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Jacque L Duncan, Karmen Trzupek, Joan Fisher, Leilla Kenney, Sari Tuupanen, Miika Mehine, Stephen P Daiger, Brian Mansfield; Multiple copies of rhodopsin as a novel cause of autosomal dominant retinitis pigmentosa. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2943.
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© ARVO (1962-2015); The Authors (2016-present)
Advanced genetic testing was conducted in selected individuals with inherited retinal diseases (IRDs) for the purpose of detecting novel disease-causing mechanisms. The selected individuals were part of a large cohort of IRD patients who were initially screened for mutations by targeted-capture next-generation sequencing (NGS).
The Foundation Fighting Blindness has supported My Retina Tracker®, a registry for IRD patients, since 2016. Registered patients are offered genetic testing which currently consists of screening by Blueprint Genetics (Helsinki, FIN) with a 266-gene retinal dystrophy panel. To date more than 9,900 people have registered with My Retina Tracker and, of these, 3,140 have completed genetic testing. For patients with apparent copy-number variants, additional testing included whole-exome NGS, targeted duplication/deletion analysis, enrollment of other family members, and extended clinical characterization.
Among patients registered with My Retina Tracker and screened by Blueprint Genetics, a 68 year old male with autosomal dominant retinitis pigmentosa (adRP) was found to have multiple copies of the rhodopsin gene, RHO, a common cause of adRP. He had night vision loss, visual field constriction, cystoid macular edema and classical RP. Subsequent testing revealed a complex duplication-rearrangement of chromosome 3q22 which encompasses the entire RHO gene, 5’ regulatory regions and flanking genes. The rearrangement consists of a 48kb triplicated region embedded within a 188kb duplication, resulting in three apparently-intact RHO genes on one chromosome and a fourth, unaltered RHO on the homologous chromosome. No other apparent causes of retinal disease were detected and his unaffected daughter has normal RHO genes, confirming that the rearrangement is on one chromosome only.
The likely cause of adRP in this male is multiple copies of the RHO gene, with perhaps as many as four functional copies. Overexpression of RHO has been demonstrated as the cause of disease in animal models, overexpression is postulated in some human IRD patients, and no other plausible causes were detected. Genes flanking RHO are also affected but are apparently not pathogenic in this case. Overexpression may be a more common cause of RP than expected and may account for a portion of the remaining cases in which mutations have not been detected to date.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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