INTRODUCTION — This monograph summarizes the interpretation of germline genetic testing of RPE65, a gene associated with autosomal recessive retinitis pigmentosa-20 (RP20) and Leber congenital amaurosis (LCA), a form of retinitis pigmentosa present at birth. Evaluation and management of retinitis pigmentosa are discussed in detail separately .
RPE65 gene — The RPE65 gene, located on chromosome 1p31, encodes for a protein that is an enzyme critical for the normal functioning of the visual cycle. This protein, RPE65, is an all-trans-retinyl ester isomerase expressed in the retinal pigment epithelium (RPE). It is responsible for the functioning of the rods and cones (photoreceptors in the retina) because of its essential role in the biochemical recycling of chromophore in the visual cycle, which results in the transmission of electrical signals to the brain. Pathogenic variants in the RPE gene lead to reduced or absent levels of RPE65. Without this important enzyme, the biochemical visual cycle is blocked, resulting in impaired vision. As RPE65 is inherited in an autosomal recessive pattern, affected individuals are homozygous or compound heterozygous for a pathogenic variant in the RPE65 gene.
How to read the report — Confirm that the testing was performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory (or other nationally certified laboratory); if this is not the case, testing should be repeated in a certified laboratory. These and other caveats are summarized in the checklist (table 1).
Disease association — Retinitis pigmentosa comprises a complex group of inherited retinal dystrophies characterized by progressive degeneration, primarily affecting the photoreceptors and RPE, the supportive layer for the photoreceptors. Retinitis pigmentosa may occur alone or as part of a syndrome and may be inherited as a dominant, recessive, or X-linked trait or occur sporadically. The same pathogenic variant may cause different symptoms in different individuals, and the same syndrome may be caused by pathogenic variants in other genes. The clinical manifestations of retinitis pigmentosa include reduction in light sensitivity (night blindness), loss of peripheral vision from progressive loss of rods, and variable decrease in central vision due to loss of cones, cataracts, or macular edema.
The diagnosis of retinitis pigmentosa is made by a combination of the following:
●History of nyctalopia (difficulty adapting to the dark) and gradual peripheral vision loss.
●Retinal fundus examination findings of "waxy pallor" of the optic nerve, retinal arterial attenuation, and pigmentary changes in the peripheral retina.
●Ancillary testing results (attenuation of the rod response, and later cone response, on the full-field electroretinogram [ERG], constriction of the visual field on Goldmann perimetry, and abnormal dark adaptometry).
As treatment is available for confirmed biallelic RPE65 mutation-associated retinal dystrophy, it is important that genetic testing be offered for patients with LCA and early-onset retinitis pigmentosa. If genetic testing confirms that the patient does NOT have the RPE65 mutation in both alleles, the molecular diagnosis may help determine eligibility for inclusion into ongoing retinitis pigmentosa clinical trials.
Biallelic pathogenic variant in RPE65 — Retinal gene therapy (voretigene neparvovec-rzyl) was US Food and Drug Administration (FDA)-approved in 2017 for RPE65-associated inherited retinal disease. Genetic testing must confirm the RPE65 mutation in both genes and there must be viable retinal cells, as determined by a health care professional. The treatment is administered in the operating room, via a subretinal injection. Phase 3 clinical trial results showed improvements in ambulatory navigation, light sensitivity, and visual fields up to four years after a single injection .
Experimental approaches to treatment for retinitis pigmentosa include stem cell transplantation, and electronic retinal prostheses. Patients with retinitis pigmentosa and macular edema are treated with an oral or topical carbonic anhydrase inhibitor. In patients with retinitis pigmentosa and cataracts, cataract extraction may improve central vision. However, patients must be aware that there will likely be no improvement in their visual field and no impact on progression of disease. (See 'Locating an expert' below and "Retinitis pigmentosa: Treatment", section on 'Gene therapy'.)
VUS or negative genetic testing — Management of individuals with negative genetic testing depends on the likelihood of disease.
●Negative genetic testing for a known familial pathogenic variant – Negative testing for a pathogenic variant of RPE65 previously identified in other family members very likely excludes retinitis pigmentosa in the patient undergoing testing, with caveats noted above. (See 'How to read the report' above and 'Disease association' above.)
●Negative genetic testing if familial variant unknown – If retinitis pigmentosa is suspected based on personal or family history and a familial variant has not been characterized, then negative testing of RPE65 cannot be used to exclude the disorder. Consultation with a genetics expert is advised to determine the next steps, which may include panel testing for other retinitis pigmentosa genes or more extensive testing of RPE65. Genetic variants in the RPE65 gene are responsible for a small percentage of individuals with retinitis pigmentosa. (See "Retinitis pigmentosa: Clinical presentation and diagnosis", section on 'Genetics'.)
●Variant of uncertain significance (VUS) – Often, the genetic testing results in a VUS, meaning the pathogenicity of the variant has not been determined. Individuals with a VUS may benefit from consultation with an expert in retinitis pigmentosa or a genetics expert to assist in determining what is known about the variant. (See 'Locating an expert' below.)
CONSIDERATIONS FOR FAMILY MEMBERS
Preconception counseling — RPE65-associated retinitis pigmentosa is inherited in an autosomal recessive pattern. Therefore, the children of an individual who carries an RPE65 mutation will be obligate carriers if their parent has two pathogenic or likely pathogenic RPE65 variants. They could be affected with retinitis pigmentosa if their other parent is also a carrier of a disease variant.
●Patients who test positive for a pathogenic variant or likely pathogenic variant should inform their at-risk relatives about the importance of genetic counseling and possible testing.
●Siblings of a patient with biallelic germline RPE65 variants have a 25 percent chance of having inherited both RPE65 variants and a 50 percent chance of being carriers (heterozygotes) of a single RPE65 variant if they have the same biological parents.
●Reproductive counseling should be provided to discuss reproductive options. Each child has a 25 percent risk of being affected if both parents are carriers. Some may elect to conceive using donor gametes or in vitro fertilization (IVF) with preimplantation genetic testing (PGT). (See "In vitro fertilization: Overview of clinical issues and questions", section on 'When are donor oocytes used?' and "Donor insemination" and "Preimplantation genetic testing".)
Information about RPE65
•Clinical features and diagnosis – (See "Retinitis pigmentosa: Clinical presentation and diagnosis".)
•Treatment – (See "Retinitis pigmentosa: Treatment".)
●Retinitis pigmentosa resources
•Foundation for Fighting Blindness (FFB)
•Lighthouse Guild – Retinitis pigmentosa
•American Academy of Ophthalmology – Eye Smart: Retinitis Pigmentosa Treatment
•National Organization for Rare Disorders (NORD) – Retinitis pigmentosa
Locating an expert
●Clinical geneticists – American College of Medical Genetics and Genomics (ACMG)
●Genetic counselors – National Society of Genetic Counselors (NSGC). Genetic testing laboratories may also provide online or telephone access to a genetic counselor.
●National Institutes of Health (NIH) Cancer Genetics Services Directory
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