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Carlo Rivolta, Koji M. Nishiguchi; Are We All Carriers Of Blinding Mutations?. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1578.
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Retinal degenerations (RD) that are inherited as a recessive trait are caused by numerous mutations in more than 100 different genes, unlike the majority of other Mendelian diseases. Laws of population genetics predict that, on a purely theoretical ground, such a high number of genes should translate into an extremely elevated frequency of unaffected carriers of mutations. In this study we estimate the proportion of these individuals within the general population, via the analyses of data from whole-genome sequencing.
We first developed a specific in-silico pipeline to ascertain the presence of pathogenic RD variants within a cohort of 16 unrelated patients, whose full genome was sequenced according to the Complete Genomics procedure. Subsequently, we applied the same analytical workflow to the genomes of 46 publicly-available control individuals that were sequenced by the same technique and included samples from: European Americans, African Americans, Mexicans, Italians, Maasai, Yoruba, Luhyas, Chinese, Japanese, and Gujaratis. All RD mutations detected in silico were validated by Sanger sequencing.
We identified clear-cut, null recessive RD mutations in 10 out of the 46 unaffected individuals analyzed (~22%). All mutations were detected in a heterozygous state, as expected. No genome carried more than one RD mutation.
Approximately one in 4-5 individuals from the general population is a carrier of mutations that are responsible for retinal degeneration. Although rather high, this figure probably represents an underestimation of the real frequency, since no mutations other than definite null changes (nonsense or frameshift variants) were considered at this stage. Since RD are generally monogenic, this situation has a limited influence on the overall prevalence of the diseases, which indeed is rather low (~1 case in 5,000 people). In addition to their relevance to population genetics, our results are important for DNA research performed on large cohorts of patients, as well as for routine molecular diagnostics.
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