June 2015
Volume 56, Issue 7
ARVO Annual Meeting Abstract  |   June 2015
Absence of genotype-phenotype correlations in RPE65 gene mutations associated with autosomal recessive retinal dystrophy
Author Affiliations & Notes
  • Daniel C Chung
    FM Kirby Ctr Molecular Ophth, Scheie Eye Institute, Philadelphia, PA
  • Karmen Trzupek
    InformedDNA, St. Petersburg, FL
  • Jennifer Wellman
    Spark Therapeutics, Inc, Philadelphia, PA
  • Katherine High
    Spark Therapeutics, Inc, Philadelphia, PA
  • Footnotes
    Commercial Relationships Daniel Chung, None; Karmen Trzupek, Spark Therapeutics, Inc (C); Jennifer Wellman, Spark Therapeutics, Inc (E), Spark Therapeutics, Inc (I); Katherine High, Spark Therapeutics, Inc (E), Spark Therapeutics, Inc (I), Spark Therapeutics, Inc (S)
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 2891. doi:
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      Daniel C Chung, Karmen Trzupek, Jennifer Wellman, Katherine High; Absence of genotype-phenotype correlations in RPE65 gene mutations associated with autosomal recessive retinal dystrophy. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2891.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose: In many inherited disorders, genotype-phenotype correlations provide insight into onset of disease, rate of progression, and degree of severity. Both LCA2 and RP20 are caused by mutations in the RPE65 gene. We examined the various mutations in the RPE65 gene to determine whether genotype-phenotype correlations exist.<br />

Methods: Genotype data were obtained from individuals enrolled in the phase 1/2 and phase 3 gene therapy clinical trials at The Children’s Hospital of Philadelphia. These mutations were compared with mutations in the RPE65 gene from patients with autosomal recessive forms of inherited retinal dystrophy reported in the literature. Disease course and additional clinical data were evaluated.

Results: <br /> Over 125 discrete mutations were identified in the RPE65 gene in individuals with inherited retinal disease. These include missense and nonsense point mutations, frameshift mutations resulting from small insertions and deletions, and splice site mutations. Patient diagnoses included Leber congenital amaurosis (LCA) type 2, early onset retinal dystrophy (EORD), and early onset retinitis pigmentosa (RP) type 20. Several recurrent mutations were noted across patients with LCA as well as later onset retinal dystrophies, including the missense mutation Tyr368His and the common splice site mutation in intron 1 (IVS1+5G>A). Nonsense and frameshift mutations were also described in patients across all diagnosis groups.

Conclusions: In the cohort of subjects reviewed in this study, no clear genotype-phenotype correlations emerged. The distinction between RP20, LCA2, and other clinical diagnosis given to those with autosomal recessive RPE65 mutations appears to be based primarily on clinical symptoms and age of onset, and unrelated to underlying genotype. Possible factors linked to this lack of correlation include effects of modifier genes, wide differences among clinicians in assignment of clinical classification, or other causes.


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