• Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top EDTA tube (K2EDTA or K3EDTA)
  • Alternate specimens:
    Saliva, assisted saliva, buccal swab and gDNA
  • Sample requirements
  • Request a sample kit



BCO3; LCA2; RP20; mRPE65; rd12; sRPE65

Associated disorders

The RPE65 gene is associated with autosomal recessive Leber congenital amaurosis (LCA) (MedGen UID: 348473), and retinitis pigmentosa (RP) (MedGen UID: 462436). One variant in the RPE65 gene is associated with autosomal dominant retinal dystrophy with choroidal involvement (PMID: 21654732, 27307694).

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Invitae tests that include this gene:

The RPE65 gene encodes the 65 kD retinal pigment epithelium specific protein, an enzyme that is expressed the retina that has an important role in the retinoid visual cycle.

OMIM: 180069

Clinical condition
The RPE65 gene is associated with Leber congenital amaurosis 2 (LCA2; MedGen UID: 348473) and retinitis pigmentosa 20 (RP20; MedGen UID: 462436).

LCA2 is characterized by early-onset childhood retinal dystrophy resulting in vision loss (typically evident in the first year of life), retinal dysfunction, pendular nystagmus, and non-detectable electroretinogram responses (PMID: 20006823, 27307694). Visual impairment can remain stable or be slowly progressive over time. Visual acuity is generally less than 20/400, which is consistent with the ability to detect bright lights or hand motions (PMID: 27307694). Additional clinical symptoms can include photophobia, keratoconus, cataracts, night blindness, near-absent pupillary reactions, Franseschetti’s oculo-digital sign (eye poking, pressing, or rubbing), variable appearance of the ocular fundus, and high-grade hypermetropia (PMID: 20006823, 12615170). By later childhood, retinal pigment epithelial granularity, signs of macular atrophy, and retinal vessel attenuation may be visible upon exam (PMID: 12615170, 12015276). Translucent retinal pigment epithelium and star-shaped maculopathy may also be apparent (PMID: 20811047, 12615170, 12015276).

RP20 is characterized by childhood onset retinal dystrophy, nystagmus, night blindness, severe visual impairment, and retinal pigment epithelium (RPE) defects (PMID: 9501220). Individuals with RP20 exhibit photoreceptor degeneration but maintain good central vision for the first decade of life, in contrast to individuals with LCA2, who lose vision within a few months of life or at birth (PMID: 9501220). Attenuated retinal vessels and increased retinal pigment changes with age, along with reduced or non-detectable electroretinogram, are seen in patients with both LCA2 and RP20 (PMID: 9501220).

Gene information
The RPE65 encodes the 65-kD RPE-specific protein, an enzyme that is expressed in the retina and has an important role in the retinoid visual cycle (PMID: 16150724). When light hits photosensitive pigments in the retina, it converts 11-cis retinal (a form of vitamin A) to all-trans-retinal. This conversion triggers a series of chemical reactions that create electrical signals. The RPE65 protein then helps to convert all-trans retinal back to 11-cis retinal, so the visual cycle can begin again (PMID: 16150724, 7633413, 16116091).

LCA2 and RP20 exhibit autosomal recessive inheritance, and affected individuals have two pathogenic variants—one in each copy of their RPE65 genes. Affected individuals will pass one pathogenic RPE65variant to all their children. For there to be a risk of LCA2 or RP20 in their offspring, both the patient and their partner would each have to carry a pathogenic variant in RPE65. In this case, the risk of having an affected child would be 25% (PMID: 20006823, 27307694).

The c.1430A>G (p.Asp477Gly) variant in exon 13 of RPE65 has been shown to follow an autosomal dominant inheritance pattern, and an individual with this pathogenic variant has a 50% chance of passing the condition onto their offspring. With this result, it is possible to identify at-risk relatives who can pursue testing for this specific familial variant (PMID: 27307694, 21654732).

Individuals with pathogenic variants in RPE65 should be referred for the following:

  • Electroretinogram to confirm the clinical diagnosis and assess retinal function (PMID: 28689169)
  • Clinical genetics or ocular genetics consultation and genetic counseling (PMID: 28689169, 20079931)
    • Determine if therapeutics or clinical trials exist for the patient
    • Refer relevant family members for genetic testing and counseling
  • Ophthalmology consultation for vision correction when possible and surveillance for cataracts (PMID: 28689169, 20079931)
  • Access to state and local programs for visually impaired children, including provisions of low-vision aids, orientation and mobility training, and an individualized educational plan (PMID: 28689169, 20079931; Traboulsi EI)
  • Adults who present with vision loss more consistent with RP20 should have all of the above along with options for adaptive skills training, job placement, and income assistance (PMID: 28689169, 20079931; Traboulsi EI).

Therapeutics: In December 2017, the FDA approved voretigene neparvovec-rzyl (LuxturnaTM) for the treatment of RPE65-associated retinal dystrophy (PMID: 29564403). The treatment is composed of human RPE65cDNA with a CMV enhancer and a hybrid chicken beta-actin promoter delivered via a recombinant adeno-associated virus 2 that is injected into the subretinal space (PMID: 29564403, 28393043). Pharmacological intervention is also under investigation using a synthetic prodrug QLT091001, which is a precursor to 9-cis-retinal, a protein involved in the retinoid cycle (PMID: 28689169, 29542350, 27183166). Additional information on active research can be found at clinicaltrials.gov. As this is an active area of ongoing research, it is important to stay updated with new therapeutic options and changes to practice guidelines as they become available, or refer to a specialty center for up-to-date management.

Additional reference
Traboulsi EI. A Compendium of Inherited Disorders and the Eye. New York, NY: Oxford University Press; 2006.

Review date: April 2018

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below, depending on the specific gene or test. In addition, the analysis covers select non-coding variants. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
RPE65 NM_000329.2