Menzies Institute for Medical Research, School of Medicine, University of Tasmania, Hobart, 7000 TAS, Australia; The University of Western Australia, Centre for Ophthalmology and Visual Science, Lions Eye Institute, Nedlands, 6009 WA, Australia; Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, 3002 VIC, Australia.
Statistical Genetics Laboratory, Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, 4006 QLD, Australia.
Am J Hum Genet. 2023 Jan 5;110(1):170-176. doi: 10.1016/j.ajhg.2022.11.014. Epub 2022 Dec 23.
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.
家系分析表明，携带线粒体风险变异的大多数莱伯遗传性视神经病变（LHON）家族成员从未丧失视力。线粒体单倍型似乎是影响 LHON 视力丧失风险的主要因素。包括 m.14484T>C 和 m.11778G>A 在内的线粒体变异已被添加到基因芯片中，因此许多患者和研究参与者都接受了 LHON 突变检测。对英国生物库和澳大利亚队列研究的分析发现，每 1000 人中就有超过 1 人携带 m.14484T>C 或 m.11778G>A LHON 变异。在接受检查的携带者亚组中，没有人的视力在 20/200 或更差，这表明 LHON 的外显率非常低。对 m.14484T>C 携带者的单倍群分析显示，高比例的单倍群 U 亚支系，先前在系谱中显示出低外显率。一般人群的外显率计算低于系谱计算，这很可能是因为有修饰遗传因素。这篇出现的问题回应文章针对 Watson 等人（2022 年）同时发表在《美国人类遗传学杂志》上的出现的问题回应文章。
