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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. [ABSTRACT FROM AUTHOR]

PurposeTo identify the prevalence of myocilin gene mutations in a UK glaucoma cohort.MethodsPrimary open-angle (POAG) and normal tension glaucoma patients were recruited from the Southampton University Hospital Trust Eye Clinic and satellite regional glaucoma clinics. Phenotype data relating to disease history and other potential risk factors were recorded and blood samples collected for each consenting participant. Point mutation analysis of the myocilin gene was carried out using six overlapping PCR fragments covering the entire coding sequence of the gene. A total of 316 POAG samples were examined of which 7 (2.2 %) tested positive for disease-causing mutations in this gene. One of these seven non-synonymous mutations represented a previously unreported amino-acid substitution of cysteine for arginine at codon 296 (p.R296C) of the myocilin protein.ConclusionsThis study identifies a 2.2% prevalence of myocilin mutations in a cohort of ethnically homogenous glaucoma patients selected from a UK ophthalmic clinic. A novel myocilin mutation is also described. This study identifies that myocilin genetic screening is feasible in NHS glaucoma clinics for genetic counselling and cascade testing of relatives of patients affected by myocilin glaucoma. [ABSTRACT FROM AUTHOR]