PDE6C-Related Retinopathy

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

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).

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

1. 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)" ‡).
2. 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.
3. 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.
4. 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.
5. Progressive cone loss leads to expanding foveal ellipsoid-zone loss and outer retinal atrophy, which appears clinically as progressive maculopathy (PMID:31826238).
6. 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.
7. 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.

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

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:

1. Add the phenotypes in the §3 table. Each phenotype's evidence can quote PMID:31826238 or PMID:33001157 after just fetch-reference.
2. Build the §6 causal chain as pathophysiology nodes wired to the phenotypes, and consider conforms_to against kb/modules/phototransduction_cascade_dysfunction.yaml.
3. Record the ClinGen Definitive assertion in gene_disease_validity.
4. Add the macaque, cpfl1 mouse and zebrafish models under animal_models with modeled_mechanisms.
5. 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.

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.

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.