Abstract
Purpose :
PRPH2/RDS is associated with various autosomal dominant retinopathies including Retinitis Pigmentosa, Pattern Dystrophy, Cone Rod dystrophy, Macular dystrophy, etc. Variations in PRPH2/RDS have been shown to translate to high phenotypic variability within and between families. This study looked at 144 eyeGENE® participants representing 122 families with a PRPH2/RDS variant to assess whether genotype-phenotype correlations could be made.
Methods :
A blood sample was obtained from each participant and DNA extracted by either manual or automated methods. DNA was shipped to the Laboratory for the Molecular Diagnosis of Inherited Eye Disease at the University of Texas or GeneDx and screened for variants in PRPH2/RDS by conventional or next generation sequencing methods.
Results :
Fifty-seven variants were distributed across Exons 1, 2 and 3, with 24 (42.1%) in Exon 1, 27 (47.4%) in Exon 2, and 4 (7.0%) in Exon 3, with 1 intron 1 (1.8%) and 1 intron 2 (1.8%) near a splice variant. The most prevalent variant was IVS2, c.828+3A>T, found in 26 of 122 families (21.3%). The c.422A>G variant (p.Tyr141Cys; (Exon 1) was found at the second highest frequency 9/122 (7.4%). The c.514C>T variant (Exon 1) was the third most frequent 6/122 (4.9%). Missense variants were most prevalent, with 15 occurring in Exon 1, 19 in Exon 2, and 1 in Exon 3. There were 9 nonsense and 10 frameshift variants, along with 2 in-frame deletions.
Entry diagnoses and associated clinical features include: Stargardt disease (45.8%), Pattern dystrophy (26.4%), Retinitis pigmentosa (11.8%), Cone Rod dystrophy (8.3%), Best disease (6.3%), with 2 patients (0.7%) diagnosed with Choroideremia or Doyne Honeycomb dystrophy. The level of phenotypic and clinical detail available in eyeGENE® was variable between patients.
Conclusions :
To our knowledge, this is the largest patient cohort with PRPH2-related disease reviewed in a single study. Analysis revealed a wide range of genotypes and clinical diagnoses without obvious trends. Because disease presentation from mutations in a single gene may be variable and fit more than one clinical diagnosis, it is essential for the vision community to use standardized vocabularies. Collaborative clinical research studies using these vocabularies will enable predictive analyses to inform both genetic testing efficiencies as well as yield further insight into disease mechanisms.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.