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Editors Selection IGR 10-4

Genetics: Novel myocilin mutations

Comment by Subhabrata Chakrabarti on:

22070 Two novel myocilin mutations in a Chinese family with primary open-angle glaucoma, Xie X; Zhou X; Qu X et al., Molecular Vision, 2008; 14: 1666-1672

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Xie et al. (1352) screened the myocilin (MYOC) gene in a large Chinese POAG family, observed two novel mutations in some of the affected subjects and attempted to do a structural analysis of the variants in silico. This is essentially a candidate gene screening and not necessarily linkage (as stated in the abstract), which was technically not done. These type of large POAG-affected family, although rare to obtain, is ideal for gene mapping. The pedigree structure however, would have required further details with respect to the phenotype. It is not clear as to how the deceased individuals in generations I and II were diagnosed. It would have been helpful, if the genotypes of MYOC variants in all the subjects were given in the pedigree to indicate their pattern of segregation. The method of diagnosis of the controls and how they were matched has not been stated explicitly. Considering the fact that the entire MYOC gene was screened by re-sequencing, the authors should have provided the rationale for selective screening of a few known variants with PCR-based restriction digestions. Among the three observed variants, the Arg76Lys has been identified as a polymorphism, globally. Since the frequency of the mutant allele in a pedigree is not an indicator of its prevalence in the population, it may not be appropriate to term this as a mutation. The prevalence of a mutation is estimated from a large cohort of affected cases (combination of sporadic and index cases within families) and unaffected controls (ethnically matched from the general population). In a complex disease like POAG, where MYOC accounts for a very small proportion of cases, the disease prediction among consulters would have been appropriate if these were based Xie et al. (1352) screened the myocilin (MYOC) gene in a large Chinese POAG family, observed two novel mutations in some of the affected subjects and attempted to do a structural analysis of the variants in silico. This is essentially a candidate gene screening and not necessarily linkage (as stated in the abstract), which was technically not done. These type of large POAG-affected family, although rare to obtain, is ideal for gene mapping. The pedigree structure however, would have required further details with respect to the phenotype. It is not clear as to how the deceased individuals in generations I and II were diagnosed. It would have been helpful, if the genotypes of MYOC variants in all the subjects were given in the pedigree to indicate their pattern of segregation. The method of diagnosis of the controls and how they were matched has not been stated explicitly. Considering the fact that the entire MYOC gene was screened by re-sequencing, the authors should have provided the rationale for selective screening of a few known variants with PCR-based restriction digestions. Among the three observed variants, the Arg76Lys has been identified as a polymorphism, globally. Since the frequency of the mutant allele in a pedigree is not an indicator of its prevalence in the population, it may not be appropriate to term this as a mutation. The prevalence of a mutation is estimated from a large cohort of affected cases (combination of sporadic and index cases within families) and unaffected controls (ethnically matched from the general population). In a complex disease like POAG, where MYOC accounts for a very small proportion of cases, the disease prediction among consulters would have been appropriate if these were based on a combination of multiple clinical and genetic factors rather than a single gene variant.

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