Genomic Landscape of Sporadic Retinitis Pigmentosa

Martín-Mérida, Inmaculada; Ávila-Fernández, Almudena; Pozo‐Valero, Marta Del; Blanco‐Kelly, Fiona; Zurita, Olga; Pérez-Carro, Raquel; Aguilera-Garcia, Domingo; Riveiro-Álvarez, Rosa; Arteche, Ana; Trujillo-Tiebas, María José; Tahsin-Swafiri, Saoud; Rodríguez‐Pinilla, Elvira; Lorda‐Sánchez, Isabel; Garcı́a-Sandoval, Blanca; Cortón, Marta; Ayuso, Carmen

doi:10.1016/j.ophtha.2019.03.018

Cited by 57 publications

(55 citation statements)

References 33 publications

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“…In the Spanish, Chinese, and German cohorts, which only comprised RP cases, an X-linked pattern of inheritance among the solved cases was observed in 7.9%, 11%, and 12.1%, respectively (Birtel et al, 2018;Gao et al, 2019;Martin-Merida et al, 2019). In contrast, X-linked cases constitute 19.2% of solved patients with RP in our cohort.…”

Section: Genes and Mutation Spectrummentioning

confidence: 49%

“…Diagnostic rates varied according to the disease type ( (Carss et al, 2017;Dockery et al, 2017;Jespersgaard et al, 2019;Sharon et al, 2020;Stone et al, 2017). In addition, for comparison purposes, we focused on two studies that investigated large cohorts of patients with RP in the Spanish and Chinese populations (Gao et al, 2019;Martin-Merida et al, 2019), respectively, and a small RP cohort study performed in the German population (Birtel et al, 2018). (2018) have analyzed 116 patients with RP.…”

Section: Molecular Diagnosis Ratesmentioning

confidence: 99%

“…shows an extreme level of genetic heterogeneity (Gao et al, 2019;Martin-Merida et al, 2019), with more than 90 "disease genes" reported to date (sourced from RetNet, https://sph.uth.edu/retnet, as of January 2020).…”

Section: Introductionmentioning

confidence: 99%

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Genetic architecture of inherited retinal degeneration in Germany: A large cohort study from a single diagnostic center over a 9‐year period

et al. 2020

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We aimed to unravel the molecular genetic basis of inherited retinal degeneration (IRD) in a comprehensive cohort of patients diagnosed in the largest center for IRD in Germany. A cohort of 2,158 affected patients from 1,785 families diagnosed with IRD was analyzed by targeted next‐generation sequencing (NGS). Patients with single‐gene disorders (i.e., choroideremia and retinoschisis) were analyzed by Sanger sequencing and multiplex ligation‐dependent probe amplification. Our study cohort accounts for ∼7% of the estimated 30,000 patients with IRD in Germany, thereby providing representative data for both the prevalence of IRDs and the mutation spectrum of IRD genes for the population in Germany. We achieved a molecular diagnostic rate of 35–95%, depending on the clinical entities, with a high detection rate for achromatopsia, retinoschisis, and choroideremia, and a low detection rate for central areolar choroidal dystrophy and macular dystrophy. A total of 1,161 distinct variants were identified, including 501 novel variants, reaffirming the known vast genetic heterogeneity of IRD in a mainly outbred European population. This study demonstrates the clinical utility of panel‐based NGS in a large and highly heterogeneous cohort from an outbred population and for the first time gives a comprehensive representation of the genetic landscape of IRDs in Germany. The data are valuable and crucial for the scientific community and healthcare providers, but also for the pharmaceutical industry in the progressing field of personalized medicine and gene therapy.

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Section: Genes and Mutation Spectrummentioning

confidence: 49%

Section: Molecular Diagnosis Ratesmentioning

confidence: 99%

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Genetic architecture of inherited retinal degeneration in Germany: A large cohort study from a single diagnostic center over a 9‐year period

et al. 2020

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“…A number of prior studies have examined IRD cohorts. 4 , 8 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 Table 2 presents the most frequently involved genes in many of these published studies over the last 3 to 4 years. Obvious similarities exist in terms of genes affected across diverse geographic regions.…”

Section: Discussionmentioning

confidence: 99%

Genetic Basis of Inherited Retinal Disease in a Molecularly Characterized Cohort of More Than 3000 Families from the United Kingdom

et al. 2020

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Purpose In a large cohort of molecularly characterized inherited retinal disease (IRD) families, we investigated proportions with disease attributable to causative variants in each gene. Design Retrospective study of electronic patient records. Participants Patients and relatives managed in the Genetics Service of Moorfields Eye Hospital in whom a molecular diagnosis had been identified. Methods Genetic screening used a combination of single-gene testing, gene panel testing, whole exome sequencing, and more recently, whole genome sequencing. For this study, genes listed in the Retinal Information Network online resource ( https://sph.uth.edu/retnet/ ) were included. Transcript length was extracted for each gene (Ensembl, release 94). Main Outcome Measures We calculated proportions of families with IRD attributable to variants in each gene in the entire cohort, a cohort younger than 18 years, and a current cohort (at least 1 patient encounter between January 1, 2017, and August 2, 2019). Additionally, we explored correlation between numbers of families and gene transcript length. Results We identified 3195 families with a molecular diagnosis (variants in 135 genes), including 4236 affected individuals. The pediatric cohort comprised 452 individuals from 411 families (66 genes). The current cohort comprised 2614 families (131 genes; 3130 affected individuals). The 20 most frequently implicated genes overall (with prevalence rates per families) were as follows: ABCA4 (20.8%), USH2A (9.1%), RPGR (5.1%), PRPH2 (4.6%), BEST1 (3.9%), RS1 (3.5%), RP1 (3.3%), RHO (3.3%), CHM (2.7%), CRB1 (2.1%), PRPF31 (1.8%), MY07A (1.7%), OPA1 (1.6%), CNGB3 (1.4%), RPE65 (1.2%), EYS (1.2%), GUCY2D (1.2%), PROM1 (1.2%), CNGA3 (1.1%), and RDH12 (1.1%). These accounted for 71.8% of all molecularly diagnosed families. Spearman coefficients for correlation between numbers of families and transcript length were 0.20 ( P = 0.025) overall and 0.27 ( P = 0.017), –0.17 ( P = 0.46), and 0.71 ( P = 0.047) for genes in which variants exclusively cause recessive, dominant, or X-linked disease, respectively. Conclusions Our findings help to quantify the burden of IRD attributable to each gene. More than ...

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“…In Case 1, paternity and maternity were confirmed by multiplex analysis of 19 STR loci plus Amelogenin using the COrDIS Plus kit (Gordiz Ltd., Moscow, Russia) on the ABI PRISM® 3130XL Genetic Analyzer (Applied Biosystems Inc., Waltham, MA) according to the manufacturer’s recommendations. In Case 2, paternity was confirmed using quantitative fluorescent PCR analysis of 26 genetic markers on chromosomes 13, 18, 21 and XY (Devyser Compact QF-PCR v3, Devyser AB, Hägersten, Sweden), as previously described [ 48 ].…”

Section: Patients and Methodsmentioning

confidence: 99%

Expanding the phenotype of CRYAA nucleotide variants to a complex presentation of anterior segment dysgenesis

Marakhonov

Voskresenskaya

Ballesta

et al. 2020

Orphanet J Rare Dis

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Background Mutations in CRYAA , which encodes the α-crystallin protein, are associated with a spectrum of congenital cataract–microcornea syndromes. Results In this study, we performed clinical examination and subsequent genetic analysis in two unrelated sporadic cases of different geographical origins presenting with a complex phenotype of ocular malformation. Both cases manifested bilateral microphthalmia and severe anterior segment dysgenesis, primarily characterized by congenital aphakia, microcornea, and iris hypoplasia/aniridia. NGS-based analysis revealed two novel single nucleotide variants occurring de novo and affecting the translation termination codon of the CRYAA gene, c.520T > C and c.521A > C. Both variants are predicted to elongate the C-terminal protein domain by one-third of the original length. Conclusions Our report not only expands the mutational spectrum of CRYAA but also identifies the genetic cause of the unusual ocular phenotype described in this report.

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Genomic Landscape of Sporadic Retinitis Pigmentosa

Cited by 57 publications

References 33 publications

Genetic architecture of inherited retinal degeneration in Germany: A large cohort study from a single diagnostic center over a 9‐year period

Genetic architecture of inherited retinal degeneration in Germany: A large cohort study from a single diagnostic center over a 9‐year period

Genetic Basis of Inherited Retinal Disease in a Molecularly Characterized Cohort of More Than 3000 Families from the United Kingdom

Expanding the phenotype of CRYAA nucleotide variants to a complex presentation of anterior segment dysgenesis

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