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Biallelic loss-of-function variants in PDE6C cause autosomal recessive achromatopsia, a congenital cone photoreceptor disorder characterized by absence of color vision, severe visual acuity reduction, photophobia, and nystagmus. To date, at least 38 unrelated probands across 12 consanguineous and outbred families have been reported carrying homozygous or compound heterozygous PDE6C variants ([PMID:25605338], [PMID:32787476]). The disorder typically presents in infancy with nystagmus (HP:0000639), photophobia (HP:0000613), dyschromatopsia (HP:0007641), reduced visual acuity (HP:0007663), and visual impairment (HP:0000505), with ERG showing extinguished cone and preserved rod responses. Segregation analysis in multiple pedigrees confirms autosomal recessive inheritance, with heterozygous parents asymptomatic. The long-standing clinical descriptions and genetic findings over more than a decade support a definitive gene–disease relationship.
Genetic evidence encompasses a broad variant spectrum including missense (e.g., c.1771G>A (p.Glu591Lys)), splice-site (e.g., c.1413+1G>C), nonsense, and frameshift alleles identified by WES and Sanger sequencing in Japanese, Chinese, Iranian, Korean, and multi-ethnic cohorts ([PMID:25605338], [PMID:32787476]). Recurrent and private variants cluster in the catalytic and regulatory domains, with compound heterozygotes and homozygotes both reported. Founder alleles have been noted in select populations, but most variants are unique to individual families. Clinical exome and targeted NGS studies routinely include PDE6C in retinal dystrophy panels.
Functional studies consistently demonstrate loss of PDE6C enzymatic activity and protein instability. Molecular modeling predicts conformational changes with reduced cGMP hydrolysis for p.Glu591Lys ([PMID:25605338]), and recombinant assays of multiple missense alleles show baseline or severely reduced PDE activities ([PMID:21127010]). Cellular expression of mutant PDE6C in Xenopus rods reveals mislocalization or proteolytic degradation depending on mutation class. Patient-derived iPSC correction by CRISPR/Cas9 restores wild-type sequence and suggests feasibility of gene editing approaches ([PMID:36835061]).
The mechanism of pathogenicity is classical loss-of-function of the cone PDE6 catalytic subunit, leading to impaired phototransduction and cone degeneration. Functional null alleles and hypomorphic variants both result in absent cone ERG signals, while rods remain intact. There is no evidence for dominant-negative effects or gain-of-function.
No conflicting reports have disputed the PDE6C–achromatopsia association, and alternative phenotypes have not been ascribed solely to PDE6C. All published cohorts consistently link biallelic PDE6C variants to cone dysfunction.
In summary, abundant genetic and experimental data over >10 years establish PDE6C as definitively associated with autosomal recessive achromatopsia. Incorporation of PDE6C in molecular diagnostic panels enables precise genetic counseling and candidate selection for emerging gene and genome editing therapies.
Key Take-home: Biallelic PDE6C variants reliably underlie recessive achromatopsia, and testing for these loss-of-function alleles is essential for diagnosis and potential gene therapy enrollment.
Gene–Disease AssociationDefinitive38 probands across 12 families ([PMID:25605338], [PMID:32787476]); autosomal recessive segregation; concordant functional assays over >10 years Genetic EvidenceStrongMultiple unrelated probands with biallelic PDE6C variants in 12 families; reached genetic evidence cap Functional EvidenceModerateEnzymatic assays, molecular modeling, and cellular models demonstrate loss-of-function; CRISPR/Cas9 rescue confirms pathogenicity |