Leber hereditary optic neuropathy (LHON) is caused by missense mutations in the mitochondrial genes (mtDNA) encoding complex I subunits of the respiratory chain. However, mutations affecting genes in the nuclear genome may strikingly resemble the clinical presentation of LHON. We conducted a study to define best testing strategy using next generation sequencing in bilateral optic atrophy and inconclusive family history. Here we report on 30 unrelated individuals referred to our institution for genetic testing because of the optic nerve atrophy and clinically suspected LHON. None of the patients had lesions suggestive for multiple sclerosis on brain MRI. Genetic analysis consisted of mtDNA sequencing followed by clinical exome sequencing. In two unrelated patients mtDNA sequencing identified typical LHON pathogenic variants (m.11778G)A, m.3700G)A). Exome sequencing in three unrelated patients revealed OPA1 mutation (c.2489G)A, likely pathogenic variant), compound heterozygous mutations in ACO2 (c.2253dupC, VUS and c.719G)C, pathogenic variant) and a de novo mutation in WFS1 (c.2480C)T, likely pathogenic variant). Upon genetically guided clinical review, the last patient was found to exhibit signs on macular OCT, typical for Wolfram syndrome. We found possible causative variants in 5 of 30 patients with bilateral optic atrophy and clinically suspected LHON. In addition to typical LHON mitochondrial variants we found causative variants associated with autosomal dominant, autosomal recessive and syndromic forms of optic neuropathy and reclassified clinical diagnoses. Our results provide evidence that a combined approach with mtDNA and clinical exome sequencing is recommended in cases of clinically suspected LHON and negative family history.
B.03 Paper at an international scientific conference