Progressive cone dystrophy in PDE6C-associated achromatopsia with a likely pathogenic variant and a VUS

Area of Science:

• Ophthalmology
• Genetics
• Molecular Biology

Background:

• Achromatopsia is a rare inherited retinal disorder.
• It is characterized by reduced visual acuity, photophobia, and color blindness.
• Mutations in the PDE6C gene are a known cause of achromatopsia.

Purpose of the Study:

• To describe the clinical, imaging, and electrophysiologic findings in a patient with achromatopsia.
• To investigate the role of two heterozygous PDE6C variants in the patient's phenotype.
• To contribute to genotype-phenotype correlations in PDE6C-associated retinal disease.

Main Methods:

• Comprehensive ophthalmic evaluation including visual acuity, fundus examination, SD-OCT, FAF, and ffERG.
• Whole-exome sequencing (WES) for genetic analysis.
• Analysis of two PDE6C variants: c.2248G>C (p.Asp750His) and c.2304_2305delAA (p.Asp770Ter).

Main Results:

• The patient presented with severe cone dysfunction and visual acuity of 20/300.
• Imaging revealed bilateral macular atrophy and ellipsoid zone abnormalities.
• ffERG showed markedly reduced cone responses with preserved rod responses.
• WES identified a likely pathogenic frameshift variant (p.Asp770Ter) and a VUS missense variant (p.Asp750His) in PDE6C.

Conclusions:

• This case expands the phenotypic spectrum of PDE6C-associated retinal disease.
• The findings support a biallelic disease mechanism for achromatopsia.
• This study aids in interpreting rare PDE6C variants and understanding genotype-phenotype correlations.