Genomic newborn screening: BabyScreen+
Gene: RPE65 Green List (high evidence)Green List (high evidence)
Assessed as 'strong actionability' in paediatric patients by ClinGen.
Biallelic RPE65 mutation-associated retinal dystrophy is a form of IRD caused by biallelic pathogenic variants in RPE65; it presents as a spectrum of disease with variable age of onset and progression of vision loss. Common clinical findings across the spectrum include night blindness, progressive loss of visual fields and loss of central vision.
In LCA, night blindness often occurs from birth. Characteristically, these patients have residual cone-mediated vision in the first to third decades with progressive visual field loss until complete blindness is observed, most often in mid- to late-adulthood. A range of age of onset has been described for night blindness in RP, but it typically onsets in later childhood.
In December 2017, the FDA approved LUXTURNA (voretigene neparvovec-rzyl) gene therapy for the treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy. The FDA’s conclusion of efficacy is based on improvement in a functional vision score over 1 year in a single open-label controlled Phase 3 study of 31 affected patients. The average age of the 31 randomized patients was 15 years (range 4 to 44 years), including 64% pediatric subjects (n=20, age from 4 to 17 years) and 36% adults (n=11). Functional vision was scored by a patient’s ability to navigate a course in various luminance levels. Using both treated eyes of the 21 subjects in the LUXTURNA treatment group, 11 (52%) had a clinically meaningful score improvement, while only one of the ten (10%) subjects in the control group had a clinically meaningful score improvement. Using the first treated eye only, 15/21 (71%) had a clinically meaningful score improvement, while no comparable score improvement was observed in controls. Other secondary clinical outcomes were also examined. Analysis of white light full-field light sensitivity threshold testing showed statistically significant improvement at 1 year in the LUXTURNA treatment group compared to the control group. The change in visual acuity was not significantly different between the LUXTURNA and control groups.
LUXTURNA is administered subretinally by injection. Per the FDA package insert, the most common adverse reactions (incidence ≥ 5%) in the clinical trials for LUXTURNA included conjunctival hyperemia, cataract, increased intraocular pressure, retinal tear, dellen (thinning of the corneal stroma), and macular hole. Several other ocular adverse effects were also reported, including risk of endophthalmitis. Safety data was included on the basis of 41 patients (81 eyes).
For review: availability of therapy?
Sources: ClinGenCreated: 29 Dec 2022, 8:24 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Leber congenital amaurosis 2 MIM#204100; Retinitis pigmentosa 20 MIM#613794
Gene: rpe65 has been classified as Green List (High Evidence).
Gene: rpe65 has been classified as Green List (High Evidence).
gene: RPE65 was added gene: RPE65 was added to gNBS. Sources: ClinGen for review, treatable, ophthalmological tags were added to gene: RPE65. Mode of inheritance for gene: RPE65 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: RPE65 were set to Leber congenital amaurosis 2 MIM#204100; Retinitis pigmentosa 20 MIM#613794 Review for gene: RPE65 was set to GREEN
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at panelapp@genomicsengland.co.uk
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.