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Is the disease risk and penetrance in Leber hereditary optic neuropathy actually low?


Mackey, DA and Ong, JS and MacGregor, S and Whiteman, DC and Craig, JE and Lopez Sanchez, MIG and Kearns, LS and Staffieri, SE and Clarke, L and McGuinness, MB and Meteoukki, W and Samuel, S and Ruddle, JB and Chen, C and Fraser, CL and Harrison, J and Howell, N and Hewitt, AW, Is the disease risk and penetrance in Leber hereditary optic neuropathy actually low?, American Journal of Human Genetics, 110, (1) pp. 170-176. ISSN 0002-9297 (2023) [Refereed Article]

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DOI: doi:10.1016/j.ajhg.2022.11.014


Pedigree analysis showed that a large proportion of Leber hereditary optic neuropathy (LHON) family members who carry a mitochondrial risk variant never lose vision. Mitochondrial haplotype appears to be a major factor influencing the risk of vision loss from LHON. Mitochondrial variants, including m.14484T>C and m.11778G>A, have been added to gene arrays, and thus many patients and research participants are tested for LHON mutations. Analysis of the UK Biobank and Australian cohort studies found more than 1 in 1,000 people in the general population carry either the m.14484T>C or the m.11778G>A LHON variant. None of the subset of carriers examined had visual acuity at 20/200 or worse, suggesting a very low penetrance of LHON. Haplogroup analysis of m.14484T>C carriers showed a high rate of haplogroup U subclades, previously shown to have low penetrance in pedigrees. Penetrance calculations of the general population are lower than pedigree calculations, most likely because of modifier genetic factors. This Matters Arising Response paper addresses the Watson et al. (2022) Matters Arising paper, published concurrently in The American Journal of Human Genetics.

Item Details

Item Type:Refereed Article
Keywords:LHON; UK Biobank; haplogroup; m.11778G>A; m.14484T>C; mitochondria; mtDNA; myocilin; prevalence.
Research Division:Biomedical and Clinical Sciences
Research Group:Ophthalmology and optometry
Research Field:Optical technology
Objective Division:Health
Objective Group:Clinical health
Objective Field:Diagnosis of human diseases and conditions
UTAS Author:Mackey, DA (Professor David Mackey)
UTAS Author:Hewitt, AW (Professor Alex Hewitt)
ID Code:155573
Year Published:2023
Deposited By:Menzies Institute for Medical Research
Deposited On:2023-03-01
Last Modified:2023-03-01

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