Updating the Genetic Landscape of Inherited Retinal Dystrophies

Bohórquez, Belén García; Aller, Elena; Muñoz, Ana Rodríguez; Jaijo, Teresa; García‐García, Gema; Millán, José María

doi:10.3389/fcell.2021.645600

Cited by 22 publications

(21 citation statements)

References 109 publications

(118 reference statements)

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“…In our cohort of achromatopsia patients, we have not observed the c.673+5G>T variant yet. So far, it was only observed once in single heterozygous state in a patient diagnosed with retinitis pigmentosa 35 . This is most likely an incidental finding, as CNGA3 is thought to be primarily involved in cone dysfunction disorders 36 .…”

Section: Discussionmentioning

confidence: 99%

Systematic analysis of CNGA3 splice variants identifies different mechanisms of aberrant splicing

Reuter

Walter

Kohl

et al. 2023

Sci Rep

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Achromatopsia is an autosomal recessive cone photoreceptor disease that is frequently caused by pathogenic variants in the CNGA3 gene. Here, we present a systematic functional analysis of 20 CNGA3 splice site variants detected in our large cohort of achromatopsia patients and/or listed in common variant databases. All variants were analyzed by functional splice assays based on the pSPL3 exon trapping vector. We demonstrated that ten variants, both at canonical and non-canonical splice sites, induced aberrant splicing, including intronic nucleotide retention, exonic nucleotide deletion and exon skipping, resulting in 21 different aberrant transcripts. Of these, eleven were predicted to introduce a premature termination codon. The pathogenicity of all variants was assessed based on established guidelines for variant classification. Incorporation of the results of our functional analyses enabled re-classification of 75% of variants previously classified as variants of uncertain significance into either likely benign or likely pathogenic. Our study is the first in which a systematic characterization of putative CNGA3 splice variants has been performed. We demonstrated the utility of pSPL3 based minigene assays in the effective assessment of putative splice variants. Our findings improve the diagnosis of achromatopsia patients, who may thus benefit from future gene-based therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

Systematic analysis of CNGA3 splice variants identifies different mechanisms of aberrant splicing

Reuter

Walter

Kohl

et al. 2023

Sci Rep

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“…The retina of the human eye is a complex structure that involves the interplay of multiple retinal genes. Over the years, numerous gene mutations have been shown to play a crucial role in retinal dystrophy [ 89 , 90 , 91 ], some of them leading to clinical phase studies for drug development. Studies have shown that most of the genetic mutations associated with RP were due to photoreceptor or RPE dysfunctions (see Table 1 ) [ 92 ].…”

Section: Gene Therapymentioning

confidence: 99%

Retinitis Pigmentosa: Novel Therapeutic Targets and Drug Development

Kulbay

Toameh

et al. 2023

Pharmaceutics

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Retinitis pigmentosa (RP) is a heterogeneous group of hereditary diseases characterized by progressive degeneration of retinal photoreceptors leading to progressive visual decline. It is the most common type of inherited retinal dystrophy and has a high burden on both patients and society. This condition causes gradual loss of vision, with its typical manifestations including nyctalopia, concentric visual field loss, and ultimately bilateral central vision loss. It is one of the leading causes of visual disability and blindness in people under 60 years old and affects over 1.5 million people worldwide. There is currently no curative treatment for people with RP, and only a small group of patients with confirmed RPE65 mutations are eligible to receive the only gene therapy on the market: voretigene neparvovec. The current therapeutic armamentarium is limited to retinoids, vitamin A supplements, protection from sunlight, visual aids, and medical and surgical interventions to treat ophthalmic comorbidities, which only aim to slow down the progression of the disease. Considering such a limited therapeutic landscape, there is an urgent need for developing new and individualized therapeutic modalities targeting retinal degeneration. Although the heterogeneity of gene mutations involved in RP makes its target treatment development difficult, recent fundamental studies showed promising progress in elucidation of the photoreceptor degeneration mechanism. The discovery of novel molecule therapeutics that can selectively target specific receptors or specific pathways will serve as a solid foundation for advanced drug development. This article is a review of recent progress in novel treatment of RP focusing on preclinical stage fundamental research on molecular targets, which will serve as a starting point for advanced drug development. We will review the alterations in the molecular pathways involved in the development of RP, mainly those regarding endoplasmic reticulum (ER) stress and apoptotic pathways, maintenance of the redox balance, and genomic stability. We will then discuss the therapeutic approaches under development, such as gene and cell therapy, as well as the recent literature identifying novel potential drug targets for RP.

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“…Several high-throughput next-generation sequencing (NGS) technologies using short-read sequencing have accelerated molecular diagnoses for IRD patients, ranging from custom gene panel approaches [5,6] to whole exome sequencing (WES) [7] and whole genome sequencing (WGS) [8,9]. Each technique involves complex outputs to consider in terms of financials, total data generated (and its required storage capacity) and hands-on analysis time per sample.…”

Section: Introductionmentioning

confidence: 99%

Using single molecule Molecular Inversion Probes as a cost-effective, high-throughput sequencing approach to target all genes and loci associated with macular diseases

Hitti‐Malin

Dhaenens

Panneman

et al. 2022

Preprint

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BackgroundMacular diseases (MDs) are a subgroup of retinal disorders characterized by central vision loss that represent a major cause of vision impairment. Despite the identification of numerous genes associated with inherited MD (iMD) and risk factors associated with age-related MD (AMD), the extent of genetic and non-genetic factors that influence the expression of MD is still not fully explained. Single molecule Molecular Inversion Probes (smMIPs) have proven effective in sequencing the ABCA4 gene in patients with Stargardt disease in a cost-effective manner to identify associated coding and non-coding variation, however a large portion of patients with MDs still remain genetically unexplained.MethodsFor MD patients, we hypothesized that the missing heritability may be revealed by smMIPs-based sequencing of all MD-associated genes and risk factors. We used 17,394 smMIPs to sequence the coding regions of 105 genes and non-coding or regulatory loci associated with iMD and AMD, known pseudo-exons, and the mitochondrial genome in two test cohorts that had previously been screened for variants in the entire ABCA4 gene.ResultsSequencing of 379 probands achieved an average nucleotide coverage of 431× across all targets. Following detailed sequencing analysis of 110 probands, a diagnostic yield of 38% was observed. This established an ‘‘MD-smMIPs panel’’ that allows a genotype-first approach in a high-throughput and cost-effective manner, whilst achieving uniform and high coverage across targets.ConclusionsFurther analysis will identify known and novel variants in MD-associated genes to offer an accurate clinical diagnosis to patients and their families. Furthermore, this will reveal new genetic associations for MD and potential genetic overlaps between iMD and AMD.

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Updating the Genetic Landscape of Inherited Retinal Dystrophies

Cited by 22 publications

References 109 publications

Systematic analysis of CNGA3 splice variants identifies different mechanisms of aberrant splicing

Systematic analysis of CNGA3 splice variants identifies different mechanisms of aberrant splicing

Retinitis Pigmentosa: Novel Therapeutic Targets and Drug Development

Using single molecule Molecular Inversion Probes as a cost-effective, high-throughput sequencing approach to target all genes and loci associated with macular diseases

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