Phenotypic Variations in a Large Family with Dominant Optic Atrophy Related to a Novel OPA1 Deletion
Abstract
Purpose Dominant Optic Atrophy (DOA) is a rare disease characterized by the chronic loss of retinal ganglion cells, the neurons that transduce the visual information from the retina to the brain. DOA shows important inter and intra-familial phenotypic variations and a restricted 35% success in its molecular diagnosis. Among DOA cases, more than 50% present a pathogenic variant in OPA1 , encoding a large mitochondrial GTPase. To elucidate the high intra-familial phenotypic variations, we describe the largest-ever identified DOA family, with 64 non-syndromic individuals harboring a novel 10kb OPA1 deletion. Design Retrospective, longitudinal cohort study of a large family from the Western part of France. Participants 39 individuals were included in this study, 34 patients harboring a novel OPA1 10kb deletion and 5 healthy controls, belonging to a single family with 9 related branches. Methods Whole OPA1 gene sequencing, multiplex ligation-dependent probe amplification, and copy number variations using single nucleotide polymorphism array were used to find the genetic variation causing DOA. Microsatellite markers were analyzed to confirm the relatedness between the different family branches. Best-corrected visual acuity (BCVA), Lanthony D-15 desaturated color vision test, retinal nerve fiber layer (RNFL) and macular ganglion cells layer (GCL) thickness were recorded at two different time points for statistical longitudinal analyses. Main Outcomes Measures BCVA, RNFL and GCL thickness at first and follow-up examinations. Correlations between morphological and functional measurements. Results We disclosed the largest-ever identified DOA family, with 64 non-syndromic patients for whom we discovered a novel 10kb deletion encompassing OPA1 exons 30 and 31. Ophthalmological examination of 34 affected cases revealed a consistent phenotypic variability of the BCVA, ranging from 0 (Snellen equivalent, 20/20) to 1.61 (20/815) logarithm of the minimum angle of resolution (logMAR) at first examination, strongly correlated to RNFL and GCL thickness, but moderately with age and not with dyschromatopsia. Follow-up of individuals evidenced a significant loss of BCVA with a median of 0.018 logMAR/year (0.18 logMAR per decade) and a temporal, superior and inferior RNFL thickness loss of 1.13, 0.70 and 0.50 μm/year, respectively; while the nasal quadrant did not evolve. Conclusion The identification of a large OPA1 deletion in this DOA family illustrates the critical importance of screening for large genomic rearrangements in DOA genes, and confirms the high phenotypic variability in carriers of a single OPA1 mutation, while correlating BCVA with RNFL and GCL thickness.
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BibTeX
@article{bouzidi2026phenotypic,
title = {{Phenotypic Variations in a Large Family with Dominant Optic Atrophy Related to a Novel OPA1 Deletion}},
author = {Aymane Bouzidi and Patrizia Amati-Bonneau and Valérie Desquiret-Dumas and Cléis Beaulieu and Agnés Guichet and Céline Bris and Béatrice Bocquet and Xavier Dieu and Pascal Reynier and Delphine Mirebeau-Prunier and Clara Houdayer and Marc Planes and Sylvie Odent and Isabelle Meunier and Dominique Bonneau and Majida Charif and Guy Lenaers and Xavier Zanlonghi},
journal = {Ophthalmology Science},
year = {2026},
month = sep,
doi = {10.1016/j.xops.2026.101286},
url = {https://hal.science/hal-05771423v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - Phenotypic Variations in a Large Family with Dominant Optic Atrophy Related to a Novel OPA1 Deletion
AU - Aymane Bouzidi
AU - Patrizia Amati-Bonneau
AU - Valérie Desquiret-Dumas
AU - Cléis Beaulieu
AU - Agnés Guichet
AU - Céline Bris
AU - Béatrice Bocquet
AU - Xavier Dieu
AU - Pascal Reynier
AU - Delphine Mirebeau-Prunier
AU - Clara Houdayer
AU - Marc Planes
AU - Sylvie Odent
AU - Isabelle Meunier
AU - Dominique Bonneau
AU - Majida Charif
AU - Guy Lenaers
AU - Xavier Zanlonghi
PY - 2026
DA - 2026/09/30
JO - Ophthalmology Science
DO - 10.1016/j.xops.2026.101286
UR - https://hal.science/hal-05771423v1
AB - Purpose Dominant Optic Atrophy (DOA) is a rare disease characterized by the chronic loss of retinal ganglion cells, the neurons that transduce the visual information from the retina to the brain. DOA shows important inter and intra-familial phenotypic variations and a restricted 35% success in its molecular diagnosis. Among DOA cases, more than 50% present a pathogenic variant in OPA1 , encoding a large mitochondrial GTPase. To elucidate the high intra-familial phenotypic variations, we describe the largest-ever identified DOA family, with 64 non-syndromic individuals harboring a novel 10kb OPA1 deletion. Design Retrospective, longitudinal cohort study of a large family from the Western part of France. Participants 39 individuals were included in this study, 34 patients harboring a novel OPA1 10kb deletion and 5 healthy controls, belonging to a single family with 9 related branches. Methods Whole OPA1 gene sequencing, multiplex ligation-dependent probe amplification, and copy number variations using single nucleotide polymorphism array were used to find the genetic variation causing DOA. Microsatellite markers were analyzed to confirm the relatedness between the different family branches. Best-corrected visual acuity (BCVA), Lanthony D-15 desaturated color vision test, retinal nerve fiber layer (RNFL) and macular ganglion cells layer (GCL) thickness were recorded at two different time points for statistical longitudinal analyses. Main Outcomes Measures BCVA, RNFL and GCL thickness at first and follow-up examinations. Correlations between morphological and functional measurements. Results We disclosed the largest-ever identified DOA family, with 64 non-syndromic patients for whom we discovered a novel 10kb deletion encompassing OPA1 exons 30 and 31. Ophthalmological examination of 34 affected cases revealed a consistent phenotypic variability of the BCVA, ranging from 0 (Snellen equivalent, 20/20) to 1.61 (20/815) logarithm of the minimum angle of resolution (logMAR) at first examination, strongly correlated to RNFL and GCL thickness, but moderately with age and not with dyschromatopsia. Follow-up of individuals evidenced a significant loss of BCVA with a median of 0.018 logMAR/year (0.18 logMAR per decade) and a temporal, superior and inferior RNFL thickness loss of 1.13, 0.70 and 0.50 μm/year, respectively; while the nasal quadrant did not evolve. Conclusion The identification of a large OPA1 deletion in this DOA family illustrates the critical importance of screening for large genomic rearrangements in DOA genes, and confirms the high phenotypic variability in carriers of a single OPA1 mutation, while correlating BCVA with RNFL and GCL thickness.
SN - 2666-9145
ER -