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Abigail T Fahim, Lori S Sullivan, Sara J Bowne, Kaylie Webb-Jones, Dianna K.H. Wheaton, Kari E Branham, Mohammad Othman, Athanasios J Karoukis, Chris Andrews, John R Heckenlively, David G Birch, Stephen P Daiger; X-Chromosome Inactivation is a Biomarker of Clinical Severity in Female Carriers of X-linked Retinitis Pigmentosa. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2961.
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X-linked retinitis pigmentosa (XLRP) can manifest in female carriers with widely variable phenotypic severity, while others remain unaffected. The contribution of X-chromosome inactivation (XCI) to phenotypic variation has been postulated but not demonstrated. The purpose of this study is to describe the scope of clinical phenotype in female carriers with mutations in RPGR, and to quantify the contribution of XCI to phenotypic severity.
A cohort of 78 female carriers with RPGR mutations from 42 pedigrees with XLRP was ascertained. XCI ratios were determined in genomic DNA isolated from blood in 43 subjects and from saliva samples in 20 subjects, using methylation status of X-linked polymorphic repeats at the Androgen Receptor (AR) and RP2 loci. Clinical data included visual acuity (VA), Humphrey visual field (HVF), full field electroretinogram (ffERG), and dark adaptation (DA). Linear models were used to quantify the associations between XCI ratios and clinical parameters and severity.
Visual acuity ranged from LogMAR -0.2 to 2.0 (Snellen 20/13 to 20/2000), with an average of LogMAR 0.27 (20/37). Horizontal visual field diameter using a size III spot ranged from 0 to 60 (maximum) degrees. ERG 30hz flicker ranged from barely recordable to normal, and scotopic rod ERG ranged from non-recordable to normal. Skewed XCI towards inactivation of the normal RPGR allele was associated with more severe disease. The XCI ratios in blood and saliva samples were highly correlated (r=0.96) and were both statistically significant predictors of visual function as measured by HVF diameter, rod amplitude, flicker amplitude, and flicker implicit time. Extreme XCI skewing of 80:20 or more was found in 4% of those with mild or no disease, 25% of those with moderate disease, and 57% of those with severe disease (p=0.002).
Female carriers with mutations in RPGR demonstrate widely variable clinical severity of retinal degeneration. XCI ratios in both blood and saliva correlate with clinical severity and may serve as a biomarker of clinically significant disease. As RPGR gene therapy trials are underway, there will be a future imperative to determine which carriers require intervention and when to intervene, and XCI analysis may be a useful measurement in determining suitable candidates for early intervention.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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