Genotype–Phenotype Correlation in Dominant Optic Atrophy due to OPA1 c.3011T>C (p.Leu1004Pro): A Family-Based Case Series
Source: PubMed Central Open Access, NCBI / U.S. National Library of Medicine
Purpose: To characterize the structural, functional, and optical coherence tomography angigraphy (OCTA) phenotype associated with the OPA1 c3011T>C (p.Leu1004Pro) variant in a multigenerational family with autosomal dominant optic atrophy. Methods: In this retrospective familial case series, four affected female relatives across three generations underwent ophthalmic examination including best-corrected visual acuity (BCVA), peripapillary retinal nerve fiber layer (RNFL) and macular ganglion cell complex (GCC) imaging, Humphrey 24-2 visual fields, and 6 mm × 6 mm swept-source OCTA (SS-OCTA). Quantitative OCTA assessed parafoveal vessel density in the superficial capillary plexus (SCP). Next-generation sequencing in the index case and intrafamilial Sanger sequencing confirmed segregation. Results: All subjects carried the heterozygous OPA1 c.3011T>C variant and showed a consistent optic neuropathy pattern with temporal disc pallor, selective temporal RNFL thinning, and macular GCC loss on a preserved outer retina without microcystic changes. BCVA ranged from 0.22 to 0.82 logMAR, indicating marked intrafamilial functional variability. Visual fields demonstrated central/centrocecal or paracentral defects with relative peripheral sparing, with more extensive central depression in the oldest case. On exploratory 6 mm × 6 mm SS-OCTA, parafoveal SCP vessel density values showed intercase variation without frank macular nonperfusion; findings are interpreted descriptively in the abse
Abstract
Purpose: To characterize the structural, functional, and optical coherence tomography angigraphy (OCTA) phenotype associated with the OPA1 c3011T>C (p.Leu1004Pro) variant in a multigenerational family with autosomal dominant optic atrophy. Methods: In this retrospective familial case series, four affected female relatives across three generations underwent ophthalmic examination including best-corrected visual acuity (BCVA), peripapillary retinal nerve fiber layer (RNFL) and macular ganglion cell complex (GCC) imaging, Humphrey 24-2 visual fields, and 6 mm × 6 mm swept-source OCTA (SS-OCTA). Quantitative OCTA assessed parafoveal vessel density in the superficial capillary plexus (SCP). Next-generation sequencing in the index case and intrafamilial Sanger sequencing confirmed segregation. Results: All subjects carried the heterozygous OPA1 c.3011T>C variant and showed a consistent optic neuropathy pattern with temporal disc pallor, selective temporal RNFL thinning, and macular GCC loss on a preserved outer retina without microcystic changes. BCVA ranged from 0.22 to 0.82 logMAR, indicating marked intrafamilial functional variability. Visual fields demonstrated central/centrocecal or paracentral defects with relative peripheral sparing, with more extensive central depression in the oldest case. On exploratory 6 mm × 6 mm SS-OCTA, parafoveal SCP vessel density values showed intercase variation without frank macular nonperfusion; findings are interpreted descriptively in the absence of device and age-matched internal controls. Conclusion: The OPA1 p.Leu1004Pro variant was associated with a stereotyped structural optic neuropathy pattern, whereas functional impairment showed marked intrafamilial variability. Exploratory SCP OCTA findings are descriptive only, given the absence of device and age-matched internal controls.