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Alessia Fiorentino, Gavin Arno, Nikolas Pontikos, Kaoru Fujinami, Takaaki Hayashi, Vincent Plagnol, Michael E Cheetham, Takeshi Iwata, Andrew R Webster, Michel Michaelides, Alison J Hardcastle; Mutations in the X-linked gene PRPS1 cause retinal degeneration in females. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1243.
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Retinal dystrophies show high genetic heterogeneity, with over 250 disease-causing genes identified. Additional genes remain to be discovered. We sought to identify the cause of retinal degeneration in unsolved cases.
Patients recruited to this study were mutation negative for known disease genes. Whole exome or whole genome sequence analysis was performed. Nonsynonymous, splice site, frameshift and nonsense variants with a minor allele frequency <0.1% where considered as candidates. Further prioritization was performed by combining data on sequence conservation, gene function and expression. Segregation analysis of variants by Sanger sequencing was performed where familial samples were available.
In the first family, all affected females had patchy retinal degeneration and a tapetal reflex, with the female proband having an affected mother, consistent with dominant inheritance. Unexpectedly, WES and segregation analysis revealed a rare missense variant in PRPS1 (p.S16F). This variant was absent in Exac. Subsequently, three other unrelated female probands, with no affected male relatives, were found to have rare missense variants in PRPS1 (p.R214W, p.R196W, p.R214P). Affected members of all four families showed an asymmetrical, non-contiguous retinopathy affecting both rod and cone photoreceptor function. Hearing impairment was present in 1 family.
Mutations in PRPS1 are known to cause rare forms of non-syndromic sensorineural deafness, Charcot-Marie-Tooth disease and Arts Syndrome. Hearing loss is a common feature of these disorders, with affected males displaying phenotypic heterogeneity. In a previous report of one family with only affected females, a p.S16P variant was associated with variable degrees of optic atrophy, retinitis pigmentosa and neurological manifestations, including hearing loss, intellectual disability and peripheral neuropathy. These data highlight the unexpected finding of X-linked retinal degeneration in females caused by mutations in PRPS1. The asymmetry of the degeneration is similar to that seen in RPGR and RP2 and might be confused with an inflammatory retinopathy. Skewed X-inactivation and/or variable levels of PRS-I deficiency may contribute to the variability of disease.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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