scholarly journals Extending the spectrum of CLRN1 ‐ and ABCA4 ‐associated inherited retinal dystrophies caused by novel and recurrent variants using exome sequencing

2020 ◽  
Vol 8 (3) ◽  
Author(s):  
Mohammed Abu‐Ameerh ◽  
Hashim Mohammad ◽  
Zain Dardas ◽  
Raghda Barham ◽  
Dema Ali ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies

scholarly journals Prioritizing variants of uncertain significance for reclassification using a rule-based algorithm in inherited retinal dystrophies

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Ionut-Florin Iancu ◽  
Almudena Avila-Fernandez ◽  
Ana Arteche ◽  
Maria Jose Trujillo-Tiebas ◽  
Rosa Riveiro-Alvarez ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Rare Diseases ◽  
Molecular Diagnostic ◽  
Rule Based ◽  
Variants Of Uncertain Significance ◽  
Inherited Retinal Dystrophies ◽  
Pathogenic Variants ◽  
Retinal Dystrophies ◽  
Clinical Exome Sequencing ◽  
Uncertain Significance

AbstractInherited retinal dystrophies (IRD) are a highly heterogeneous group of rare diseases with a molecular diagnostic rate of >50%. Reclassification of variants of uncertain significance (VUS) poses a challenge for IRD diagnosis. We collected 668 IRD cases analyzed by our geneticists using two different clinical exome-sequencing tests. We identified 114 unsolved cases pending reclassification of 125 VUS and studied their genomic, functional, and laboratory-specific features, comparing them to pathogenic and likely pathogenic variants from the same cohort (N = 390). While the clinical exome used did not show differences in diagnostic rate, the more IRD-experienced geneticist reported more VUS (p = 4.07e-04). Significantly fewer VUS were reported in recessive cases (p = 2.14e-04) compared to other inheritance patterns, and of all the genes analyzed, ABCA4 and IMPG2 had the lowest and highest VUS frequencies, respectively (p = 3.89e-04, p = 6.93e-03). Moreover, few frameshift and stop-gain variants were found to be informed VUS (p = 6.73e-08 and p = 2.93e-06). Last, we applied five pathogenicity predictors and found there is a significant proof of deleteriousness when all score for pathogenicity in missense variants. Altogether, these results provided input for a set of rules that correctly reclassified ~70% of VUS as pathogenic in validation datasets. Disease- and setting-specific features influence VUS reporting. Comparison with pathogenic and likely pathogenic variants can prioritize VUS more likely to be reclassified as causal.

scholarly journals Whole exome sequencing and homozygosity mapping reveals genetic defects in consanguineous Iranian families with inherited retinal dystrophies

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Arash Salmaninejad ◽  
Nicola Bedoni ◽  
Zeinab Ravesh ◽  
Mathieu Quinodoz ◽  
Nasser Shoeibi ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Snp Array ◽  
Homozygosity Mapping ◽  
Retinal Cell ◽  
Additional Information ◽  
Inherited Retinal Dystrophies ◽  
Pathogenic Variants ◽  
Retinal Dystrophies ◽  
Whole Exome

Abstract Inherited retinal dystrophies (IRDs), displaying pronounced genetic and clinical heterogeneity, comprise of a broad range of diseases characterized by progressive retinal cell death and gradual loss of vision. By the combined use of whole exome sequencing (WES), SNP-array and WES-based homozygosity mapping, as well as directed DNA sequencing (Sanger), we have identified nine pathogenic variants in six genes (ABCA4, RPE65, MERTK, USH2A, SPATA7, TULP1) in 10 consanguineous Iranian families. Six of the nine identified variants were novel, including a putative founder mutation in ABCA4 (c.3260A>G, p.Glu1087Gly), detected in two families from Northeastern Iran. Our findings provide additional information to the molecular pathology of IRDs in Iran, hopefully contributing to better genetic counselling and patient management in the respective families from this country.

scholarly journals Whole exome sequencing using Ion Proton system enables reliable genetic diagnosis of inherited retinal dystrophies

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Marina Riera ◽  
Rafael Navarro ◽  
Sheila Ruiz-Nogales ◽  
Pilar Méndez ◽  
Anniken Burés-Jelstrup ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Diagnosis ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
Whole Exome ◽  
Ion Proton

scholarly journals Exome Sequencing Reveals Novel and Recurrent Mutations with Clinical Significance in Inherited Retinal Dystrophies

PLoS ONE ◽  
2014 ◽  
Vol 9 (12) ◽  
pp. e116176 ◽  
Author(s):  
María González-del Pozo ◽  
Cristina Méndez-Vidal ◽  
Nereida Bravo-Gil ◽  
Alicia Vela-Boza ◽  
Joaquin Dopazo ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Clinical Significance ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
Recurrent Mutations

scholarly journals A Multi-Strategy Sequencing Workflow in Inherited Retinal Dystrophies: Routine Diagnosis, Addressing Unsolved Cases and Candidate Genes Identification

2020 ◽  
Vol 21 (24) ◽  
pp. 9355
Author(s):  
Marta Martín-Sánchez ◽  
Nereida Bravo-Gil ◽  
María González-del Pozo ◽  
Cristina Méndez-Vidal ◽  
Elena Fernández-Suárez ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Candidate Genes ◽  
Diagnostic Yield ◽  
Diagnostic Algorithm ◽  
Clinical Genetics ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
Causal Variants ◽  
Simultaneous Study ◽  
Candidate Loci

The management of unsolved inherited retinal dystrophies (IRD) cases is challenging since no standard pipelines have been established. This study aimed to define a diagnostic algorithm useful for the diagnostic routine and to address unsolved cases. Here, we applied a Next-Generation Sequencing-based workflow, including a first step of panel sequencing (PS) followed by clinical-exome sequencing (CES) and whole-exome sequencing (WES), in 46 IRD patients belonging to 42 families. Twenty-six likely causal variants in retinal genes were found by PS and CES. CES and WES allowed proposing two novel candidate loci (WDFY3 and a X-linked region including CITED1), both abundantly expressed in human retina according to RT-PCR and immunohistochemistry. After comparison studies, PS showed the best quality and cost values, CES and WES involved similar analytical efforts and WES presented the highest diagnostic yield. These results reinforce the relevance of panels as a first step in the diagnostic routine and suggest WES as the next strategy for unsolved cases, reserving CES for the simultaneous study of multiple conditions. Standardizing this algorithm would enhance the efficiency and equity of clinical genetics practice. Furthermore, the identified candidate genes could contribute to increase the diagnostic yield and expand the mutational spectrum in these disorders.

scholarly journals Novel Candidate Genes and a Wide Spectrum of Structural and Point Mutations Responsible for Inherited Retinal Dystrophies Revealed by Exome Sequencing

PLoS ONE ◽  
2016 ◽  
Vol 11 (12) ◽  
pp. e0168966 ◽  
Author(s):  
Marta de Castro-Miró ◽  
Raul Tonda ◽  
Paula Escudero-Ferruz ◽  
Rosa Andrés ◽  
Andrés Mayor-Lorenzo ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Candidate Genes ◽  
Wide Spectrum ◽  
Point Mutations ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies

scholarly journals Whole exome sequencing reveals putatively novel associations in retinopathies and drusen formation

2021 ◽  
Author(s):  
Lance P. Doucette ◽  
Nicole C. L. Noel ◽  
Yi Zhai ◽  
Manlong Xu ◽  
Oana Caluseriu ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Research Setting ◽  
Genetic Etiology ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
Clinical Investigations ◽  
Whole Exome ◽  
Disease Associated Genes ◽  
Novel Associations

AbstractInherited retinal dystrophies (IRDs) affect 1 in 3000 individuals worldwide and are genetically heterogeneous, with over 270 identified genes and loci; however, there are still many identified disorders with no current genetic etiology. Whole exome sequencing (WES) provides a hypothesis-free first examination of IRD patients in either a clinical or research setting to identify the genetic cause of disease. We present a study of IRD in ten families from Alberta, Canada, through the lens of novel gene discovery. We identify the genetic etiology of IRDs in three of the families to be variants in known disease-associated genes, previously missed by clinical investigations. In addition, we identify two potentially novel associations: LRP1 in early-onset drusen formation and UBE2U in a multi-system condition presenting with retinoschisis, cataracts, learning disabilities, and developmental delay. We also describe interesting results in our unsolved cases to provide further information to other investigators of these blinding conditions.

scholarly journals NRL S50T mutation and the importance of ‘founder effects’ in inherited retinal dystrophies

2000 ◽  
Vol 8 (10) ◽  
pp. 783-787 ◽  
Author(s):  
David AR Bessant ◽  
Annette M Payne ◽  
Catherine Plant ◽  
Alan C Bird ◽  
Anand Swaroop ◽  
...  
Keyword(s):  
Founder Effects ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies

scholarly journals Bestrophinopathies: perspectives on clinical disease, Bestrophin-1 function and developing therapies

2021 ◽  
Vol 13 ◽  
pp. 251584142199719
Author(s):  
Simranjeet Singh Grewal ◽  
Joseph J. Smith ◽  
Amanda-Jayne F. Carr
Keyword(s):  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Induced Pluripotent Stem Cell ◽  
Underlying Disease ◽  
Incomplete Penetrance ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
High Acuity ◽  
Induced Pluripotent

Bestrophinopathies are a group of clinically distinct inherited retinal dystrophies that typically affect the macular region, an area synonymous with central high acuity vision. This spectrum of disorders is caused by mutations in bestrophin1 ( BEST1), a protein thought to act as a Ca2+-activated Cl- channel in the retinal pigment epithelium (RPE) of the eye. Although bestrophinopathies are rare, over 250 individual pathological mutations have been identified in the BEST1 gene, with many reported to have various clinical expressivity and incomplete penetrance. With no current clinical treatments available for patients with bestrophinopathies, understanding the role of BEST1 in cells and the pathological pathways underlying disease has become a priority. Induced pluripotent stem cell (iPSC) technology is helping to uncover disease mechanisms and develop treatments for RPE diseases, like bestrophinopathies. Here, we provide a comprehensive review of the pathophysiology of bestrophinopathies and highlight how patient-derived iPSC-RPE are being used to test new genomic therapies in vitro.

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