X-Linked Retinitis Pigmentosa Caused by Non-Canonical Splice Site Variants in RPGR

Kortüm, Friederike; Kieninger, Sinja; Mazzola, Pascale; Kohl, Susanne; Wissinger, Bernd; Prokisch, Holger; Štingl, Katarína; Weisschuh, Nicole

doi:10.3390/ijms22020850

Cited by 7 publications

(8 citation statements)

References 37 publications

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“…WES exclusively captures the protein-coding exons, but only accounts for approximately 1% of the genome. It is important to note that exon-based sequencing is likely to also reliably detect intronic variants located close to the targeted exons, such as non-canonical splice site variants, which are known causes of IRDs [ 28 , 29 , 30 ]. WGS is significantly more comprehensive including introns, promoters, and intergenic regions; in principle sequencing every nucleotide possible in a sample.…”

Section: Irds—target Panels and Whole Exome Studiesmentioning

confidence: 99%

Next-Generation Sequencing Applications for Inherited Retinal Diseases

Dockery

Whelan

Humphries

et al. 2021

IJMS

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Inherited retinal diseases (IRDs) represent a collection of phenotypically and genetically diverse conditions. IRDs phenotype(s) can be isolated to the eye or can involve multiple tissues. These conditions are associated with diverse forms of inheritance, and variants within the same gene often can be associated with multiple distinct phenotypes. Such aspects of the IRDs highlight the difficulty met when establishing a genetic diagnosis in patients. Here we provide an overview of cutting-edge next-generation sequencing techniques and strategies currently in use to maximise the effectivity of IRD gene screening. These techniques have helped researchers globally to find elusive causes of IRDs, including copy number variants, structural variants, new IRD genes and deep intronic variants, among others. Resolving a genetic diagnosis with thorough testing enables a more accurate diagnosis and more informed prognosis and should also provide information on inheritance patterns which may be of particular interest to patients of a child-bearing age. Given that IRDs are heritable conditions, genetic counselling may be offered to help inform family planning, carrier testing and prenatal screening. Additionally, a verified genetic diagnosis may enable access to appropriate clinical trials or approved medications that may be available for the condition.

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Section: Irds—target Panels and Whole Exome Studiesmentioning

confidence: 99%

Next-Generation Sequencing Applications for Inherited Retinal Diseases

Dockery

Whelan

Humphries

et al. 2021

IJMS

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“…RNA analysis using either patient blood cells or immortalized lymphoblastoid cells represents an alternative option, providing that the gene of interest is normally expressed in these cells (Wai et al, 2020). In case of the non-feasibility of both approaches, a cell culture-based minigene splicing assay has often been devised (for some most recent examples, see Damasio et al, 2021;Hao et al, 2021;Kim et al, 2021;Kortum et al, 2021;Le Tertre et al, 2021;Morbidoni et al, 2021;Qian et al, 2021;Saint-Martin et al, 2021;Torrado et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Splicing Outcomes of 5′ Splice Site GT>GC Variants That Generate Wild-Type Transcripts Differ Significantly Between Full-Length and Minigene Splicing Assays

Lin

Zou

et al. 2021

Front. Genet.

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Combining data derived from a meta-analysis of human disease-associated 5′ splice site GT>GC (i.e., +2T>C) variants and a cell culture-based full-length gene splicing assay (FLGSA) of forward engineered +2T>C substitutions, we recently estimated that ∼15–18% of +2T>C variants can generate up to 84% wild-type transcripts relative to their wild-type counterparts. Herein, we analyzed the splicing outcomes of 20 +2T>C variants that generate some wild-type transcripts in two minigene assays. We found a high discordance rate in terms of the generation of wild-type transcripts, not only between FLGSA and the minigene assays but also between the different minigene assays. In the pET01 context, all 20 wild-type minigene constructs generated the expected wild-type transcripts; of the 20 corresponding variant minigene constructs, 14 (70%) generated wild-type transcripts. In the pSPL3 context, only 18 of the 20 wild-type minigene constructs generated the expected wild-type transcripts whereas 8 of the 18 (44%) corresponding variant minigene constructs generated wild-type transcripts. Thus, in the context of a particular type of variant, we raise awareness of the limitations of minigene splicing assays and emphasize the importance of sequence context in regulating splicing. Whether or not our findings apply to other types of splice-altering variant remains to be investigated.

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“…[ 224 225 ] This protein is involved in microtubule organization and ciliary protein trafficking. [ 226 ]…”

Section: Gtpase Regulator Gene For Retinitis Pigmentosamentioning

confidence: 99%

“…More than 500 genetic variants of RPGR are known to be involved in various retinal dystrophies, most of which are frameshift and nonsense, while 10% of the variants are splice site variants. [ 226 ] Variants of RPGR affect protein trafficking and, thus, also have an adverse effect on the function and survival of photoreceptors. [ 228 ]…”

Section: Gtpase Regulator Gene For Retinitis Pigmentosamentioning

confidence: 99%

Genetic dissection of non-syndromic retinitis pigmentosa

Bhardwaj

Yadav

et al. 2022

Indian Journal of Ophthalmology

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Retinitis pigmentosa (RP) belongs to a group of pigmentary retinopathies. It is the most common form of inherited retinal dystrophy, characterized by progressive degradation of photoreceptors that leads to nyctalopia, and ultimately, complete vision loss. RP is distinguished by the continuous retinal degeneration that progresses from the mid-periphery to the central and peripheral retina. RP was first described and named by Franciscus Cornelius Donders in the year 1857. It is one of the leading causes of bilateral blindness in adults, with an incidence of 1 in 3000 people worldwide. In this review, we are going to focus on the genetic heterogeneity of this disease, which is provided by various inheritance patterns, numerosity of variations and inter-/intra-familial variations based upon penetrance and expressivity. Although over 90 genes have been identified in RP patients, the genetic cause of approximately 50% of RP cases remains unknown. Heterogeneity of RP makes it an extremely complicated ocular impairment. It is so complicated that it is known as “fever of unknown origin”. For prognosis and proper management of the disease, it is necessary to understand its genetic heterogeneity so that each phenotype related to the various genetic variations could be treated.

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X-Linked Retinitis Pigmentosa Caused by Non-Canonical Splice Site Variants in RPGR

Cited by 7 publications

References 37 publications

Next-Generation Sequencing Applications for Inherited Retinal Diseases

Next-Generation Sequencing Applications for Inherited Retinal Diseases

Splicing Outcomes of 5′ Splice Site GT>GC Variants That Generate Wild-Type Transcripts Differ Significantly Between Full-Length and Minigene Splicing Assays

Genetic dissection of non-syndromic retinitis pigmentosa

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