Purpose: Several OPA1 variants cause dominant optic atrophy (DOA), the most common hereditary optic atrophy. Here, we describe a newly discovered OPA1 deletion in 3 patients with DOA.
Methods: A female proband, her brother, and her mother underwent complete ophthalmologic examinations that included optical coherence tomography and visual field assessments using a Humphrey Field Analyzer with both standard automated perimetry (SAP) and short-wavelength automated perimetry (SWAP). Genomic DNA from each patient was examined to detect genomic rearrangements involving OPA1; the genetic analysis involved both multiplex ligation probe amplification and conventional Sanger sequencing.
Results: Each patient had temporal optic disc pallor and significant thinning of the retinal nerve fiber layer in both eyes, although there was phenotypic variability among the patients that ranged from asymptomatic to moderately decreased visual acuity. For the affected brother and mother, the mean deviation values from SAP were within the normal range, whereas those from SWAP were significantly below the normal range (P < .05). The genetic analysis identified a newly discovered heterozygous deletion that encompasses exons 9-14 and revealed a breakpoint junction that directly connects intron 8 to intron 14.
Conclusions: This newly described deletion is likely to lead to loss of function in the functionally important GTPase domain encoded by exons 9-16, and the heterozygosity suggested that haploinsufficiency caused the phenotypes. The deletion may be associated with mild DOA phenotypes ranging from asymptomatic to moderately decreased visual acuity.
Keywords: Genetics; Hereditary optic neuropathy; Mutation; OPA1.