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Multiple copies of rhodopsin as a novel cause of autosomal dominant retinitis pigmentosa

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Posterboard#: A0226

Abstract Number: 2943 - A0226

AuthorBlock: Jacque L. Duncan1, Karmen Trzupek2, Joan Fisher3, Leilla Kenney3, Sari Tuupanen4, Miika Mehine4, Stephen P. Daiger5,6, Brian Mansfield3
1Ophthalmology, Univ of California - SF, San Francisco, California, United States; 2InformedDNA, St. Petersburg, Florida, United States; 3Foundation Fighting Blindness, Columbia, Maryland, United States; 4Blueprint Genetics Oy, Biomedicum, Helsinki, Finland; 5School of Public Health, University of Texas Health Science Center, Houston, Texas, United States; 6Ruiz Department of Ophthalmology and Visual Science, University of Texas Health Science Center, Houston, Texas, United States;

DisclosureBlock: Jacque L. Duncan, AGTC Therapeutics Code C (Consultant), Editas Medicine Code C (Consultant), Ionis Pharmaceuticals Code C (Consultant), Novelion Therapeutics Code C (Consultant), ProQR Therapeutics Code C (Consultant), SparingVision Code C (Consultant), Spark Therapeutics Code C (Consultant), Karmen Trzupek, InformedDNA Code E (Employment), AGTC Therapeutics Code C (Consultant), Spark Therapeutics Code C (Consultant), Joan Fisher, None; Leilla Kenney, Foundation Fighting Blindness Code E (Employment), Sari Tuupanen, Blueprint Genetics Code E (Employment), Miika Mehine, Blueprint Genetics Code E (Employment), Stephen P. Daiger, None; Brian Mansfield, None;

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.

Layman Abstract (optional): Provide a 50-200 word description of your work that non-scientists can understand. Describe the big picture and the implications of your findings, not the study itself and the associated details.
Advanced genetic testing of individuals with inherited retinal degenerations may reveal novel mechanisms of photoreceptor degeneration. Among participants in a registry for inherited retinal degenerations patients, 3,140 were tested with a 266-gene retinal dystrophy panel. Multiple copies of the rhodopsin (RHO) gene were identified in a patient with autosomal dominant retinitis pigmentosa, suggesting overexpression of rhodopsin may cause retinal degeneration in humans. Overexpression of rhodopsin may be a more common cause of retinitis pigmentosa than expected and may account for a portion of the remaining cases in which mutations have not been detected to date.