Abstract
To assess the clinical utility of next-generation sequencing (NGS) for the diagnosis of patients with optic atrophy (OA). Retrospective cohort study. 97 patients were referred to the McMaster University Medical Center (Hamilton, Ontario) for evaluation of bilateral OA. All patients were sent for NGS including a 22 nuclear gene panel and/or complete mitochondrial DNA (mtDNA) sequencing. Positive genetic test results and abnormal vibration sensation were compared in patients +/- environmental exposures or a family history. 19/94 (20.2%) had a positive nuclear variant, of which 15/19 (78.9%) were in the OPA1 gene. No positive mtDNA variants were identified. The detection of a positive genetic variant was significantly different in patients who reported excessive ethanol use, but not in patients who smoke (0/19 (0%) vs. 19/78 (24.4%), P = 0.0164 and 4/22 (18.2%) vs. 15/74 (20.3%), P = 0.829, respectively). Patients with a positive family history were more likely to have a positive genetic variant compared to patients with a negative family history (P = 0.0112). There were significantly more excessive drinkers with an abnormal vibration sensation (P = 0.026), and with a similar trend in smokers (P = 0.074). All positive genetic variants were identified in nuclear genes. We identified a potential independent pathophysiological link between a history of excessive ethanol consumption and bilateral OA. Further investigations should evaluate and identify potential environmental risk factors for OA.
Highlights
Inherited optic neuropathies are genetic disorders characterized by the slow loss of the retinal ganglion cells (RGCs) and their axons that form the optic nerve [1]
The main purpose of the current study was to determine the proportion of patients with pathogenic mutations in mitochondrial DNA (mtDNA) or select nuclear genes associated with optic atrophy
Pathogenic or likely pathogenic variants were identified in 22/ 94 (23.4%). One patient and his mother were identified to have a heterozygous likely pathogenic variant in the ACO2 gene, which previously has only been reported with an autosomal recessive pattern of inheritance [29]
Summary
Inherited optic neuropathies are genetic disorders characterized by the slow loss of the retinal ganglion cells (RGCs) and their axons that form the optic nerve [1]. As with any optic neuropathy, optic atrophy (OA) is the end result of the insult affecting an optic nerve and tends to be symmetric in inherited optic neuropathies. It is defined as variable loss of the optic nerve axons and subsequent optic nerve pallor visible on examination with variable deterioration of central visual acuity [2]. The two most common forms of inherited optic neuropathy are autosomal dominant optic atrophy (DOA) secondary to pathogenic variants within OPA1 (OMIM: 165500), and maternally inherited Leber hereditary optic neuropathy (LHON) (OMIM: 535000) [3]. Rarer cases of OA can be caused by pathogenic variants in the nuclear-encoded mitochondrial genes such as WFS1, MFN2, POLG, and ACO2 [9]
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