Scaling New Heights in the Genetic Diagnosis of Inherited Retinal Dystrophies

2019 ◽  
pp. 215-219 ◽  
Author(s):  
Roser Gonzàlez-Duarte ◽  
Marta de Castro-Miró ◽  
Miquel Tuson ◽  
Valeria Ramírez-Castañeda ◽  
Rebeca Valero Gils ◽  
...  
Keyword(s):  
Genetic Diagnosis ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies

scholarly journals Updating the Genetic Landscape of Inherited Retinal Dystrophies

2021 ◽  
Vol 9 ◽  
Author(s):  
Belén García Bohórquez ◽  
Elena Aller ◽  
Ana Rodríguez Muñoz ◽  
Teresa Jaijo ◽  
Gema García García ◽  
...  
Keyword(s):  
Genetic Diagnosis ◽  
Diagnostic Process ◽  
Reproductive Decisions ◽  
Inherited Retinal Dystrophies ◽  
Pathogenic Variants ◽  
Retinal Dystrophies ◽  
Genetic Landscape ◽  
Custom Panel ◽  
Generation Sequencing ◽  
Autosomal Recessive Pattern

Inherited retinal dystrophies (IRD) are a group of diseases characterized by the loss or dysfunction of photoreceptors and a high genetic and clinical heterogeneity. Currently, over 270 genes have been associated with IRD which makes genetic diagnosis very difficult. The recent advent of next generation sequencing has greatly facilitated the diagnostic process, enabling to provide the patients with accurate genetic counseling in some cases. We studied 92 patients who were clinically diagnosed with IRD with two different custom panels. In total, we resolved 53 patients (57.6%); in 12 patients (13%), we found only one mutation in a gene with a known autosomal recessive pattern of inheritance; and 27 patients (29.3%) remained unsolved. We identified 120 pathogenic or likely pathogenic variants; 30 of them were novel. Among the cone-rod dystrophy patients, ABCA4 was the most common mutated gene, meanwhile, USH2A was the most prevalent among the retinitis pigmentosa patients. Interestingly, 10 families carried pathogenic variants in more than one IRD gene, and we identified two deep-intronic variants previously described as pathogenic in ABCA4 and CEP290. In conclusion, the IRD study through custom panel sequencing demonstrates its efficacy for genetic diagnosis, as well as the importance of including deep-intronic regions in their design. This genetic diagnosis will allow patients to make accurate reproductive decisions, enroll in gene-based clinical trials, and benefit from future gene-based treatments.

scholarly journals VarGenius-HZD Allows Accurate Detection of Rare Homozygous or Hemizygous Deletions in Targeted Sequencing Leveraging Breadth of Coverage

Genes ◽  
2021 ◽  
Vol 12 (12) ◽  
pp. 1979
Author(s):  
Francesco Musacchia ◽  
Marianthi Karali ◽  
Annalaura Torella ◽  
Steve Laurie ◽  
Valeria Policastro ◽  
...  
Keyword(s):  
Genetic Diagnosis ◽  
Targeted Sequencing ◽  
Sequencing Data ◽  
Scalable Algorithm ◽  
1000 Genomes ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
Homozygous Deletions ◽  
Selection Of ◽  
Higher Sensitivity

Homozygous deletions (HDs) may be the cause of rare diseases and cancer, and their discovery in targeted sequencing is a challenging task. Different tools have been developed to disentangle HD discovery but a sensitive caller is still lacking. We present VarGenius-HZD, a sensitive and scalable algorithm that leverages breadth-of-coverage for the detection of rare homozygous and hemizygous single-exon deletions (HDs). To assess its effectiveness, we detected both real and synthetic rare HDs in fifty exomes from the 1000 Genomes Project obtaining higher sensitivity in comparison with state-of-the-art algorithms that each missed at least one event. We then applied our tool on targeted sequencing data from patients with Inherited Retinal Dystrophies and solved five cases that still lacked a genetic diagnosis. We provide VarGenius-HZD either stand-alone or integrated within our recently developed software, enabling the automated selection of samples using the internal database. Hence, it could be extremely useful for both diagnostic and research purposes.

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 VarGenius-HZD allows accurate detection of rare homozygous or hemizygous deletions in targeted sequencing leveraging breadth of coverage

2021 ◽  
Author(s):  
Francesco Musacchia ◽  
Marianthi Karali ◽  
Annalaura Torella ◽  
Steve Laurie ◽  
Valeria Policastro ◽  
...  
Keyword(s):  
Genetic Diagnosis ◽  
Targeted Sequencing ◽  
Supplementary Information ◽  
Sequencing Data ◽  
Scalable Algorithm ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
Homozygous Deletions ◽  
Selection Of ◽  
Higher Sensitivity

Motivation: Homozygous deletions (HDs) may be the cause of rare diseases and cancer and their discovery in targeted sequencing is a challenging task. Different tools have been developed to disentangle HD discovery but a sensitive caller is still lacking. Results: We present VarGenius-HZD, a sensitive and scalable algorithm that leverages breadth-of-coverage for the detection of rare homozygous and hemizygous single-exon deletions (HDs). To assess its effectiveness we detected both real and synthetic rare HDs in fifty exomes from the 1000 Genomes Project obtaining higher sensitivity in comparison with state-of-the-art algorithms which missed at least one event each. We then applied our tool on targeted sequencing data from patients with Inherited Retinal Dystrophies and solved five cases that still lacked a genetic diagnosis. Availability and implementation: We provide VarGenius-HZD either stand-alone or integrated within our recently developed software enabling the automated selection of samples using the internal database. Hence, it could be extremely useful for both diagnostic and research purposes. Our tool is available under GNU General Public License, version 3 at: https://github.com/frankMusacchia/VarGenius-HZD Contact: [email protected] Supplementary information is available online.

scholarly journals Genetic landscape of 6089 inherited retinal dystrophies affected cases in Spain and their therapeutic and extended epidemiological implications

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Irene Perea-Romero ◽  
◽  
Gema Gordo ◽  
Ionut F. Iancu ◽  
Marta Del Pozo-Valero ◽  
...  
Keyword(s):  
Genetic Diagnosis ◽  
Cross Sectional Study ◽  
Molecular Techniques ◽  
Cross Sectional ◽  
Autonomous Communities ◽  
Inherited Retinal Dystrophies ◽  
Pathogenic Variants ◽  
Retinal Dystrophies ◽  
Family Pedigree ◽  
Genetic Landscape

AbstractInherited retinal diseases (IRDs), defined by dysfunction or progressive loss of photoreceptors, are disorders characterized by elevated heterogeneity, both at the clinical and genetic levels. Our main goal was to address the genetic landscape of IRD in the largest cohort of Spanish patients reported to date. A retrospective hospital-based cross-sectional study was carried out on 6089 IRD affected individuals (from 4403 unrelated families), referred for genetic testing from all the Spanish autonomous communities. Clinical, demographic and familiar data were collected from each patient, including family pedigree, age of appearance of visual symptoms, presence of any systemic findings and geographical origin. Genetic studies were performed to the 3951 families with available DNA using different molecular techniques. Overall, 53.2% (2100/3951) of the studied families were genetically characterized, and 1549 different likely causative variants in 142 genes were identified. The most common phenotype encountered is retinitis pigmentosa (RP) (55.6% of families, 2447/4403). The most recurrently mutated genes were PRPH2, ABCA4 and RS1 in autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL) NON-RP cases, respectively; RHO, USH2A and RPGR in AD, AR and XL for non-syndromic RP; and USH2A and MYO7A in syndromic IRD. Pathogenic variants c.3386G > T (p.Arg1129Leu) in ABCA4 and c.2276G > T (p.Cys759Phe) in USH2A were the most frequent variants identified. Our study provides the general landscape for IRD in Spain, reporting the largest cohort ever presented. Our results have important implications for genetic diagnosis, counselling and new therapeutic strategies to both the Spanish population and other related populations.

scholarly journals Identification of a novel RPGR mutation associated with X-linked cone-rod dystrophy in a Chinese family

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yafang Wang ◽  
Shu Liu ◽  
Yuanqi Zhai ◽  
Yang Liu ◽  
Xiaoling Wan ◽  
...  
Keyword(s):  
Novel Mutation ◽  
Genetic Diagnosis ◽  
Chinese Family ◽  
Central Visual Field ◽  
Mammalian Expression ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
Whole Exome ◽  
Vision Defects ◽  
Female Carriers

Abstract Background Cone-rod dystrophy (CORD) is a group of inherited retinal dystrophies, characterized by decreased visual acuity, color vision defects, photophobia, and decreased sensitivity in the central visual field. Our study has identified a novel pathogenic variant associated with X-linked cone-rod dystrophy (XLCORD) in a Chinese family. Methods All six family members, including the proband, affected siblings, cousins and female carriers, have underwent thorough ophthalmic examinations. The whole exome sequencing was performed for the proband, followed by Sanger sequencing for spilt-sample validation. A mammalian expression vector (AAV-MCS) with mutated retinitis pigmentosa GTPase regulator (RPGR) sequence was expressed in HEK293 T cells. The mutated protein was verified by Western blotting and immunohistochemistry. Results A novel mutation in the RPGR gene (c.2383G > T, p.E795X) is identified to be responsible for CORD pathogenesis. Conclusions Our findings have expanded the spectrum of CORD-associated mutations in RPGR gene and serve as a basis for genetic diagnosis for X-linked CORD.

scholarly journals The Genetic Landscape of Inherited Retinal Diseases in a Mexican Cohort: Genes, Mutations and Phenotypes

Genes ◽  
2021 ◽  
Vol 12 (11) ◽  
pp. 1824
Author(s):  
Cristina Villanueva-Mendoza ◽  
Miquel Tuson ◽  
David Apam-Garduño ◽  
Marta de Castro-Miró ◽  
Raul Tonda ◽  
...  
Keyword(s):  
Diagnostic Yield ◽  
Novel Mutation ◽  
Genetic Diagnosis ◽  
Inherited Retinal Dystrophies ◽  
Pathogenic Variants ◽  
Retinal Dystrophies ◽  
Whole Exome ◽  
Genetic Landscape ◽  
Genetic Features ◽  
Gene Panels

In this work, we aimed to provide the genetic diagnosis of a large cohort of patients affected with inherited retinal dystrophies (IRDs) from Mexico. Our data add valuable information to the genetic portrait in rare ocular diseases of Mesoamerican populations, which are mostly under-represented in genetic studies. A cohort of 144 unrelated probands with a clinical diagnosis of IRD were analyzed by next-generation sequencing using target gene panels (overall including 346 genes and 65 intronic sequences). Four unsolved cases were analyzed by whole-exome sequencing (WES). The pathogenicity of new variants was assessed by in silico prediction algorithms and classified following the American College of Medical Genetics and Genomics (ACMG) guidelines. Pathogenic or likely pathogenic variants were identified in 105 probands, with a final diagnostic yield of 72.9%; 17 cases (11.8%) were partially solved. Eighteen patients were clinically reclassified after a genetic diagnostic test (17.1%). In our Mexican cohort, mutations in 48 genes were found, with ABCA4, CRB1, RPGR and USH2A as the major contributors. Notably, over 50 new putatively pathogenic variants were identified. Our data highlight cases with relevant clinical and genetic features due to mutations in the RAB28 and CWC27 genes, enrich the novel mutation repertoire and expand the IRD landscape of the Mexican population.

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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