Gene test interpretation: RPE65 (retinitis pigmentosa and Leber congenital amaurosis gene)

INTRODUCTION — 

This monograph summarizes the interpretation of germline genetic testing of RPE65, a gene associated with certain forms of retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA). Evaluation and management of RP are discussed in detail separately [1].

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. The checklist summarizes these and other caveats (table 1).

RPE65 gene — The RPE65 gene, located on chromosome 1p31, encodes retinoid isomerohydrolase, an enzyme critical for the normal functioning of the visual cycle.

The RPE65 protein is an all-trans-retinyl ester isomerase expressed in the retinal pigment epithelium (RPE). It is responsible for functioning of the rods and cones (photoreceptors in the retina). It mediates biochemical recycling of chromophore in the visual cycle, which results in the transmission of electrical signals to the brain. Rods mostly provide vision at low light and peripheral vision; cones mostly provide color vision and spatial detail (fine-detailed central vision) in bright light. (See "Overview of vitamin A", section on 'Vision'.)

Pathogenic variants in the RPE65 gene lead to reduced or absent levels of the RPE65 enzyme, which in turn blocks the biochemical visual cycle and impairs vision.

There is no clear genotype-phenotype correlation; even patients with the same pathogenic variant can have markedly different retinal pathology. Three conditions can occur:

●Autosomal recessive retinitis pigmentosa 20 (RP20)

●Autosomal recessive Leber congenital amaurosis 2 (LCA), a form of RP present at birth

●Autosomal dominant retinitis pigmentosa 87 with choroidal involvement

For the autosomal recessive disorders (RP20 and LCA), affected individuals are homozygous or compound heterozygous for a pathogenic variant in the RPE65 gene. (See "Retinitis pigmentosa: Clinical presentation and diagnosis", section on 'Inheritance'.)

RETINITIS PIGMENTOSA (RP)

Disease association — RP comprises a group of inherited retinal dystrophies characterized by progressive degeneration of photoreceptors and their supportive layer, the retinal pigment epithelium (RPE). Pathogenic variants have been identified in numerous genes, as discussed separately. (See "Retinitis pigmentosa: Clinical presentation and diagnosis", section on 'Gene mutations'.)

The same pathogenic variant may cause different symptoms in different individuals (variable expressivity), and the same syndrome may be caused by pathogenic variants in different genes. (See "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Penetrance and expressivity'.)

Ocular manifestations of RP include (see "Retinitis pigmentosa: Clinical presentation and diagnosis", section on 'Clinical manifestations'):

●Reduction in light sensitivity (also called nyctalopia or night blindness)

●Peripheral vision loss

●Decrease in visual acuity

●Cataracts

●Macular edema

RP diagnosis — RP diagnosis requires a combination of symptoms, fundoscopic changes, and specialized ophthalmologic testing such as full-field electroretinography (ERG), Goldmann perimetry, and dark adaptometry. (See "Retinitis pigmentosa: Clinical presentation and diagnosis", section on 'Diagnosis'.)

Genetic testing is not required for diagnosis but is critical for determining whether a patient is eligible to receive the only available US Food and Drug Administration (FDA)-approved treatment for biallelic RPE65 pathogenic variants (the gene therapy voretigene neparvovec-rzyl) or for participation in ongoing RP/Leber congenital amaurosis (LCA) clinical trials. (See 'Biallelic pathogenic variant in RPE65' below.)

The American Academy of Ophthalmology published a seminal report in 2012 about when and how to recommend genetic testing for inherited retinal disease [2]; this was updated in 2014 [3].

MANAGEMENT

Biallelic pathogenic variant in RPE65 — The table (table 2) and flowchart (algorithm 1) summarize management implications.

Retinal gene therapy (voretigene neparvovec-rzyl; Luxturna) was approved by the US Food and Drug Administration (FDA) in 2017 for RPE65-associated inherited retinal disease. Genetic testing must confirm the RPE65 variant at both alleles, and there must be viable retinal cells as determined by a health care professional using visual acuity testing or ancillary testing with visual fields and/or electroretinography (ERG).

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 [4]. (See "Retinitis pigmentosa: Treatment", section on 'Gene therapy'.)

Experimental approaches to treatment for retinitis pigmentosa (RP) include retinal stem cell transplantation and electronic retinal prostheses. (See 'Locating an expert' below and "Retinitis pigmentosa: Treatment", section on 'Experimental therapies'.)

Patients with RP and macular edema are treated with an oral or topical carbonic anhydrase inhibitor. In patients with RP 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.

VUS or negative genetic testing — Management of individuals with negative genetic testing or a variant of uncertain significance (VUS) 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 relatives very likely excludes RP 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 RP 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 RP genes or more extensive testing of RPE65. Only a small percentage of individuals with RP have pathogenic variants in RPE65. (See "Retinitis pigmentosa: Clinical presentation and diagnosis", section on 'Genetics'.)

●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 RP or a genetics expert to assist in determining what is known about the variant. (See 'Locating an expert' below.)

CONSIDERATIONS FOR RELATIVES

Reproductive counseling and testing — RPE65-associated retinitis pigmentosa (RP) is inherited in an autosomal recessive pattern.

●The children of a parent who has two pathogenic or likely pathogenic variants in RPE65 are likely to be obligate carriers. They could be affected with RP if their other parent is also a carrier of a pathogenic variant in RPE65.

●The parents of a child with RP and biallelic pathogenic variants in RPE65 are likely to each be carriers. Their additional children have a 25 percent chance of being unaffected noncarriers, a 50 percent chance of being heterozygous carriers, and a 25 percent chance of being affected with RP.

Individuals who are planning further childbearing can be counseled about these risks (algorithm 1). If they are interested in pursuing in vitro fertilization (IVF) with preimplantation genetic diagnosis (PGD), they can be referred to a specialized center that performs these procedures [5]. (See "In vitro fertilization: Overview of clinical issues and questions", section on 'When are donor oocytes used?' and "Donor insemination" and "Preimplantation genetic testing".)

At-risk relatives

●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 (algorithm 1).

●Siblings of a patient with biallelic germline pathogenic variants in RPE65 have a 25 percent chance of having inherited both RPE65 variants and a 50 percent chance of being heterozygous carriers if they have the same biological parents. (See 'Reproductive counseling and testing' above.)

RESOURCES

Information about RPE65

●UpToDate topics

•Genetics – (See "Retinitis pigmentosa: Clinical presentation and diagnosis", section on 'Genetics'.)

•Clinical features and diagnosis – (See "Retinitis pigmentosa: Clinical presentation and diagnosis".)

•Treatment – (See "Retinitis pigmentosa: Treatment".)

●Retinitis pigmentosa (RP) 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

•Retina International (RI)

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.

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Seema Garg, MD, PhD, who contributed to earlier versions of this topic review.