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Stephen P. Daiger, Michelle R. O'Byrne, Abigail T. Fahim, Sara J. Bowne, Lori S. Sullivan, David G. Birch, Kaylie D. Webb, Dianna K. Wheaton; Factors Modifying Severity and Penetrance in Males and Females with Retinitis Pigmentosa Caused by Mutations in the X-Linked RPGR Gene. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4540.
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To determine factors influencing severity of retinal disease in males with mutations in RPGR, and penetrance and severity in carrier females from the same families. Factors considered included the type and location within the gene of RPGR mutations and the possible influence of coding-SNP’s in genes producing proteins that interact with RPGR.
A total of 58 families with X-linked retinitis pigmentosa, with 53 distinct RPGR mutations, were ascertained, including 98 affected males and 75 carrier females. Mutations were determined by dideoxy-sequencing of RPGR in affected males, including ORF15 and exon 9A. Mutations were confirmed by sequencing in affected and unaffected at-risk females, or assumed in obligate carriers. Clinical measures (both eyes in females) included visual acuity, Humphrey visual fields, OCT, fdOCT, dark-adaptation, ffERG and mfERG. Coding-SNP’s and SNP haplotypes were determined in CEP290, ICQB1, RPGRIP1 and RPGRIP1L. Between-measure correlations were determined by Excel, with or without correction for normality. Family-based association of SNP’s with measures of severity was evaluated using PLINK.
Severity of disease in affected males and females is influenced by mutation type and may be modified by coding-SNP’s in genes interacting with RPGR. In males, mutations in exons 1-14 are more severe than ORF15 mutations, and two SNP alleles, in ICQB1 and RPGRIP1L, showed association with severity. In females, correlations of between-eye measurements were .75 or greater, with the exception of visual acuity, and some clinical measures are also correlated. This allows use of mean-eye values for most clinical measure and reduction of values to several discriminants. Evaluation of association between coding-SNP’s and clinical discriminants in females is underway.
Mutations in RPGR are among the most common causes of retinitis pigmentosa. Penetrance and clinical consequences of RPGR mutations are highly variable, even among individuals with the same mutation. Penetrance in males is nearly 100%, as expected of X-linked diseases, but many carrier females also have retinal disease. Males are generally more severely affected than carrier females, but some females are severely affected. Findings in this study contribute to an understanding of variable severity in males with RPGR mutations, and may contribute to an understanding of incomplete penetrance and variable expression in females.
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