Autosomal dominant retinal dystrophies caused by a founder splice site mutation, c.828+3A>T, in PRPH2 and protein haplotypes in trans as modifiers

Suma Shankar, Dianna K. Hughbanks-Wheaton, David G. Birch, Lori S. Sullivan, Karen N. Conneely, Sara J. Bowne, Edwin M. Stone, Stephen P. Daiger

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


Purpose. We determined the phenotypic variation, disease progression, and potential modifiers of autosomal dominant retinal dystrophies caused by a splice site founder mutation, c.828+3A>T, in the PRPH2 gene. Methods. A total of 62 individuals (19 families) harboring the PRPH2 c.828+3A>T mutation, had phenotype analysis by fundus appearance, electrophysiology, and visual fields. The PRPH2 haplotypes in trans were sequenced for potential modifying variants and generalized estimating equations (GEE) used for statistical analysis. Results. Several distinct phenotypes caused by the PRPH2 c.828+3A>T mutation were observed and fell into two clinical categories: Group I(N = 44) with mild pattern dystrophies (PD) and Group II (N =18) with more severe cone-rod dystrophy (CRD), retinitis pigmentosa (RP), and central areolar chorioretinal dystrophy (CACD). The PRPH2 Gln304-Lys310-Asp338 protein haplotype in trans was found in Group I only (29.6% vs. 0%), whereas the Glu304- Lys310-Gly338 haplotype was predominant in Group II (94.4% vs. 70.4%). Generalized estimating equations analysis for PD versus the CRD/CACD/RP phenotypes in individuals over 43 years alone with the PRPH2 haplotypes in trans and age as predictors, adjusted for correlation within families, confirmed a significant effect of haplotype on severity (P = 0.03) with an estimated odds ratio of 7.16 (95% confidence interval [CI] = [2.8, 18.4]). Conclusions. The PRPH2 c.828+3A>T mutation results in multiple distinct phenotypes likely modified by protein haplotypes in trans; the odds of having the CACD/RP-like phenotype (versus the PD phenotype) are 7.16 times greater with a Glu304-Lys310-Gly338 haplotype in trans. Further functional studies of the modifying haplotypes in trans and PRPH2 splice variants may offer therapeutic targets.

Original languageEnglish (US)
Pages (from-to)349-359
Number of pages11
JournalInvestigative Ophthalmology and Visual Science
Issue number2
StatePublished - Feb 1 2016
Externally publishedYes


  • Genetic modifiers
  • Phenotype
  • Retinal dystrophy

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience


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