Phenotypic Variations in a Large Family with Dominant Optic Atrophy Related to a Novel OPA1 Deletion

Dominant optic atrophy (DOA) is a rare disease characterized by the chronic loss of retinal ganglion cells that transduce the visual information from the retina to the brain. Dominant optic atrophy shows interfamilial and intrafamilial phenotypic variations and a restricted 35% molecular diagnosis, with half presenting a pathogenic variant in optic atrophy 1 (OPA1), encoding a large mitochondrial GTPase. Here, we describe the largest ever identified DOA family, with 64 nonsyndromic individuals harboring a novel 10-kb OPA1 deletion.

Retrospective, longitudinal cohort study of a family from the Western part of France.

Thirty-nine individuals were included, 34 patients harboring a novel OPA1 10-kb deletion and 5 healthy controls.

OPA1 sequencing, multiplex ligation-dependent probe amplification, and copy number variations using single nucleotide polymorphism array identified the genetic variation causing DOA. The relatedness between the different family branches was analyzed by micro-satellite markers. Best-corrected visual acuity (BCVA), Lanthony D-15 desaturated color vision test, retinal nerve fiber layer (RNFL), and macular ganglion cell layer (GCL) thickness were recorded at 2 different time points for longitudinal analyses.

Best-corrected visual acuity, RNFL and GCL thickness at first and follow-up examinations. Correlations between morphological and functional measurements.

We disclosed the largest ever identified DOA family, with 64 nonsyndromic patients for whom we discovered a novel 10-kb deletion encompassing OPA1 exons 30 and 31. Ophthalmic examination revealed a consistent BCVAvariability, ranging from 0 (Snellen equivalent, 20/20) to 1.61 (20/815) logarithm of the minimum angle of resolution (logMAR), strongly correlated to RNFL and GCL thickness, but moderately with age and not with dyschromatopsia. Follow-up of individuals evidenced a significant BCVA loss with a median of 0.018 logMAR per year (0.18 logMAR per decade) and a temporal, superior, and inferior RNFL thickness loss of 1.13, 0.70, and 0.50 μm/yr, respectively, whereas the nasal quadrant did not evolve.

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 intrafamilial phenotypic variability while correlating BCVA with RNFL and GCL thickness.

The authors have no proprietary or commercial interest in any materials discussed in this article.