Documenta ophthalmologica. Advances in ophthalmology · 2026
Progressive cone dystrophy in PDE6C-associated achromatopsia with a likely pathogenic variant and a VUS.
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O'Connell Mia, Kong Jian, Soucy Megan, Brodie Scott E, Tsang Stephen H
Аннотация
PURPOSE: To report the clinical phenotype, multimodal imaging findings, and electrophysiologic characteristics of a 62-year-old patient with achromatopsia harboring two heterozygous PDE6C (NM_006204.3) variants: a variant of uncertain significance, c.2248G > C (p.Asp750His), and a likely pathogenic variant, c.2304_2305delAA (p.Asp770Ter).
METHODS: The patient underwent comprehensive ophthalmic evaluation, including best-corrected visual acuity (BCVA), slit-lamp examination, dilated fundus examination, spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence (FAF), and full-field electroretinography (ffERG) according to ISCEV standards. Genetic testing was performed using whole-exome sequencing (WES).
RESULTS: BCVA was 20/300 in both eyes at the most recent visit. Ten months earlier, BCVA was 20/150 in the right eye and 20/100 in the left eye. Fundus examination demonstrated bilateral central macular atrophic lesions with corresponding autofluorescence abnormalities. SD-OCT revealed irregular attenuation and focal loss of the ellipsoid zone with relative preservation of the retinal pigment epithelium. ffERG showed severe cone dysfunction, characterized by markedly reduced light-adapted single-flash responses and near-extinguished 30 Hz flicker responses, with relatively preserved rod-mediated scotopic responses. Genetic testing identified two heterozygous PDE6C variants: a likely pathogenic frameshift variant (c.2304_2305delAA; p.Asp770Ter), predicted to result in premature truncation of the protein, and a missense variant (c.2248G > C; p.Asp750His) located in the catalytic phosphodiesterase domain, not previously reported, and currently classified as a variant of uncertain significance.
CONCLUSIONS: This case expands the phenotypic spectrum of PDE6C-associated retinal disease by describing a severe cone dysfunction phenotype with clinical features consistent with achromatopsia. In the context of an autosomal recessive condition, the presence of a likely pathogenic variant alongside a variant of uncertain significance, combined with a consistent clinical and electrophysiologic phenotype, supports a possible biallelic disease mechanism. These findings contribute to emerging genotype-phenotype correlations and may aid in interpreting rare PDE6C variants.
METHODS: The patient underwent comprehensive ophthalmic evaluation, including best-corrected visual acuity (BCVA), slit-lamp examination, dilated fundus examination, spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence (FAF), and full-field electroretinography (ffERG) according to ISCEV standards. Genetic testing was performed using whole-exome sequencing (WES).
RESULTS: BCVA was 20/300 in both eyes at the most recent visit. Ten months earlier, BCVA was 20/150 in the right eye and 20/100 in the left eye. Fundus examination demonstrated bilateral central macular atrophic lesions with corresponding autofluorescence abnormalities. SD-OCT revealed irregular attenuation and focal loss of the ellipsoid zone with relative preservation of the retinal pigment epithelium. ffERG showed severe cone dysfunction, characterized by markedly reduced light-adapted single-flash responses and near-extinguished 30 Hz flicker responses, with relatively preserved rod-mediated scotopic responses. Genetic testing identified two heterozygous PDE6C variants: a likely pathogenic frameshift variant (c.2304_2305delAA; p.Asp770Ter), predicted to result in premature truncation of the protein, and a missense variant (c.2248G > C; p.Asp750His) located in the catalytic phosphodiesterase domain, not previously reported, and currently classified as a variant of uncertain significance.
CONCLUSIONS: This case expands the phenotypic spectrum of PDE6C-associated retinal disease by describing a severe cone dysfunction phenotype with clinical features consistent with achromatopsia. In the context of an autosomal recessive condition, the presence of a likely pathogenic variant alongside a variant of uncertain significance, combined with a consistent clinical and electrophysiologic phenotype, supports a possible biallelic disease mechanism. These findings contribute to emerging genotype-phenotype correlations and may aid in interpreting rare PDE6C variants.