Abstract
Inherited retinal diseases (IRD) comprise a heterogeneous set of clinical and genetic disorders that lead to blindness. Given the emerging opportunities in precision medicine and gene therapy, it has become increasingly important to determine whether DNA variants with uncertain significance (VUS) are responsible for patients’ IRD. This research was performed to assess the functional consequence of six VUS identified in patients with IRD. Clinical assessments included an ophthalmic examination, best-corrected visual acuity, and kinetic perimetry. Imaging was acquired with the Optos ultra-widefield camera and spectral domain optical coherence tomography (SD-OCT). Genetic testing was performed by Molecular Vision Laboratories. VUS that were predicted to alter splicing were analyzed with a minigene assay, which revealed that VUS in the genes OPA1, CNGB1, and CLUAP1 altered spicing mechanisms. Due to emerging gene and cell therapies, these results expand the genotype-phenotype correlations for patients diagnosed with an IRD.
Highlights
Inherited retinal diseases (IRDs) have a prevalence of 1 per 3000 individuals and are among the leading causes of vision impairments that develop due to a genetic mutation [1]
Further measures in genetic diagnosis can be attained when variants with uncertain significance (VUS) that alter the splicing patterns measures in genetic diagnosis can be attained when VUS that alter the splicing patterns are evaluated through functional analysis
Splice assays represent a viable choice to assess the effect of VUS on splicing mechanisms in the absence of patient cells, or if the gene of the effect of VUS on splicing mechanisms in the absence of patient cells, or if the gene of interest is exclusively expressed in the retina
Summary
Inherited retinal diseases (IRDs) have a prevalence of 1 per 3000 individuals and are among the leading causes of vision impairments that develop due to a genetic mutation [1]. IRD comprises a largely heterogeneous set of clinical and genetic disorders that lead to blindness. Despite the need for a definitive genetic diagnosis, NGS frequently identifies DNA changes that are classified as variants of uncertain significance (VUS), leaving the genetic, clinical, or both diagnoses unresolved. Functional analysis of VUS impacts the standard for patient care, which will lead to earlier diagnosis, new treatments, and prevention of blindness. RNAseq studies of the retina have shown that a large fraction of the human genome is alternatively spliced with about 50% of genes displaying various exon composition compared to the reference sequence [3,4,5]. There are numerous variants that have not been characterized at the transcript level, especially those
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