The top 10 most frequently involved genes in hereditary optic neuropathies in 2186 probands

Hereditary optic neuropathies are caused by the degeneration of retinal ganglion cells whose axons form the optic nerves, with a consistent genetic heterogeneity. As part of our diagnostic activity, we retrospectively evaluated the combination of Leber hereditary optic neuropathy mutations testing w...

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Published in:Brain (London, England : 1878) England : 1878), 2023-02, Vol.146 (2), p.455-460
Main Authors: Rocatcher, Aude, Desquiret-Dumas, Valérie, Charif, Majida, Ferré, Marc, Gohier, Philippe, Mirebeau-Prunier, Delphine, Verny, Christophe, Milea, Dan, Lenaers, Guy, Bonneau, Dominique, Reynier, Pascal, Amati-Bonneau, Patrizia
Format: Article
Language:English
Subjects:
ATP-Dependent Proteases - genetics
ATPases Associated with Diverse Cellular Activities - genetics
Carrier Proteins - genetics
DNA, Mitochondrial - genetics
Humans
Life Sciences
Membrane Proteins - genetics
Mitochondrial Proteins - genetics
Mutation - genetics
Optic Atrophy, Autosomal Dominant - genetics
Optic Atrophy, Autosomal Dominant - pathology
Optic Atrophy, Hereditary, Leber - genetics
Optic Nerve Diseases - genetics
Retrospective Studies
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Summary:Hereditary optic neuropathies are caused by the degeneration of retinal ganglion cells whose axons form the optic nerves, with a consistent genetic heterogeneity. As part of our diagnostic activity, we retrospectively evaluated the combination of Leber hereditary optic neuropathy mutations testing with the exon sequencing of 87 nuclear genes on 2186 patients referred for suspected hereditary optic neuropathies. The positive diagnosis rate in individuals referred for Leber hereditary optic neuropathy testing was 18% (199/1126 index cases), with 92% (184/199) carrying one of the three main pathogenic variants of mitochondrial DNA (m.11778G>A, 66.5%; m.3460G>A, 15% and m.14484T>C, 11%). The positive diagnosis rate in individuals referred for autosomal dominant or recessive optic neuropathies was 27% (451/1680 index cases), with 10 genes accounting together for 96% of this cohort. This represents an overall positive diagnostic rate of 30%. The identified top 10 nuclear genes included OPA1, WFS1, ACO2, SPG7, MFN2, AFG3L2, RTN4IP1, TMEM126A, NR2F1 and FDXR. Eleven additional genes, each accounting for less than 1% of cases, were identified in 17 individuals. Our results show that 10 major genes account for more than 96% of the cases diagnosed with our nuclear gene panel.
ISSN:0006-8950
1460-2156
DOI:10.1093/brain/awac395