Approach to an individual with a pathogenic variant or likely pathogenic variant in the RPE65 gene

RPE65 is one of many genes associated with retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA); only a small percentage of individuals with RP have pathogenic variants in RPE65. Genetic counseling may include information about individual risk, risk for first-degree relatives, additional testing that may be indicated, and referral to a specialty center.

• A negative finding on RPE65 genetic testing must be interpreted in the context of the personal and family history:
  • If the family history is positive for RP, the familial variant(s) are known, and the individual tests negative for these variant(s), they likely can be reassured they are not at increased risk for RP/LCA.
  • If the family history is positive for RP and the familial variant(s) are not known, negative testing for RPE65 cannot be used to exclude the disorder. Consultation with a genetics expert is advised.
• Individuals with a VUS in RPE65 should be managed based on their personal and family history and not the VUS. Additional genetic testing may be indicated. A VUS may be reclassified as pathogenic or benign in the future if/when more data on its pathogenicity become available.
• Individuals with RP/LCA may warrant additional treatments for cataracts or macular edema.