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Editors Selection IGR 12-3

Basic research: Genetics: Myocilin gene dosage

Comment by Ravi Thomas & Subhabrata Chakrabarti on:

18060 Myocilin variants in Indian patients with open-angle glaucoma, Bhattacharjee A; Acharya M; Mukhopadhyay A et al., Archives of Ophthalmology, 2007; 125: 823-829

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Bhattacharjee et al. (457) analyze myocilin (MYOC) in a cohort from West Bengal, India.The prevalence of MYOC mutations was estimated in 315 patients with POAG and 100 age and ethnically-matched normal controls. Seven mutations including a novel Gly399Asp variant were observed in 11 patients, a frequency of 2.2%, similar to the global estimate. The most common Gln368Stop mutation was also noted but on haplotype background different from Caucasians. Four intragenic SNPs in MYOC were typed across four linguistic groups to validate these for predictive testing. Almost half the cases (5/11) with mutations were JOAG; asMYOC frequency grossly differs between JOAG and POAG, a separate analysis may be useful.

This is the largest published study on MYOC but may not be representative of the Indian population at large. We have some reservations about the definition of patients and controls and hence of the phenotype. The cases were recruited from two different centres but uniformity in diagnosis and inclusion/exclusion criteria are not clear. Normal volunteers in the linguistic groups did not undergo any ocular examination; they need to be handled with caution for analysis and interpretation. As far as definition is concerned, there seems to be some confusion about the IOP cut off. Three mirror gonioscopy is probably not appropriate. No cut off is provided for cup-disc-ratio nor other disc or NFL signs. Additionally, the nerve fibre layer analyzer was used, but no specifics provided.

This problem with definitions may have major implications: while age is one explanation for non-manifestation of phenotype in the presence of mutation (Fig 1a), non-specific definition may be another.

From our personal experience with primary congenital glaucoma, misdiagnosis leads errors in frequency of the mutant allele.The lesson to be learnt from the article may be similar - phenotype definition must be very specific.

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