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

David A. Mackey; Jue Sheng Ong; Stuart MacGregor; David C. Whiteman; Jamie E. Craig; M. Isabel G. Lopez Sanchez; Lisa S. Kearns; Sandra E. Staffieri; Linda Clarke; Myra B. McGuinness; Wafaa Meteoukki; Sona Samuel; Jonathan B. Ruddle; Celia Chen; Clare L. Fraser; John Harrison; Neil Howell; Alex W. Hewitt

doi:10.1016/j.ajhg.2022.11.014

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

David A. Mackey^*, Jue Sheng Ong, Stuart MacGregor, David C. Whiteman, Jamie E. Craig, M. Isabel G. Lopez Sanchez, Lisa S. Kearns, Sandra E. Staffieri, Linda Clarke, Myra B. McGuinness, Wafaa Meteoukki, Sona Samuel, Jonathan B. Ruddle, Celia Chen, Clare L. Fraser, John Harrison, Neil Howell, Alex W. Hewitt

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

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.

Original language	English
Pages (from-to)	170-176
Number of pages	8
Journal	American Journal of Human Genetics
Volume	110
Issue number	1
DOIs	https://doi.org/10.1016/j.ajhg.2022.11.014
Publication status	Published - 5 Jan 2023
Externally published	Yes

Bibliographical note

Copyright the Author(s) 2022. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

haplogroup
LHON
m.11778G>A
m.14484T>C
mitochondria
mtDNA
myocilin
prevalence
UK Biobank

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10.1016/j.ajhg.2022.11.014Licence: CC BY

Publisher version (open access)Final published version, 1.01 MBLicence: CC BY

Cite this

Mackey, D. A., Ong, J. S., MacGregor, S., Whiteman, D. C., Craig, J. E., Lopez Sanchez, M. I. G., Kearns, L. S., Staffieri, S. E., Clarke, L., McGuinness, M. B., Meteoukki, W., Samuel, S., Ruddle, J. B., Chen, C., Fraser, C. L., Harrison, J., Howell, N., & Hewitt, A. W. (2023). Is the disease risk and penetrance in Leber hereditary optic neuropathy actually low? American Journal of Human Genetics, 110(1), 170-176. https://doi.org/10.1016/j.ajhg.2022.11.014

@article{f38265a1c5d046868d03afb2f2b68690,

title = "Is the disease risk and penetrance in Leber hereditary optic neuropathy actually low?",

abstract = "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.",

keywords = "haplogroup, LHON, m.11778G>A, m.14484T>C, mitochondria, mtDNA, myocilin, prevalence, UK Biobank",

author = "Mackey, {David A.} and Ong, {Jue Sheng} and Stuart MacGregor and Whiteman, {David C.} and Craig, {Jamie E.} and {Lopez Sanchez}, {M. Isabel G.} and Kearns, {Lisa S.} and Staffieri, {Sandra E.} and Linda Clarke and McGuinness, {Myra B.} and Wafaa Meteoukki and Sona Samuel and Ruddle, {Jonathan B.} and Celia Chen and Fraser, {Clare L.} and John Harrison and Neil Howell and Hewitt, {Alex W.}",

note = "Copyright the Author(s) 2022. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.",

year = "2023",

month = jan,

day = "5",

doi = "10.1016/j.ajhg.2022.11.014",

language = "English",

volume = "110",

pages = "170--176",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "University of Chicago Press",