scholarly journals Whole exome sequencing in 17 consanguineous Iranian pedigrees expands the mutational spectrum of inherited retinal dystrophies

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Atta Ur Rehman ◽  
Neda Sepahi ◽  
Nicola Bedoni ◽  
Zeinab Ravesh ◽  
Arash Salmaninejad ◽  
...  
Keyword(s):  
Disease Genes ◽  
Homozygous State ◽  
Traditional Practice ◽  
Genomic Variants ◽  
Mutational Spectrum ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
Whole Exome ◽  
Human Disorders ◽  
Generation Sequencing

AbstractInherited retinal dystrophies (IRDs) constitute one of the most heterogeneous groups of Mendelian human disorders. Using autozygome-guided next-generation sequencing methods in 17 consanguineous pedigrees of Iranian descent with isolated or syndromic IRD, we identified 17 distinct genomic variants in 11 previously-reported disease genes. Consistent with a recessive inheritance pattern, as suggested by pedigrees, variants discovered in our study were exclusively bi-allelic and mostly in a homozygous state (in 15 families out of 17, or 88%). Out of the 17 variants identified, 5 (29%) were never reported before. Interestingly, two mutations (GUCY2D:c.564dup, p.Ala189ArgfsTer130 and TULP1:c.1199G > A, p.Arg400Gln) were also identified in four separate pedigrees (two pedigrees each). In addition to expanding the mutational spectrum of IRDs, our findings confirm that the traditional practice of endogamy in the Iranian population is a prime cause for the appearance of IRDs.

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 Unique Variant Spectrum in a Jordanian Cohort with Inherited Retinal Dystrophies

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 593
Author(s):  
Bilal Azab ◽  
Zain Dardas ◽  
Dunia Aburizeg ◽  
Muawyah Al-Bdour ◽  
Mohammed Abu-Ameerh ◽  
...  
Keyword(s):  
Sanger Sequencing ◽  
Segregation Analysis ◽  
Clinical Findings ◽  
Genetic Defects ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
Large Patient ◽  
Whole Exome ◽  
Sequence Variations ◽  
Powerful Approach

Whole Exome Sequencing (WES) is a powerful approach for detecting sequence variations in the human genome. The aim of this study was to investigate the genetic defects in Jordanian patients with inherited retinal dystrophies (IRDs) using WES. WES was performed on proband patients’ DNA samples from 55 Jordanian families. Sanger sequencing was used for validation and segregation analysis of the detected, potential disease-causing variants (DCVs). Thirty-five putatively causative variants (6 novel and 29 known) in 21 IRD-associated genes were identified in 71% of probands (39 of the 55 families). Three families showed phenotypes different from the typically reported clinical findings associated with the causative genes. To our knowledge, this is the largest genetic analysis of IRDs in the Jordanian population to date. Our study also confirms that WES is a powerful tool for the molecular diagnosis of IRDs in large patient cohorts.

scholarly journals Gene Therapy in Retinal Dystrophies

2019 ◽  
Vol 20 (22) ◽  
pp. 5722 ◽  
Author(s):  
Ziccardi ◽  
Cordeddu ◽  
Gaddini ◽  
Matteucci ◽  
Parravano ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Current Knowledge ◽  
Disease Genes ◽  
New Era ◽  
Gene Therapy Approach ◽  
Inherited Retinal Dystrophies ◽  
Diagnosis And Prognosis ◽  
Retinal Dystrophies ◽  
Degenerative Disorders

Inherited retinal dystrophies (IRDs) are a group of clinically and genetically heterogeneous degenerative disorders. To date, mutations have been associated with IRDs in over 270 disease genes, but molecular diagnosis still remains elusive in about a third of cases. The methodologic developments in genome sequencing techniques that we have witnessed in this last decade have represented a turning point not only in diagnosis and prognosis but, above all, in the identification of new therapeutic perspectives. The discovery of new disease genes and pathogenetic mechanisms underlying IRDs has laid the groundwork for gene therapy approaches. Several clinical trials are ongoing, and the recent approval of Luxturna, the first gene therapy product for Leber congenital amaurosis, marks the beginning of a new era. Due to its anatomical and functional characteristics, the retina is the organ of choice for gene therapy, although there are quite a few difficulties in the translational approaches from preclinical models to humans. In the first part of this review, an overview of the current knowledge on methodological issues and future perspectives of gene therapy applied to IRDs is discussed; in the second part, the state of the art of clinical trials on the gene therapy approach in IRDs is illustrated.

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 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 Application of Whole Exome and Targeted Panel Sequencing in the Clinical Molecular Diagnosis of 319 Chinese Families with Inherited Retinal Dystrophy and Comparison Study

Genes ◽  
2018 ◽  
Vol 9 (7) ◽  
pp. 360 ◽  
Author(s):  
Likun Wang ◽  
Jinlu Zhang ◽  
Ningning Chen ◽  
Lei Wang ◽  
Fengsheng Zhang ◽  
...  
Keyword(s):  
Sanger Sequencing ◽  
Diagnostic Yield ◽  
Retinal Dystrophy ◽  
Chinese Patients ◽  
Eye Disease ◽  
Disease Genes ◽  
Inherited Retinal Dystrophies ◽  
Whole Exome ◽  
Pros And Cons ◽  
Panel Sequencing

Inherited retinal dystrophies (IRDs) are a group of clinically and genetically heterogeneous diseases involving more than 280 genes and no less than 20 different clinical phenotypes. In this study, our aims were to identify the disease-causing gene variants of 319 Chinese patients with IRD, and compare the pros and cons of targeted panel sequencing and whole exome sequencing (WES). Patients were assigned for analysis with a hereditary eye disease enrichment panel (HEDEP) or WES examination based on time of recruitment. This HEDEP was able to capture 441 hereditary eye disease genes, which included 291 genes related to IRD. As RPGR ORF15 was difficult to capture, all samples were subjected to Sanger sequencing for this region. Among the 163 disease-causing variants identified in this study, 73 had been previously reported, and the other 90 were novel. Genes most commonly implicated in different inheritances of IRDs in this cohort were presented. HEDEP and WES achieved diagnostic yield with 41.2% and 33.0%, respectively. In addition, nine patients were found to carry pathogenic mutations in the RPGR ORF15 region with Sanger sequencing. Our study demonstrates that HEDEP can be used as a first-tier test for patients with IRDs.

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