Inherited retinal diseases: Linking genes, disease-causing variants, and relevant therapeutic modalities

Schneider, Nina; Sundaresan, Yogapriya; Gopalakrishnan, Prakadeeswari; Beryozkin, Avigail; Hanany, Mor; Levanon, Erez Y.; Banin, Eyal; Ben-Aroya, Shay; Sharon, Dror

doi:10.1016/j.preteyeres.2021.101029

Cited by 90 publications

(87 citation statements)

References 422 publications

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“…The later stages include cone dysfunction, including constricted visual fields, loss of central vision, and reduced light‐adapted ERG responses. RP has extreme locus heterogeneity, with >90 genes associated with the nonsyndromic form, and is associated with hundreds of syndromic disorders, including ciliopathies, peroxisomal disorders, and multiple (>500) malformation syndromes (Hartong et al, 2006; Schneider et al, 2021; Verbakel et al, 2018). Recently, a Food and Drug Administration‐approved gene‐directed therapy, the first in its class, has emerged for early‐onset retinal degeneration caused by variants in the RPE65 gene (MIM# 180069).…”

Section: Introductionmentioning

confidence: 99%

Tissue‐specific genotype–phenotype correlations among USH2A‐related disorders in the RUSH2A study

et al. 2022

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We assessed genotype–phenotype correlations among the visual, auditory, and olfactory phenotypes of 127 participants with Usher syndrome (USH2) (n =80) or nonsyndromic autosomal recessive retinitis pigmentosa (ARRP) (n = 47) due to USH2A variants, using clinical data and molecular diagnostics from the Rate of Progression in USH2A Related Retinal Degeneration (RUSH2A) study. USH2A truncating alleles were associated with USH2 and had a dose‐dependent effect on hearing loss severity with no effect on visual loss severity within the USH2 subgroup. A group of missense alleles in an interfibronectin domain appeared to be hypomorphic in ARRP. These alleles were associated with later age of onset, larger visual field area, better sensitivity thresholds, and better electroretinographic responses. No effect of genotype on the severity of olfactory deficits was observed. This study unveils a unique, tissue‐specific USH2A allelic hierarchy with important prognostic implications for patient counseling and treatment trial endpoints. These findings may inform clinical care or research approaches in others with allelic disorders or pleiotropic phenotypes.

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Section: Introductionmentioning

confidence: 99%

Tissue‐specific genotype–phenotype correlations among USH2A‐related disorders in the RUSH2A study

et al. 2022

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“…Identifying genes, or genetic regions, with particular characteristics might shed light on particular selection pressures, and also help in future interpretation of novel variants 6 7. The range of genes and variants involved in IRDs has been recently reviewed comprehensively by Schneider et al ,8 who discussed, among other things, the prevalence of different types of variant, as well as their amenability to various gene-based therapeutic approaches.…”

Section: Introductionmentioning

confidence: 99%

Exploring the mutational landscape of genes associated with inherited retinal disease using large genomic datasets: identifying loss of function intolerance and outlying propensities for missense changes

et al. 2022

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BackgroundLarge databases permit quantitative description of genes in terms of intolerance to loss of function (‘haploinsufficiency’) and prevalence of missense variants. We explored these parameters in inherited retinal disease (IRD) genes.MethodsIRD genes (from the ‘RetNet’ resource) were classified by probability of loss of function intolerance (pLI) using online Genome Aggregation Database (gnomAD) and DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources (DECIPHER) databases. Genes were identified having pLI ≥0.9 together with one or both of the following: upper bound of CI <0.35 for observed to expected (o/e) ratio of loss of function variants in the gnomAD resource; haploinsufficiency score <10 in the DECIPHER resource. IRD genes in which missense variants appeared under-represented or over-represented (Z score for o/e ratio of <−2.99 or >2.99, respectively) were also identified. The genes were evaluated in the gene ontology Protein Analysis THrough Evolutionary Relationships (PANTHER) resource.ResultsOf 280 analysed genes, 39 (13.9%) were predicted loss of function intolerant. A greater proportion of X-linked than autosomal IRD genes fulfilled these criteria, as expected. Most autosomal genes were associated with dominant disease. PANTHER analysis showed >100 fold enrichment of spliceosome tri-snRNP complex assembly. Most encoded proteins were longer than the median length in the UniProt database. Fourteen genes (11 of which were in the ‘haploinsufficient’ group) showed under-representation of missense variants. Six genes (SAMD11, ALMS1, WFS1, RP1L1, KCNV2, ADAMTS18) showed over-representation of missense variants.ConclusionA minority of IRD-associated genes appear to be ‘haploinsufficient’. Over-representation of spliceosome pathways was observed. When interpreting genetic tests, variants found in genes with over-representation of missense variants should be interpreted with caution.

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“…Inherited retinal degenerations (IRDs) are important causes of vision loss in both children and adults (1, 2). Rod-cone degeneration, also called retinitis pigmentosa (RP) is the most common form of IRD, and affects approximately 1 in 3500 individuals worldwide (3).…”

Section: Introductionmentioning

confidence: 99%

The RNA content of extracellular vesicles fromPRPF31^+/−hiPSC-RPE show potential as biomarkers of retinal degeneration

Getachew

Mehrotra

Fernández-Godino

et al. 2022

Preprint

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Retinitis pigmentosa (RP) is the most common form of inherited retinal degeneration (IRD) and causes vision loss via dysfunction and death of the photoreceptor cells and retinal pigment epithelium (RPE) of the retina. Mutations in pre-mRNA processing factor 31 (PRPF31) are associated with autosomal dominant RP, and are thought to cause retinal degeneration by causing cell autonomous defects in RPE function. Genetic therapies such as adeno-associated virus (AAV) mediated gene therapy show great promise for treating IRDs, however in many cases it is challenging to measure clinical efficacy in a timely manner because IRDs progress slowly. A potential solution to this challenge is the use of additional outcome measures, such as biomarkers. Extracellular vesicles (EVs) are lipid enclosed vesicles that are secreted by cells and their RNA contents have been proposed as potential biomarkers in cancer and other diseases. We hypothesize EV RNAs can be used as biomarkers of the health status of the neural retina and RPE. To test this hypothesis for the RPE, we used PRPF31+/+ and PRPF31+/− human induced pluripotent stem cell (hiPSC)-derived RPE to investigate the RNAs contained in RPE-derived EVs, and how they change in disease. We also compared the RNA contents of RPE-EVs with the RNAs contained in the hiPSC-RPE cells themselves. We found that EVs from mutant PRPF31+/− hiPSC-RPE cells contain distinct RNAs compared to EV from the control PRPF31+/+ hiPSC-RPE cells, suggesting EV RNA contents change during disease and can potentially serve as biomarkers of retinal degeneration.

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Inherited retinal diseases: Linking genes, disease-causing variants, and relevant therapeutic modalities

Cited by 90 publications

References 422 publications

Tissue‐specific genotype–phenotype correlations among USH2A‐related disorders in the RUSH2A study

Tissue‐specific genotype–phenotype correlations among USH2A‐related disorders in the RUSH2A study

Exploring the mutational landscape of genes associated with inherited retinal disease using large genomic datasets: identifying loss of function intolerance and outlying propensities for missense changes

The RNA content of extracellular vesicles fromPRPF31^+/−hiPSC-RPE show potential as biomarkers of retinal degeneration

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Inherited retinal diseases: Linking genes, disease-causing variants, and relevant therapeutic modalities

Cited by 90 publications

References 422 publications

Tissue‐specific genotype–phenotype correlations among USH2A‐related disorders in the RUSH2A study

Tissue‐specific genotype–phenotype correlations among USH2A‐related disorders in the RUSH2A study

Exploring the mutational landscape of genes associated with inherited retinal disease using large genomic datasets: identifying loss of function intolerance and outlying propensities for missense changes

The RNA content of extracellular vesicles fromPRPF31+/−hiPSC-RPE show potential as biomarkers of retinal degeneration

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The RNA content of extracellular vesicles fromPRPF31^+/−hiPSC-RPE show potential as biomarkers of retinal degeneration