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Human Molecular Genetics, 2003, Vol. 12, No. 5 583-584
© 2003 Oxford University Press
Retinitis pigmentosa and allied diseases: numerous diseases, genes, and inheritance patterns
Human Molecular Genetics 11, 1219–1227 (2002)
An error has been found on page 1224 of this article, concerning the calculation of the frequency of heterozygous, unaffected carriers of recessive alleles causing retinitis pigmentosa. Specifically, the allele frequency was erroneously used as the measure of carrier frequency.
The following page shows the corrected version of page 1224 and Figure 2.
Female carriers of mutations in X-linked RP genes are all mosaics because of differential X chromosome inactivation (Lyonization). They usually have fundus features and/or electroretinographic abnormalities that indicate a modest loss of photoreceptors (100,101). However, some carrier females exhibit signs and symptoms of retinal degeneration that is presumably due to unfavorable Lyonization that inactivates the normal X chromosome in the majority of their retinal cells. The signs and symptoms can be so severe that some clinicians will entertain the diagnosis of RP and consider the family to have an X-linked dominant form of RP. However, in most such families, the carrier females will have disease far less severe than their affected male relatives, so that the designation of X-linked dominant inheritance is probably not accurate.
NUMEROUS GENES IMPLY NUMEROUS CARRIERS
The high number of recessive genes that can cause RP must be taken into account when estimating the frequency of unaffected carriers of one or more recessive mutations. The frequency of recessive RP is roughly one in 6000 (102,103). If all cases of recessive RP were caused by mutations in the same gene, the carrier frequency is calculated as 2(1/6000)0.5[1-(1/6000)0.5], or about 1/39. However, if there were two recessive RP genes each contributing to half of the cases, the prevalence of each one would be one in 12000, and the carrier frequency of each would be one in 55, for a combined carrier frequency of about one in 28. Figure 2 illustrates the results of similar calculations and shows how the aggregate carrier frequency increases as the number of recessive RP genes increases. Although the exact number of recessive RP genes is still not known, at least 45 have been identified or implicated by linkage studies, and it is likely that many more exist. With this number alone, the aggregate carrier frequency becomes greater than 15%. This is higher than the carrier frequency for cystic fibrosis, a recessive disease often cited as having one of the highest carrier frequencies among Caucasians. The actual aggregate carrier frequency would be lower if some genes account for a higher proportion of cases than others and if there were numerous examples of digenic diallelic RP. It would be higher if one includes other recessively inherited photoreceptor diseases such as cone–rod degeneration or macular degeneration. The high carrier frequency explains the many instances where patients with a retinal disease that is clearly the result of a mutation in one gene are found also to carry a mutation in another RP gene, or where unaffected control individuals are found to carry recessive RP alleles (104–107).
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It should be noted that for the genetic counseling of an individual patient, it is not the aggregate frequency but the individual gene carrier frequency that is important. Although the aggregate carrier frequency increases with an increase in the number of RP genes, the carrier frequency for any single gene decreases (Fig. 2). For example, if there are 45 recessive RP genes of equal frequencies, the aggregate carrier frequency would be 15.9%, but the carrier frequency for any given one of the 45 genes would be only one in 260, or 0.0038. Thus, the chance that a known obligate carrier (e.g., the offspring of a patient with recessive RP) will have a spouse who is also a carrier (with a resulting one in four chance of each of their children being affected) is much lower than would be expected if there were only one or a few recessive RP genes.
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