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Elise Heon, Anjali Vig, Erika Tavares, Ajoy Vincent; The number of RPGR cases remains under-represented. Invest. Ophthalmol. Vis. Sci. 2019;60(9):389.
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Identification of the genetic cause of the retinal degeneration in three male patients.
This study was approved by the ethics board of the Hospital for Sick Children (Toronto). Two male patients affected with retinal degeneration for whom no mutation was identified through standard of care clinical testing, underwent whole genome sequencing (WGS). Another case was studied twice using different CLIA-approved Laboratory. Pedigress were drawn. Clinical information collected related to general health, family and personnal history and ocular phenotyping (VA, exam, imaging, functional studies). DNA was extracted from whole blood using standard procedures. Research based WGS was analysed using internal filtering protocols. Variant validation was done using publicly available tools and segregation analysis. Variant pathogenicity calling respected the criteria of the American College of Medical Geneticists. Final research results were confirmed by a CLIA approved laboratory.
Two of the participants were Caucasian while one was East Indian. RPGR ORF15 were identified, in 3 males who previously a negative genetic testing result, using a different filtering approach of the next generation sequences. Several parameters were changed such as removing the quality pass filter and accepting a lower coverage. The ORF15 variants identified (c.232_2354del and c.2405_2406del) met all our validation parameters and were confirmed by a CLIA approved laboratory. Though there were some phenotype difference between the patients, they all had a visual impairment and an ocular phenotype compatible with an RPGR-related retinal degeneration. Genetic counseling was provided accordingly and the WGS analysis approach for males affected with retinal degeneration was modified.
Because the RPGR sequence is very GC rich, full sequence coverage has been challenging. When doing WGS it has been useful to loosen the traditionally used filtering criteria and accept a lower coverage to identify ORF15 variants. Because gene replacement therapy is being trialed clinically, it is imperative that the real burden of disease be identified.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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