula lutea ✓; UBERON:0001786 fovea centralis ✓.
Cells: Cone photoreceptors (CL:0000573) primarily; rods (CL:0000604) secondarily.
Subcellular: Cone outer segment disc membranes, where PDE6 is held by prenylation.

8. Temporal Development

Onset: Congenital or early infancy. Nystagmus and photophobia appear in the first months. Patients in one cohort were diagnosed between birth and 5 years.
Progression:
Children: function is severely reduced from the start, with few structural changes.
Adults: progressive maculopathy (EZ lesion grows a mean of 48.3 µm/yr; hypoautofluorescent area grows a mean of 0.13 mm²/yr; PMID:31826238). Some patients develop a cone-rod dystrophy pattern.
Older adults: "few or no residual foveal cones" (paraphrase of PMID:31826238).
Course: Lifelong, slowly progressive. There is no remission.
Critical window: Childhood, while cones remain, is the likely window for gene therapy. In macaques, cone ERG is already absent at 3 months but foveal ONL thinning progresses over years (PMID:39641747). In mice, the gene therapy window narrows with age (shown for a related cone disease, PMID:41286353).

9. Inheritance and Population

Inheritance: Autosomal recessive (HP:0000007 ✓). Penetrance is complete for biallelic null genotypes. Heterozygous carriers are unaffected: in macaques, "Heterozygotes could not be distinguished from wildtypes in any parameters" ‡ (PMID:39641747).
Expressivity: Variable, from complete ACHM through incomplete ACHM and cone dystrophy to cone-rod dystrophy. Allelic severity probably contributes (PMID:21127010).
Anticipation and germline mosaicism: Not applicable / not reported.
Epidemiology:
Achromatopsia overall: about 1 in 30,000 (GeneReviews PMID:20301591; check the exact wording in the cached file).
PDE6C accounts for a small share of ACHM: "less than 2% of the cases" (PMID:32306724, secondary statement).
In the Tübingen cohort, 15 index cases came from a pre-selected group of 176, within an overall ACHM cohort of 1,074 independent families ‡ (PMID:30080950). That would put PDE6C roughly in the 1–2% range of ACHM; this is my inference, not a figure the paper states.
Implied prevalence is well under 1 in 1,000,000 (prevalence class BELOW_1_IN_1000000, or report as CASES_IN_LITERATURE).
Geography / populations: Reported from Europe (Netherlands, Germany, UK, Denmark), the Middle East (Iran, Saudi Arabia, UAE; PMID:39024658), Pakistan, China, Japan and Korea. Enrichment in consanguineous families is expected; no specific founder alleles have been documented.
Sex ratio: 1:1 (autosomal).

10. Diagnostics

Clinical examination: Nystagmus, photophobia, reduced acuity, and colour vision testing (HRR, Farnsworth D-15, anomaloscope).
Electrophysiology: Full-field ERG (ISCEV) shows absent or near-absent light-adapted and 30-Hz flicker responses. Rod responses are normal or later reduced. S-cone ERG is also absent; this separates the disease from blue cone monochromacy.
Imaging: OCT shows EZ disruption, a foveal hyporeflective zone, or atrophy, and typically no foveal hypoplasia. This helps distinguish PDE6C disease from ATF6-ACHM, which does show foveal hypoplasia. Fundus autofluorescence shows central hypo- or hyper-autofluorescence. Adaptive optics can quantify residual cones.
Genetic testing: An inherited retinal disease (IRD) gene panel or exome that includes CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, ATF6 and RPGRIP1. GeneReviews: "biallelic pathogenic (or likely pathogenic) variants in ATF6, CNGA3, CNGB3, GNAT2, PDE6C, or PDE6H confirms the clinical diagnosis" (PMID:20301591, cached). Confirm splice variants with minigene or RNA assays (PMID:21127010). CNV analysis is advisable.
Differential diagnosis:
other ACHM genes (CNGA3, CNGB3, GNAT2, PDE6H, ATF6, RPGRIP1 exon-18 deletion);
blue cone monochromacy (X-linked; S-cone ERG preserved);
early cone/cone-rod dystrophies (ABCA4, GUCY2D, CRX, KCNV2);
Leber congenital amaurosis;
albinism and congenital stationary night blindness (nystagmus with different ERG patterns).
Screening: No newborn screening. Cascade carrier testing within families is possible.
LOINC: None specific to this disease. Measurement codes for ERG or genetic panels would be generic.

11. Outcome / Prognosis

Life expectancy: Normal. There is no disease-specific mortality.
Morbidity: Lifelong legal blindness or low vision is common (acuity about 20/200). Patients are photophobic and colour-blind, and adults lose central vision slowly.
Prognostic factors: Probably allele severity (partial versus null), age, and myopia, which is linked to atrophy. Not formally validated.
Complications: High myopia, macular atrophy and amblyopia.

12. Treatment

There is no approved disease-modifying therapy, and no PDE6C-specific clinical trial was found. AAV gene-augmentation trials have run for CNGA3 and CNGB3 achromatopsia (for example NCT02599922, NCT02935517, NCT03758404, NCT03001310), but they do not include PDE6C. Check ClinicalTrials.gov again for any new PDE6C trials.

Approach	NCIT term	Status / evidence
Tinted / filter lenses, red contact lenses, low-vision aids	NCIT:C15747 Supportive Care ✓; NCIT:C15315 Rehabilitation ✓	standard of care (GeneReviews PMID:20301591)
Refractive correction of high myopia	(term not looked up)	routine care
Genetic counselling	NCIT:C15240 Genetic Counseling ✓	recommended
AAV gene augmentation (PDE6C ± PDE6H)	NCIT:C15238 Gene Therapy ✓; modality `GENE_THERAPY`	preclinical. In rd10/cpfl1 mice, cone rescue needed both PDE6α′ and γ′: "improved photopic cone responses were achieved only after supplementation of both cone PDE6α' and PDE6γ' subunits" (PMID:30038560; quote taken from the search summary, verify)
HDAC inhibition (trichostatin A)	Pharmacotherapy	preclinical. "increased cone survival for up to 16 days post-injection" ‡ (PMID:28172811, mouse)
Necroptosis inhibition (RIP1/RIP3)	Pharmacotherapy	preclinical (zebrafish, PMID:24413151)
CRISPR correction in patient iPSCs	`GENE_EDITING`	in vitro (PMID:36835061, PMID:40083649; check which gene each study corrected; see also review PMID:42264060)
Photoreceptor transplantation	`CELL_THERAPY`	preclinical (cpfl1; PMID:25183393, PMID:27367586)

Pharmacogenomics: none relevant. PDE5 inhibitors (sildenafil) also inhibit PDE6, but there are no data on their use in this disease.

13. Prevention

Primary prevention: Genetic counselling. Carrier testing of relatives and partners in consanguineous families. Prenatal diagnosis or PGT when the familial variants are known.
Secondary prevention: Early molecular diagnosis to support enrolment in future gene therapy while cones remain.
Tertiary prevention: Photoprotection and treatment of refractive error and amblyopia. Whether photoprotection slows degeneration is unproven.
No vaccines or public-health measures apply.

14. Other Species / Natural Disease

Rhesus macaque (Macaca mulatta, NCBITaxon:9544): naturally occurring homozygous PDE6C R565Q (OMIA:002163-9544).
"a homozygous R565Q missense mutation in the catalytic domain of PDE6C" ‡ (PMID:30667376). The mutant protein is stable and correctly localised but catalytically dead.
Natural history from 102 eyes of 51 animals: cone ERG absent from 3 months, foveal ONL thinning with age, and late rod decline (PMID:39641747).
This model has a fovea, which makes it the closest model of the human disease.
Evolution: PDE6 genes are conserved across vertebrates (PMID:27296292). Pde6c has been lost in the common vampire bat (PMID:35333583), and premature termination codons appear in cavefish (PMID:39833658). These are natural gene losses in species adapted to dim light.
Zoonotic potential: None.

15. Model Organisms

Model	Genotype	Recapitulation	Limitations	Key PMIDs
cpfl1 mouse (Mus musculus)	spontaneous Pde6c mutation (CXB-1 strain, chr 19), loss of function	no cone function; rapid cone degeneration that peaks around P24 with cGMP accumulation	mice have no fovea and few cones; degeneration is faster than in humans	19887631, 20593360, 20238063, 28172811
rd10/cpfl1 double mutant	Pde6b + Pde6c loss	both rods and cones degenerate; used for gene therapy	double-mutant background is artificial	30038560
Zebrafish pde6c^w59 (Danio rerio)	nonsense mutation (Stearns et al. 2007, J Neurosci 27:13866; PMID not confirmed)	rapid cone degeneration from 4 dpf; rod bystander death; RIP3-dependent necroptosis	cone-rich retina that regenerates	24413151, 20053919, 23365220, 29231925, 41995141
Rhesus macaque	PDE6C R565Q homozygous	absent cone ERG; progressive foveal cone loss; late rod decline	colony-limited; few animals	30667376, 39641747
Human iPSC / organoids	patient-derived	CRISPR correction studies	does not reproduce fovea or degeneration timing	36835061, 40083649 (gene to be confirmed)
In vitro enzymology	recombinant PDE6C mutants in insect cells	quantifies loss of catalytic activity	lacks cellular context	21127010, 38110033, 39739818

Resources: MGI (cpfl1 allele), ZFIN (ZDB-PUB-071219-20 for pde6c^w59), OMIA, JAX.

Notes for curating the KB entry

The existing kb/disorders/PDE6C-Related_Retinopathy.yaml is a 59-line skeleton. It has a gene, one pathophysiology node with no evidence, and one phenotype. Priorities:

Add the phenotypes in the §3 table. Each phenotype's evidence can quote PMID:31826238 or PMID:33001157 after just fetch-reference.
Build the §6 causal chain as pathophysiology nodes wired to the phenotypes, and consider conforms_to against kb/modules/phototransduction_cascade_dysfunction.yaml.
Record the ClinGen Definitive assertion in gene_disease_validity.
Add the macaque, cpfl1 mouse and zebrafish models under animal_models with modeled_mechanisms.
Find the PMID for Stearns 2007; it was not resolved in this session.

Sources

Thiadens et al. 2009, PMID:19615668 (abstract cached locally); EUR repository
Chang et al. 2009 PNAS, PMID:19887631; PMC2780790
Grau et al. 2011 Hum Mol Genet, PMID:21127010; PMC3269206
Weisschuh et al. 2018 Hum Mutat, PMID:30080950; PubMed
Georgiou et al. 2019 IOVS, PMID:31826238; PMC6905659
Daich Varela et al. 2020 IOVS, PMID:33001157
Bushehri et al. 2020, PMID:32306724; PMC7275818
Moshiri et al. 2019 JCI, PMID:30667376; Ardon et al. 2024 IOVS, PMID:39641747; OMIA 4146
Trifunović et al. 2010, PMID:20593360; Trifunović et al. 2016, PMID:28172811; Viringipurampeer et al. 2014, PMID:24413151; Kolandaivelu et al. 2011, PMID:21799013
Deng et al. 2018, PMID:30038560; PMC6046437
Singh et al. 2024 JBC, PMID:38110033; Singh et al. 2025 PNAS, PMID:39739818
O'Connell et al. 2026, PMID:42525358; Lecigne et al. 2026, PMID:42660982 (no abstract available)
GeneReviews: Achromatopsia, PMID:20301591 (cached locally)
OMIM #613093 mirror; MedlinePlus PDE6C; PanelApp Australia
ZFIN pde6c^w59 publication; zebrafish expression profiling, PMC5726315
Frontiers Mol Neurosci 2018 (rd10/cpfl1); BCM AAV therapeutic window, PMC12036465

Reference Validation

Checked with linkml-reference-validator 0.4.0.

Outcome	Count
References checked	49
Resolved	49
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	8
Quoted claims found in source	6
Quoted claims not found in source	2
References weighed for topical relevance	49
On topic	35
Off topic	0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

PMID:31826238 (abstract only): "few or no residual foveal cones"
closest text in source: "Nonconfocal adaptive optics scanning light ophthalmoscopy revealed residual foveal cones in only one of two cases"
PMID:32306724 (abstract only): "less than 2% of the cases"
Text part not found as substring: 'less than 2% of the cases' (note: only abstract available for PMID:32306724, full text may contain this excerpt)

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	42
Resolved	40
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	2
Terms whose name was checked	1
Terms named correctly	0
Terms named as a different term	0
Terms whose name is worth a second look	1

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

CL:0000573 (2 mentions) - the report calls it "Cells: Cone photoreceptors"; CL calls it retinal cone cell**

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, OMIA.

40 of 42 terms resolved to a current term; the rest could not be looked up either way.

PDE6C-Related Retinopathy

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References & Deep Research

References

Deep Research

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Notes for curating the KB entry

Sources

Reference Validation

Quotes not found in the cited source

Term Validation

Terms whose name is worth a second look

Prefixes with no resolver