Advanced diagnostic genetic testing in inherited retinal disease: experience from a single tertiary referral centre in the <scp>UK</scp> National Health Service

Khan, Kamron; Chana, Ravinder K.; Ali, Nazia; Wright, Genevieve; Webster, Andrew R.; Moore, Anthony T.; Michaelides, Michel

doi:10.1111/cge.12798

Cited by 18 publications

(19 citation statements)

References 33 publications

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“…Targeted NGS analysis is a valuable method for molecular genetic diagnostics of IRDs as also supported by several previous studies 16–18 . Our detection rate of 48% is relatively low compared to other studies; however, this may be biased as our study population was derived from clinical biobank samples that had been extensively investigated over the years in several research projects and diagnostics efforts, resulting in many solved cases not included in the present study.…”

Section: Discussionsupporting

confidence: 56%

Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy

Jespersgaard

Fang

Bertelsen

et al. 2019

Sci Rep

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Inherited retinal diseases (IRDs) are a common cause of visual impairment. IRD covers a set of genetically highly heterogeneous disorders with more than 150 genes associated with one or more clinical forms of IRD. Molecular genetic diagnosis has become increasingly important especially due to expanding number of gene therapy strategies under development. Next generation sequencing (NGS) of gene panels has proven a valuable diagnostic tool in IRD. We present the molecular findings of 677 individuals, residing in Denmark, with IRD and report 806 variants of which 187 are novel. We found that deletions and duplications spanning one or more exons can explain 3% of the cases, and thus copy number variation (CNV) analysis is important in molecular genetic diagnostics of IRD. Seven percent of the individuals have variants classified as pathogenic or likely-pathogenic in more than one gene. Possible Danish founder variants in EYS and RP1 are reported. A significant number of variants were classified as variants with unknown significance; reporting of these will hopefully contribute to the elucidation of the actual clinical consequence making the classification less troublesome in the future. In conclusion, this study underlines the relevance of performing targeted sequencing of IRD including CNV analysis as well as the importance of interaction with clinical diagnoses.

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Section: Discussionsupporting

confidence: 56%

Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy

Jespersgaard

Fang

Bertelsen

et al. 2019

Sci Rep

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“…The molecular diagnosis was achieved in 58.62% of IRDs patients (17/29). This diagnostic yield is in line with previous works 30 that similarly analyzed population-specific IRDs genes, and it is somewhat higher than other studies involving more genes 31 , 32 . It demonstrates that a consistent and adapted design of the panel guarantees a good diagnostic yield while reducing sequencing costs, time and analytical effort.…”

Section: Discussionsupporting

confidence: 91%

Searching the second hit in patients with inherited retinal dystrophies and monoallelic variants in ABCA4, USH2A and CEP290 by whole-gene targeted sequencing

Pozo

Martín-Sánchez

Bravo-Gil

et al. 2018

Sci Rep

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Inherited Retinal Dystrophies are clinically and genetically heterogeneous disorders affecting the photoreceptors. Although NGS has shown to be helpful for the molecular diagnosis of these conditions, some cases remain unsolved. Among these, several individuals harboured monoallelic variants in a recessive gene, suggesting that a comprehensive screening could improve the overall diagnosis. In order to assess the contribution of non-coding variations in a cohort of 29 patients, 25 of them with monoallelic mutations, we performed targeted NGS. The design comprised the entire genomic sequence of three genes (USH2A, ABCA4 and CEP290), the coding exons of 76 genes and two disease-associated intronic regions in OFD1 and PRPF31. As a result, likely causative mutations (8 novel) were identified in 17 probands (diagnostic rate: 58.62%), including two copy-number variations in USH2A (one deletion of exons 22–55 and one duplication of exons 46–47). Possibly damaging deep-intronic mutations were identified in one family, and another with a monoallelic variant harboured causal mutations in a different locus. In conclusion, due to the high prevalence of carriers of IRD mutations and the results obtained here, sequencing entire genes do not seem to be the approach of choice for detecting the second hit in IRD patients with monoallelic variants.

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“…Only 32% of the patients were classified as genetically solved. Other studies of IRD report somewhat higher diagnostic yield, with detection rates from 39% to 76% (O'Sullivan et al 2012;Eisenberger et al 2013;Huang et al 2015;Ellingford et al 2016;Patel et al 2016;Tiwari et al 2016;Carss et al 2017;Khan et al 2017;Stone et al 2017). High-throughput sequencing (HTS) had a higher diagnostic yield Diagnosis uncertain 0% (n = 0/8) -AD, autosomal dominant; AR, autosomal recessive; XL, X-linked.…”

Section: Discussionmentioning

confidence: 99%

Inherited retinal disease in Norway – a characterization of current clinical and genetic knowledge

Holtan

Selmer

Heimdal

et al. 2019

Acta Ophthalmologica

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Purpose The purpose of this study was to characterize current clinical and genetic knowledge of patients with inherited retinal disease in Norway and give an estimate of the prevalence. These data are necessary to identify patients eligible for new personalized medicines, to facilitate genetic counselling for their families and to plan clinical follow‐up. Methods A patient registry including clinical and genetic data was established. Clinical data were retrieved during 2003–2018. Genetic testing was performed in the period 2007–2018. Results The material included 866 patients with 41 clinical diagnoses at the cut‐off date. The most prevalent diseases were as follows: retinitis pigmentosa (54%), Stargardt macular dystrophy (6.5%) and Leber congenital amaurosis (5.2%). A genetic diagnosis was identified in 32% of patients. In total, 207 disease‐causing variants in 56 genes were reported. The most commonly reported disease‐causing genes were ABCA4, USH2A and BEST1. The estimated adjusted minimum prevalence of inherited retinal disease in the south‐east region of Norway was 1: 3,856 (2.6/10 000). Conclusion This population‐based study demonstrated an estimated prevalence for all inherited retinal diseases in south‐east Norway and described the distribution of clinical diagnoses, onset of symptoms, inheritance patterns and genetic data and thereby expands our knowledge of inherited retinal disease in Norway. The newly established registry and biobank will support patient feasibility for future clinical trials, treatment selection and counselling of families.

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Advanced diagnostic genetic testing in inherited retinal disease: experience from a single tertiary referral centre in the UK National Health Service

Abstract: Background/Aims

Cited by 18 publications

References 33 publications

Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy

Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy

Searching the second hit in patients with inherited retinal dystrophies and monoallelic variants in ABCA4, USH2A and CEP290 by whole-gene targeted sequencing

Inherited retinal disease in Norway – a characterization of current clinical and genetic knowledge

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