Retinal Diseases Caused by Mutations in Genes Not Specifically Associated with the Clinical Diagnosis

Wang, Xia; Feng, Yanming; Li, Jianli; Zhang, Wei; Wang, Jing; Lewis, Richard A.; Wong, Lee‐Jun C.

doi:10.1371/journal.pone.0165405

Cited by 9 publications

(12 citation statements)

References 51 publications

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“…One likely reason is that disease‐causing variants within non‐coding regions may remain undetected using standard targeted NGS. Other possible explanations include mutations in genes that have not yet been associated with retinal dystrophies, hypomorphic variants or genetic testing of patients with disease entities mimicking RP (eg, autoimmune retinopathy in patients with cancer or autoimmune disease), which all may potentially be associated with a specific retinal phenotype and/or systemic diseases . Hence, we hypothesized that genetically unsolved RP‐patients may reveal characteristics that differ from genetically solved RP‐patients.…”

Section: Introductionmentioning

confidence: 99%

Genetic testing in patients with retinitis pigmentosa: Features of unsolved cases

Birtel

Gliem

Oishi

et al. 2019

Clinical Exper Ophthalmology

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Importance Uncommon characteristics in genetically unsolved retinitis pigmentosa (RP) patients may indicate an incorrect clinical diagnosis or as yet unknown genetic causes resulting in specific retinal phenotypes. The diagnostic yield of targeted next‐generation sequencing may be increased by a reasonable preselection of RP‐patients. Background To systematically evaluate and compare features of genetically solved and unsolved RP‐patients. Design Retrospective, observational study. Participants One‐hundred and twelve consecutive RP‐patients who underwent extensive molecular genetic analysis. Methods Characterization of patients based on multimodal imaging and medical history. Main Outcome Measures Differences between genetically solved and unsolved RP‐patients. Results Compared to genetically solved patients (n = 77), genetically unsolved patients (n = 35) more frequently had an age of disease‐onset above 30 years (60% vs 8%; P < 0.0001), showed atypical fundus features (49% vs 8%; P < 0. 0001) and indicators for phenocopies (eg, autoimmune diseases) (17% vs 0%; P < 0. 001). Evidence for a particular inheritance pattern was less common (20% vs 49%; P < 0. 01). The diagnostic yield was 84% (71/85) in patients with first symptoms below 30 years‐of‐age, compared to 69% (77/112) in the overall cohort. The other selection criteria alone or in combination resulted in limited further increase of the diagnostic yield (up to 89%) while excluding considerably more patients (up to 56%) from genetic testing. Conclusions and Relevance The medical history and retinal phenotype differ between genetically solved and a subgroup of unsolved RP‐patients, which may reflect undetected genotypes or retinal conditions mimicking RP. Patient stratification may inform on the individual likelihood of identifying disease‐causing mutations and may impact patient counselling.

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Section: Introductionmentioning

confidence: 99%

Genetic testing in patients with retinitis pigmentosa: Features of unsolved cases

Birtel

Gliem

Oishi

et al. 2019

Clinical Exper Ophthalmology

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“…It remains possible that variants of RIMS1 are associated with a dominant disease given the probability of loss-of-function intolerance (pLI) of the gene is 0.99 (0–1 scale) in the gnomAD dataset suggesting that haploinsufficiency is not tolerated, and that murine knockout exhibits a complex neurological phenotype. 16 However, no proven cases of inherited disease consequent upon loss of function variants exist to date, 12 – 14 to our knowledge, and no cases of confirmed RIMS1 disease are known. In the original publication, affected members of the study also showed enhanced cognition and this may be consequent on the p.Arg820His variant in RIMS1 17 and that co-inheritance of these two phenotypes is coincidental in the family.…”

Section: Discussionmentioning

confidence: 89%

“…In addition, no other compelling evidence for pathogenic variants in RIMS1 have been identified to date. 12 – 14 The only other report in the literature of the p.Arg820His variant was seen in a simplex patient with RP and a discordant phenotype. 7 …”

Section: Discussionmentioning

confidence: 99%

Dominant Cone Rod Dystrophy, Previously Assigned to a Missense Variant in RIMS1, Is Fully Explained by Co-Inheritance of a Dominant Allele of PROM1

Martin-Gutierrez

Schiff

Wright

et al. 2022

Invest. Ophthalmol. Vis. Sci.

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Purpose Autosomal dominant cone rod dystrophy 7 (CORD7) was initially linked to the gene RIMS1 and reported in a 4-generation British family in 1998. The purpose of this study was to investigate the legitimacy of this association, and to correctly characterize the genetic cause of this condition. Methods The allele frequency of RIMS1 c.2459G>A, p.Arg820His, was investigated in the Genomes Aggregation Dataset (gnomAD) datasets and whole genome sequencing (WGS) was performed for 4 members of the CORD7 family with filtering of rare pathogenic variants in a virtual gene panel comprising all genes known to be associated with inherited retinal dystrophy (IRD). Cytogenetic analysis was performed to rule out interchromosomal translocation. Results RIMS1 p.Arg820His has a maximal carrier frequency of >1:5000 in Europeans. A previously well-characterized PROM1 variant: c.1118C>T, p.Arg373Cys, was detected in 9 affected members of the CORD7 family who underwent WGS or direct sequencing. One affected family member is now known to have macular dystrophy in the absence of RIMS1 p.Arg820His. Clinical analysis of affected family members and 27 individuals with retinopathy associated with the same – PROM1 – variant showed consistent phenotypes. Conclusions The case for pathogenicity of RIMS1 p.Arg820His is not strong based on its presence on 10 alleles in the gnomAD dataset and absence from additional CORD affected individuals. The finding of a known pathogenic variant in PROM1 correlates well with the phenotypic characteristics of the affected individuals, and is likely to account for the condition. Clear evidence of association between RIMS1 and a retinal dystrophy is yet to be described.

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“…21 22 A later report described a patient with the same RIMS1 variant, but a different phenotype (retinitis pigmentosa), 23 and there have further variants reported, but without detailed evidence to secure a causative relationship. [24][25][26] Implication of AHR in retinal disease comes from a report of a single family. 27 For KIAA1549, there is a single report of two families.…”

Section: Discussionmentioning

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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Retinal Diseases Caused by Mutations in Genes Not Specifically Associated with the Clinical Diagnosis

Cited by 9 publications

References 51 publications

Genetic testing in patients with retinitis pigmentosa: Features of unsolved cases

Genetic testing in patients with retinitis pigmentosa: Features of unsolved cases

Dominant Cone Rod Dystrophy, Previously Assigned to a Missense Variant in RIMS1, Is Fully Explained by Co-Inheritance of a Dominant Allele of PROM1

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

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