The research output of rod-cone dystrophy genetics

Jaffal, Lama; Mrad, Zamzam; Ibrahim, Mariam; Salami, Ali; Audo, Isabelle; Zeitz, Christina; Shamieh, Said El

doi:10.1186/s13023-022-02318-5

Cited by 3 publications

(2 citation statements)

References 50 publications

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“…Our work validated the NGS-detected CNVs [31], emphasizing the diagnostic value of this tool for identifying structural abnormalities in many diseases including RCD. These outcomes emphasize the value of functional assays, such as qPCR, as a diagnostic tool for validating NGS-detected CNVs, increasing the molecular diagnosis rate and thus allowing improved management and better genetic counseling afterward [32].…”

Section: Discussionmentioning

confidence: 99%

A Novel Copy Number Variation in PRPF31 Causes Dominant Rod-Cone Dystrophy By Haploinsufficiency

Mousawi,

Choukeir,

Jaffal

et al. 2024

Preprint

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Background and Objectives: Rod-cone dystrophy (RCD), also known as Retinitis Pigmentosa, is the most common group of retinal dystrophies, affecting around 1:4,000 individuals worldwide. Herein, our objective was to identify the genetic cause of RCD in two Lebanese families with distinct inheritance patterns and explore the potential role of PRPF31 haploinsufficiency. Methods The study combined next-generation sequencing, real-time PCR (qPCR), and chromosomal microarray to identify, validate, and delineate the causative copy number variations (CNVs) identified in both families of this study. gene expression analysis using qPCR and Western Blot were conducted to assess the PRPF31 variant's impact on gene expression levels. Results A novel heterozygous deletion (701 bp) spanning exons 6 and 7 of PRPF31 was identified in the first family (F11), leading to autosomal dominant RCD through haploinsufficiency, evidenced by reduced mRNA and total absence of protein expression levels in the affected individuals (F11:III.2 and F11:II.1). A rare previously reported homozygous deletion in MERTK was found in the second family (F26), causing autosomal recessive RCD. These findings highlight the diversity of CNVs contributing to RCD and the critical role of haploinsufficiency in autosomal dominant RCD pathogenesis. Conclusion The current study expands the mutational spectrum associated with PRPF31 and MERTK genes in RCD, underscoring the importance of CNVs in its etiology. Identifying haploinsufficiency as a disease mechanism in PRPF31-related autosomal dominant RCD represents a stepping stone for future analyses regarding gene augmentation therapies.

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Section: Discussionmentioning

confidence: 99%

A Novel Copy Number Variation in PRPF31 Causes Dominant Rod-Cone Dystrophy By Haploinsufficiency

Mousawi,

Choukeir,

Jaffal

et al. 2024

Preprint

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“… 31 In research, rod-cone dystrophy is either referred to as a form of RP or vice versa, or the terms are used synonymously. 29 , 32 , 33 Clinically, RP is preferred and will be used here.…”

Section: Introductionmentioning

confidence: 99%

Overcoming the Challenges to Clinical Development of X-Linked Retinitis Pigmentosa Therapies: Proceedings of an Expert Panel

Birch

Cheetham

Daiger

et al. 2023

Trans. Vis. Sci. Tech.

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X-linked retinitis pigmentosa (XLRP) is a rare inherited retinal disease manifesting as impaired night vision and peripheral vision loss that progresses to legal blindness. Although several trials of ocular gene therapy for XLRP have been conducted or are in progress, there is currently no approved treatment. In July 2022, the Foundation Fighting Blindness convened an expert panel to examine relevant research and make recommendations for overcoming the challenges and capitalizing on the opportunities in conducting clinical trials of RPGR -targeted therapy for XLRP. Data presented concerned RPGR structure and mutation types known to cause XLRP, RPGR mutation–associated retinal phenotype diversity, patterns in genotype/phenotype relationships, disease onset and progression from natural history studies, and the various functional and structural tests used to monitor disease progression. Panel recommendations include considerations, such as genetic screening and other factors that can impact clinical trial inclusion criteria, the influence of age on defining and stratifying participant cohorts, the importance of conducting natural history studies early in clinical development programs, and the merits and drawbacks of available tests for measuring treatment outcomes. We recognize the need to work with regulators to adopt clinically meaningful end points that would best determine the efficacy of a trial. Given the promise of RPGR -targeted gene therapy for XLRP and the difficulties encountered in phase III clinical trials to date, we hope these recommendations will help speed progress to finding a cure. Translational Relevance Examination of relevant data and recommendations for the successful clinical development of gene therapies for RPGR -associated XLRP.

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Editorial: The genetics of inherited retinal diseases in understudied ethnic groups: Novel associations, challenges, and perspectives

Shamieh

Maltese

2022

Front. Genet.

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Editorial on the Research TopicThe genetics of inherited retinal diseases in understudied ethnic groups: Novel associations, challenges, and perspectives Inherited retinal dystrophies (IRDs) cover a broad array of rare retinal diseases with diversify in genetic bases and phenotypes, affecting roughly as many as one in 2,000 individuals (Chen et al., 2021). Night or color blindness, tunnel vision, and later development to total blindness are all common vision impairment manifestations of IRDs that usually worsen with age (Chen et al., 2021). Cases of IRDs may be syndromic if they are coupled with extra-ocular symptoms or nonsyndromic if they are restricted to the eye (Hartong, 2006;Berson, 2006;Dryja, 2006). Interestingly, IRDs include over 20 different phenotypes (Hartong et al., 2006). The age of onset, the rate of progression, and the underlying causal genes may assist in categorizing these distinct phenotypes (Hartong et al., 2006;Perea-Romero et al., 2021). Retinitis pigmentosa (RP) (OMIM 500004), also known as rod-cone dystrophy, is the most common non-syndromic IRD, affecting around 1.5 million individuals globally (Chen et al., 2021). Other non-syndromic forms include cone-rod dystrophies (OMIM 120970), Stargardt disease (OMIM 248200), X-linked retinoschisis (OMIM 312700) and many others. On the other hand, the most common syndromic form is Usher syndrome (USH) (OMIM 276900), a combination of hearing loss and RP (Castiglione and Moller, 2022).Although several genetic studies have identified novel IRDs-associated genes and genetic variations, most of these associations and gene prevalence data were based on cohorts in Western Europe and North America (Smirnov et al., 2021;Colombo et al., 2021). Although the genetic basis of IRDs varies among patient cohorts, even replication for the major findings is still lacking in understudied ethnicities (Jaffal et al., 2021). Growing evidence is continuously showing the importance of better investigating these ethnicities (Amish, Mennonites, Turks, Middle Eastern

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The research output of rod-cone dystrophy genetics

Cited by 3 publications

References 50 publications

A Novel Copy Number Variation in PRPF31 Causes Dominant Rod-Cone Dystrophy By Haploinsufficiency

A Novel Copy Number Variation in PRPF31 Causes Dominant Rod-Cone Dystrophy By Haploinsufficiency

Overcoming the Challenges to Clinical Development of X-Linked Retinitis Pigmentosa Therapies: Proceedings of an Expert Panel

Editorial: The genetics of inherited retinal diseases in understudied ethnic groups: Novel associations, challenges, and perspectives

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