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

Abstract

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.

Transcriptome Analyses of lncRNAs in A2E-Stressed Retinal Epithelial Cells Unveil Advanced Links between Metabolic Impairments Related to Oxidative Stress and Retinitis Pigmentosa

“…Aside from their well-established roles in cancer [67], lncRNAs are crucial to cardiovascular [68], neurological [69], respiratory [70] and neurodegenerative [71] diseases. Among them, retinitis pigmentosa, an eye-related group of pathologies characterized by very heterogeneous genotypes but quite overlapping phenotypes, shows unusually complex molecular genetic causes, most of which are still unknown [72]. Recently, many experiments showed the important involvement of lncRNAs in retinal disorders, especially regulating angiogenesis, photoreceptor maturation, cell cycle in photoreceptor progenitor cells, apoptosis and cell viability, retinal vessel dysfunction, endothelial cell proliferation, vulnerability of the optic nerve, Muller cell proliferation and neurodegeneration [73].…”

Effects of A2E-Induced Oxidative Stress on Retinal Epithelial Cells: New Insights on Differential Gene Response and Retinal Dystrophies

“…Rods represent about 95% of all photoreceptors, and oxidative metabolism of fatty acids is their main energy source [12]. Main causes of rod death are genetic mutations, and more than 80 RP-causative genes have been already identified (https://sph.uth.edu/RetNet/sum-dis.htm#B-diseases), even if a relevant number of them are still unknown [13]. Conversely, cone degeneration is usually a late event frequently resulting from cytotoxic effects of high oxygen levels in the retina after rod reduction.…”

Comprehensive Geno- and Phenotyping in a Complex Pedigree Including Four Different Inherited Retinal Dystrophies

“…ABCA4-related retinopathy, one of the most common monogenic causes for retinal degeneration, is known for a broad phenotypic spectrum, ranging from mild Stargardt disease to severe cone-rod dystrophy [11,30]. It is caused by biallelic mutations in the ATP-binding cassette sub-family A member 4 (ABCA4) gene [31].…”

“…The development of high-throughput DNA sequencing methods has made it more feasible to also achieve diagnoses on a molecular level. Targeted Next-Generation Sequencing (NGS) in particular has been proven as an efficient tool and allows IRD differentiation according to their genetic causes in daily practice [4][5][6][7][8][9][10][11][12][13][14][15][16]. One strength of NGS is that a large variety of genes associated with IRDs can be studied simultaneously at relatively low cost.…”