Genotype-Phenotype Correlations Reveal Positive Inheritance and Phenotype Associations for PROM1-Associated Inherited Retinal Degenerations
Shoukat, M.; Papp, K. M.; Misaghi, E.; Kalra, D. J.; MacDonald, I. M.; Benson, M. D.; Carr, B. J.
Show abstract
Genetic variants in PROM1 are associated with inherited blindness, but clinical phenotypes vary widely with currently no consensus on disease expectations or predicted patient outcomes. To address this issue, we performed chi-square correlation analysis on 190 published pathogenic and likely pathogenic variants from ClinVar Miner and the Human Gene Mutation Database. We identified a statistically significant increase in observed cases of dominantly inherited missense variants, which were associated with milder forms of macular dystrophy. Recessive inheritance of truncating frameshift variants was associated with more severe forms of inherited retinal degeneration such as rod-cone dystrophy. We also present case studies from 7 patients with phenotypes that are unique, unreported, or do not match the reported phenotype in online databases. We report two patients with VUS that have clinical phenotypes and dominantly inherited missense variants, one patient with a long natural history at our clinic, two patients with the same variant, but a different clinical diagnosis, and two patients with retinal deposits comprising subretinal drusenoid deposits (SDD) and soft drusen.
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