Background: Inherited retinal diseases (IRDs) are clinically complex and genetically heterogeneous visual impairment disorders with varying penetrance and severity. Disease-causing variants in at least 289 nuclear and mitochondrial genes have been implicated in their pathogenesis.
Methods: Whole exome sequencing results were analyzed using established pipelines and the results were further confirmed by Sanger sequencing and minigene splicing assay.
High-level visual functions such as reading and face recognition rely on global processes, which are often insensitive to high spatial frequencies. However, it is unknown whether a sharp cone signal is necessary for the development of these skills or whether a blurry rod signal is sufficient. CNGA3/B3-achromatopsia is a congenital disease stemming from cone dysfunction, leading to rod-only vision characterized by nystagmus, impaired acuity, and complete color blindness.
View Article and Find Full Text PDFInherited retinal diseases (IRDs) are extremely heterogeneous with at least 350 causative genes, complicating the process of genetic diagnosis. We analyzed samples of 252 index cases with IRDs using the Blueprint Genetics panel for "Retinal Dystrophy" that includes 351 genes. The cause of disease could be identified in 55% of cases.
View Article and Find Full Text PDFRetinitis pigmentosa (RP) is a heterogeneous inherited retinal disorder. Mutations in cause autosomal recessive (AR) RP. We aimed to characterize the genotype, expression pattern, and phenotype in a large cohort of cases.
View Article and Find Full Text PDFInherited retinal diseases (IRDs) are a clinically and genetically heterogeneous group of diseases which cause visual loss due to Mendelian mutations in over 250 genes, making genetic diagnosis challenging and time-consuming. Here, we developed a new tool, CDIP (Cost-effective Deep-sequencing IRD Panel) in which a simultaneous sequencing of common mutations is performed. CDIP is based on simultaneous amplification of 47 amplicons harboring common mutations followed by next-generation sequencing (NGS).
View Article and Find Full Text PDF: Visual acuity (VA) assessments are crucial in ophthalmology but traditionally rely on in-clinic evaluations. The emergence of telemedicine has spurred interest in creating dependable self-administered VA tests for use beyond standard clinical environments. This study evaluated the practicality and validity of a self-administered near VA card test against traditional Snellen and Rosenbaum Pocket Vision Screener (RPVS) methods for home monitoring and enhancing clinical workflow.
View Article and Find Full Text PDFRetinal disorders caused by genetic or environmental factors cause severe visual impairment and often result in blindness. The past ten years have seen rapid progress in our understanding of the biological basis of these conditions, as well as significant advances towards gene and cell-based therapies. Regulatory challenges remain, but there is reason to hope that creative approaches will lead to safe and effective breakthrough treatments for these conditions in the near future.
View Article and Find Full Text PDFInherited macular dystrophies (iMDs) are a group of genetic disorders, which affect the central region of the retina. To investigate the genetic basis of iMDs, we used single-molecule Molecular Inversion Probes to sequence 105 maculopathy-associated genes in 1352 patients diagnosed with iMDs. Within this cohort, 39.
View Article and Find Full Text PDFFor 15 years, gene therapy has been viewed as a beacon of hope for inherited retinal diseases. Many preclinical investigations have centered around vectors with maximal gene expression capabilities, yet despite efficient gene transfer, minimal physiological improvements have been observed in various ciliopathies. Retinitis pigmentosa-type 28 (RP28) is the consequence of bi-allelic null mutations in the FAM161A, an essential protein for the structure of the photoreceptor connecting cilium (CC).
View Article and Find Full Text PDFPurpose: Inherited retinal diseases (IRDs) are a group of monogenic conditions that can lead to progressive blindness. Their missing heritability is still considerable, due in part to the presence of disease genes that await molecular identification. The purpose of this work was to identify novel genetic associations with IRDs.
View Article and Find Full Text PDFAdenosine deaminases acting on RNA (ADARs) are endogenous enzymes catalyzing the deamination of adenosines to inosines, which are then read as guanosines during translation. This ability to recode makes ADAR an attractive therapeutic tool to edit genetic mutations and reprogram genetic information at the mRNA level. Using the endogenous ADARs and guiding them to a selected target has promising therapeutic potential.
View Article and Find Full Text PDFInvest Ophthalmol Vis Sci
October 2023
Background: Inherited retinal diseases (IRDs) include a range of vision loss conditions caused by variants in different genes. The clinical and genetic heterogeneity make identification of the genetic cause challenging. Here, a cohort of 491 unsolved cases from our cohort of Israeli and Palestinian families with IRDs underwent whole exome sequencing (WES), including detection of CNVs as well as single nucleotide variants (SNVs).
View Article and Find Full Text PDFCold Spring Harb Perspect Med
July 2024
With the rapid expansion of methods encompassed by the term gene therapy, new trials exploring the safety and efficacy of these methods are initiated more frequently. As a result, important questions arise pertaining the design of these trials and patient participation. One of the most important aspects of any clinical trial is the ability to measure the trial's outcome in a manner that will reflect the effect of the treatment and allow its quantification, whether the trial is aimed at preservation or restoration of retinal cells (photoreceptors and others), vision, or both.
View Article and Find Full Text PDFPhotoreceptor cell degeneration and death is the major hallmark of a wide group of human blinding diseases including age-related macular degeneration and inherited retinal diseases such as retinitis pigmentosa. In recent years, inherited retinal diseases have become the "testing ground" for novel therapeutic modalities, including gene and cell-based therapies. Currently there is no available treatment for retinitis pigmentosa caused by FAM161A biallelic pathogenic variants.
View Article and Find Full Text PDFRetinitis pigmentosa (RP) is the predominant form of inherited retinal degenerations (IRDs) caused by abnormalities and loss of photoreceptor cells ensuing diminishment of vision. RP is a heterogenous genetic disorder associated with mutations in over 80 genes, showing various inheritance patterns. Laboratory mouse models are important for our understanding of disease mechanisms, modifier effects, and development of therapeutic modalities.
View Article and Find Full Text PDFInherited retinal diseases (IRDs) are an extremely diverse group of ocular disorders characterized by progressive loss of photoreceptors leading to blindness. So far, pathogenic variants in over 300 genes are reported to structurally and functionally affect the retina resulting in visual impairment. Around 15% of all IRD mutations are known to affect an essential regulatory mechanism, pre-mRNA splicing, which contributes to the transcriptomic diversity.
View Article and Find Full Text PDFNonsense mutations occur within the open-reading frame of a gene resulting in a premature termination codon (PTC). PTC-containing mRNAs can either be degeraded or cause premature translation termination producing a truncated protein that can be either nonfunctional or toxic. Translational readthrough inducing drugs (TRIDs) are small molecules that are able to induce readthrough, resulting in the restoration of full-length protein expression.
View Article and Find Full Text PDFHow will people who spent their visual lives with only rods respond to cone function restoration? Will they be able suddenly see the colors of the rainbow? CNGA3-achromatopsia is a congenital hereditary disease in which cone dysfunction leads patients to have rod photoreceptor-driven vision only in daylight, seeing the world in blurry shades of gray. We studied color perception in four CNGA3-achromatopsia patients following monocular retinal gene augmentation therapy. Following treatment, although some cortical changes were reported, patients did not report a dramatic change in their vision.
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