Presentation: Patient with optic neuropathy

A healthy young man presents to the eye clinic with sudden painless progressive visual loss. He reports that his vision was first affected in one eye, and was subsequently lost in the other eye a number of weeks later. Profound central visual loss is noted, but examination of the eyes does not initially show a problem.

• Genomic testing should be considered if a patient has a known family history of Leber hereditary optic neuropathy (LHON).
• Testing should also be considered in the presence of painless central visual loss in a patient of any gender without a family history of LHON.
• Finally, testing should be considered in the presence of undiagnosed optic neuropathies in all age groups where vascular causes are not suspected, and where clinical investigations have excluded nutritional, toxic and infectious causes of inflammation or compression of the optic nerve.
• Unaffected individuals may present with a family history of an adult-onset genetic condition. Where signs and/or symptoms suggestive of that condition are not present in the patient, they should be offered referral to a local clinical genetics service to discuss testing as part of a predictive (presymptomatic) testing pathway.
• A genetic diagnosis may have implications for other family members, and this can be particularly relevant during a pregnancy. Testing for mitochondrial conditions during pregnancy can be particularly complex. If the patient or a close relative is pregnant, the case should be discussed with your local clinical genetics service.

• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria document for information about individual tests and their associated eligibility criteria. You can also access a spreadsheet containing details of all available tests.
  • • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see Genomic testing in the devolved nations.
• To find out which genes are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• Decide which of the tests best suits the needs of your patient and/or their family. For optic neuropathies, there are a number of available panels.
  • R42 Leber hereditary optic neuropathy. This includes targeted variant testing of the three main mitochondrial variants known to cause Leber hereditary optic neuropathy (LHON). Also included is whole mitochondrial genome sequencing, which will identify other rare mitochondrial variants associated with LHON.
  • R41 optic neuropathy. This is undertaken using whole exome sequencing or medium-sized panel sequencing and will detect variants in genes known to cause optic neuropathy and exon-level copy number variants. The three common LHON variants will also be tested for, using targeted variant testing. However, if LHON is suspected, R42 should be used as a first-line test in preference.
• Neither of the tests outlined above use whole genome sequencing, so you should use your local Genomic Laboratory Hub test order form and consent (record of discussion) form.
• When testing in children, parental samples may be helpful for interpretation of the proband’s result but are not typically required for either of the tests recommended above. Parental samples can be taken alongside that of the proband, and their DNA stored, or can be requested at a later date if needed.
• Most tests are DNA based, and an EDTA sample (typically a purple-topped tube) is required. There are a few tests for which a different type of tube is used; see Samples for genomic testing in rare disease.
• If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.
• Information about patient eligibility and test indications was correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

For clinicians

• NHS England: National Genomic Test Directory

References:

• Chen BS, Newman NJ and Yu-Wai-Man P. ‘Developments in the treatment of Leber hereditary optic neuropathy’. Neuro-Ophthalmology 2022: volume 22, pages 881–892. DOI: 10.1007/s11910-022-01246-y
• Hage R and Vignal-Clermont C. ‘Leber hereditary optic neuropathy: Review of treatment and management’. Frontiers in Neurology 2021: volume 12. DOI: 10.3389/fneur.2021.651639
• Nagarajan H, Selvaumar A, Sundaramurthy S and others. ‘Whole mitochondrial genome sequencing in individuals with Leber hereditary optic neuropathy negative for the common pathogenic mitochondrial DNA variants‘. Frontiers in Neurology 2025: volume 16. DOI: 10.3389/fneur.2025.1584748

For patients

• LHON
• LHON Society
• Royal National Institute for Blind People