Phenotype and genotype spectrum of patients with a bilateral optic neuropathy in population of Slovenia

Abstract

Purpose : The aim of the study was to identify the proportion of genetic causes in patients with unclarified progressive bilateral optic neuropathy in population of Slovenia using mitochondrial (mtDNA) and exome sequencing.

Methods : 47 patients (33 males, 14 females; average age 41.7 years, range 3-83 years) with bilateral optic neuropathy that were referred to tertiary neuro-ophthalmology service, Eye Clinic UMC Ljubljana were included in our study. Full clinical examination, visual acuity, color vision, visual field, OCT retinal and RNFL thickness, electrophysiology; and a detailed diagnostic workup to exclude glaucoma, compressive, demyelinating, inflammatory, infective, infiltrative or toxic causes were performed. Genetic analysis consisted of whole mtDNA sequencing followed by sequencing of the whole exome with analysis of the known nuclear genes associated with optic neuropathy. We also compared (chi square statistic) the variant burden of mitochondrial genes in 27 patients and control group (350 controls).

Results : All patients had a bilateral loss of visual acuity with central scotoma, dyschromatopsia and thinning of ganglion cell complex. Electrophysiology showed reduced PERG N95 wave and delayed and reduced P100 wave. Pathogenic variants in mtDNA associated with LHON were found in 8 patients. In addition, we identified 6 different variants of unknown significance in mitochondrial genome and 2 different variants of unknown significance in nuclear genome. Secondary mtDNA variants previously reported in association with or as a risk factor for the development of LHON are listed in the Tables 1 and 2. No significant differences in the burden of all mitochondrial variants were found. Exome sequencing identified one heterozygous OPA1 pathogenic variant, two ACO2 pathogenic variants in compound heterozygous state, one pathogenic homozygous variant in C12orf65 gene and one de novo likely pathogenic WFS1variant. The results are summarized in Tables 1 and 2.

Conclusions : We found possible genetic causative variants in 12 of 47 (25.53%) patients with bilateral optic neuropathy whilst 35 patients remained undiagnosed. As we are the only tertiary centre in Slovenia, our results also show low prevalence of LHON in patients of Slovenian population. Combined analysis with mtDNA and clinical exome sequencing is a recommended approach for patients with a bilateral optic neuropathy.

This is a 2020 ARVO Annual Meeting abstract.