Clinical and Genetic Re-Evaluation of Inherited Retinal Degeneration Pedigrees following Initial Negative Findings on Panel-Based Next Generation Sequencing

Stephenson, Kirk; Zhu, Julia; Dockery, Adrian; Whelan, Laura; Burke, Tomas R.; Turner, Jacqueline A.; O’Byrne, James J.; Farrar, G. Jane; Keegan, David

doi:10.3390/ijms23020995

Cited by 10 publications

(8 citation statements)

References 40 publications

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“…Of this total cohort 82.1% was fully resolved (i.e., biallelic USH-associated variants), with 23.1% (n = 6/26) of the unresolved remainder having one allele identified, helping to guide further focused genetic analysis such as single gene or long-read sequencing (i.e., introns and exons). 41 , 50 The c.2299delG variant is the most common pathogenic USH2A mutation associated with USH, 51 which accounted for 17.5% of USH2A cases in our cohort (10.6% of candidate variants in any USH gene). The most commonly detected USH2A variant associated with nonsyndromic RP is the c.2276G>T variant.…”

Section: Discussionmentioning

confidence: 82%

Usher Syndrome on the Island of Ireland: A Genotype-Phenotype Review

Stephenson

Whelan

Zhu

et al. 2023

Invest. Ophthalmol. Vis. Sci.

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Purpose Usher syndrome (USH) is a genetically heterogeneous group of autosomal recessive (AR) syndromic inherited retinal degenerations (IRDs) representing 50% of deaf-blindness. All subtypes include retinitis pigmentosa, sensorineural hearing loss, and vestibular abnormalities. Thorough phenotyping may facilitate genetic diagnosis and intervention. Here we report the clinical/genetic features of an Irish USH cohort. Methods USH patients were selected from the Irish IRD registry (Target 5000). Patients were examined clinically (deep-phenotyping) and genetically using a 254 IRD–associated gene target capture sequencing panel, USH2A exon, and whole genome sequencing. Results The study identified 145 patients (24.1% USH1 [n = 35], 73.8% USH2 [n = 107], 1.4% USH3 [n = 2], and 0.7% USH4 [n = 1]). A genetic diagnosis was reached in 82.1%, the majority (80.7%) being MYO7A or USH2A genotypes. Mean visual acuity and visual field (VF) were 0.47 ± 0.58 LogMAR and 31.3° ± 32.8°, respectively, at a mean age of 43 years. Legal blindness criteria were met in 40.7%. Cataract was present in 77.4%. ADGRV1 genotypes had the most VF loss, whereas USH2A patients had greater myopia and CDH23 had the most astigmatism. Variants absent from gnomAD non-Finnish Europeans and ClinVar represented more than 20% of the variants identified and were detected in ADGRV1, ARSG, CDH23, MYO7A , and USH2A. Conclusions USH is a genetically diverse group of AR IRDs that have a profound impact on affected individuals and their families. The prevalence and phenotype/genotype characteristics of USH in Ireland have, as yet, gone unreported. Understanding the genotype of Irish USH patients may guide clinical and genetic characterization facilitating access to existing/novel therapeutics.

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Section: Discussionmentioning

confidence: 82%

Usher Syndrome on the Island of Ireland: A Genotype-Phenotype Review

Stephenson

Whelan

Zhu

et al. 2023

Invest. Ophthalmol. Vis. Sci.

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“…The need to achieve an accurate genetic diagnosis for IRD patients is increasingly important as novel gene therapies are in clinical trials for a growing number of aetiologies [32,34,51,63] and a molecular diagnosis is often a prerequisite for access to clinical trials and approved treatments. In this cohort, 43.3% of the children (26 out of 60 tested positive) meet the criteria for gene therapies (approved or in clinical trials).…”

Section: Discussionmentioning

confidence: 99%

“…Of 10 unresolved patients with clinically AR IRD, a single allele was detected in 5 patients (50%, ACMG class 5 in two cases, class 4 in one case, and class 3 in two cases). Further studies including whole gene sequencing (i.e., single allele cases) and/or whole exome/genome sequencing (i.e., no candidate genetic variants) are planned to resolve these cases [51].…”

Section: Genetic Analysismentioning

confidence: 99%

Electrophysiology-Guided Genetic Characterisation Maximises Molecular Diagnosis in an Irish Paediatric Inherited Retinal Degeneration Population

Zhu

Stephenson

Dockery

et al. 2022

Genes

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Inherited retinal degenerations (IRDs) account for over one third of the underlying causes of blindness in the paediatric population. Patients with IRDs often experience long delays prior to reaching a definitive diagnosis. Children attending a tertiary care paediatric ophthalmology department with phenotypic (i.e., clinical and/or electrophysiologic) evidence suggestive of IRD were contacted for genetic testing during the SARS-CoV-2-19 pandemic using a “telegenetics” approach. Genetic testing approach was panel-based next generation sequencing (351 genes) via a commercial laboratory (Blueprint Genetics, Helsinki, Finland). Of 70 patient samples from 57 pedigrees undergoing genetic testing, a causative genetic variant(s) was detected for 60 patients (85.7%) from 47 (82.5%) pedigrees. Of the 60 genetically resolved IRD patients, 5% (n = 3) are eligible for approved therapies (RPE65) and 38.3% (n = 23) are eligible for clinical trial-based gene therapies including CEP290 (n = 2), CNGA3 (n = 3), CNGB3 (n = 6), RPGR (n = 5) and RS1 (n = 7). The early introduction of genetic testing in the diagnostic/care pathway for children with IRDs is critical for genetic counselling of these families prior to upcoming gene therapy trials. Herein, we describe the pathway used, the clinical and genetic findings, and the therapeutic implications of the first systematic coordinated round of genetic testing of a paediatric IRD cohort in Ireland.

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“…RP is clinically and genetically heterogeneous, with mutations detected in as many as ∼70 different genes [12]. At present, molecular diagnostic yields in RP do not exceed 70% [13, 14]. The identification of novel pathogenic variants in known genes not only helps refine molecular diagnoses but also allows patients to access gene-based clinical trials or therapies.…”

Section: Introductionmentioning

confidence: 99%

A Novel Intronic Deletion in PDE6B Causes Autosomal Recessive Retinitis Pigmentosa by Interfering with RNA Splicing

Ullah¹,

Rehman²,

Folcher³

et al. 2023

Ophthalmic Res

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Introduction: Retinitis pigmentosa (RP) is a rare degenerative retinal disease caused by mutations in approximately seventy genes. Currently, despite the availability of large-scale DNA sequencing technologies, ~30-40% of patients still cannot be diagnosed at the molecular level. In this study, we investigate a novel intronic deletion of PDE6B, encoding the beta subunit of phosphodiesterase 6, in association with recessive RP. Methods: Three unrelated consanguineous families were recruited from the North-Western part of Pakistan. Whole exome sequencing was performed for the probands of each family and the data were analyzed according to an in-house computer pipeline. Relevant DNA variants in all available members of these families were assessed through Sanger sequencing. A minigene-based splicing assay was also performed. Results: The clinical phenotype for all patients was compatible with rod cone degeneration, with onset during childhood. Whole exome sequencing revealed a homozygous 18 bp intronic deletion (NM_000283.3: c.1921-20_1921-3del) in PDE6B, which co-segregated with disease in 10 affected individuals. In-vitro splicing tests showed that this deletion causes aberrant RNA splicing of the gene, leading to the in-frame deletion of 6 codons and likely to disease. Discussion/Conclusion: Our findings further expand the mutational spectrum of the PDE6B gene.

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Clinical and Genetic Re-Evaluation of Inherited Retinal Degeneration Pedigrees following Initial Negative Findings on Panel-Based Next Generation Sequencing

Cited by 10 publications

References 40 publications

Usher Syndrome on the Island of Ireland: A Genotype-Phenotype Review

Usher Syndrome on the Island of Ireland: A Genotype-Phenotype Review

Electrophysiology-Guided Genetic Characterisation Maximises Molecular Diagnosis in an Irish Paediatric Inherited Retinal Degeneration Population

A Novel Intronic Deletion in PDE6B Causes Autosomal Recessive Retinitis Pigmentosa by Interfering with RNA Splicing

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