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Genomic screening of ABCA4 and array CGH analysis underline the genetic variability of Greek patients with inherited retinal diseases.

ABSTRACT: BACKGROUND:Retinal dystrophies are a clinically and genetically heterogeneous group of disorders which affect more than two million people worldwide. The present study focused on the role of the ABCA4 gene in the pathogenesis of hereditary retinal dystrophies (autosomal recessive Stargardt disease, autosomal recessive cone-rod dystrophy, and autosomal recessive retinitis pigmentosa) in patients of Greek origin. MATERIALS AND METHODS:Our cohort included 26 unrelated patients and their first degree healthy relatives. The ABCA4 mutation screening involved Sanger sequencing of all exons and flanking regions. Evaluation of novel variants included sequencing of control samples, family segregation analysis and characterization by in silico prediction tools. Twenty five patients were also screened for copy number variations by array-comparative genomic hybridization. RESULTS:Excluding known disease-causing mutations and polymorphisms, two novel variants were identified in coding and non-coding regions of ABCA4. Array-CGH analysis revealed two partial deletions of USH2A and MYO3A in two patients with nonsyndromic autosomal recessive retinitis pigmentosa. CONCLUSIONS:The ABCA4 mutation spectrum in Greek patients differs from other populations. Bioinformatic tools, segregation analysis along with clinical data from the patients seemed to be crucial for the evaluation of genetic variants and particularly for the discrimination between causative and non-causative variants.

SUBMITTER: Tsipi M

PROVIDER: S-EPMC4792891 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Genomic screening of ABCA4 and array CGH analysis underline the genetic variability of Greek patients with inherited retinal diseases.

Tsipi Maria M Tzetis Maria M Kosma Konstantina K Moschos Marilita M Braoudaki Maria M Poulou Myrto M Kanavakis Emmanuel E Kitsiou-Tzeli Sofia S

Meta gene 20160216

<h4>Background</h4>Retinal dystrophies are a clinically and genetically heterogeneous group of disorders which affect more than two million people worldwide. The present study focused on the role of the ABCA4 gene in the pathogenesis of hereditary retinal dystrophies (autosomal recessive Stargardt disease, autosomal recessive cone-rod dystrophy, and autosomal recessive retinitis pigmentosa) in patients of Greek origin.<h4>Materials and methods</h4>Our cohort included 26 unrelated patients and th ...[more]

PMID: 27014590

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Project description:BackgroundArray-based Comparative Genomic Hybridization (CGH) data have been used to infer phylogenetic relationships. However, the reliability of array CGH analysis to determine evolutionary relationships has not been well established. In most CGH work, all species and strains are compared to a single reference species, whose genome was used to design the array. In the accompanying work, we critically evaluated CGH-based phylogeny using simulated competitive hybridization data. This work showed that a limited number of conditions, principally the tree topology and placement of the reference taxon in the tree, had a strong effect on the ability to recover the correct tree topology. Here, we add to our simulation study by testing the use of CGH as a phylogenetic tool with experimental CGH data from competitive hybridizations between N. crassa and other Neurospora species. In the discussion, we add to our empirical study of Neurospora by reanalyzing of data from a previous CGH phylogenetic analysis of the yeast sensu stricto complex.ResultsArray ratio data for Neurospora and related species were normalized with loess, robust spline, and linear ratio based methods, and then used to construct Neighbor-Joining and parsimony trees. These trees were compared to published phylogenetic analyses for Neurospora based on multilocus sequence analysis (MLSA). For the Neurospora dataset, the best combination of methods resulted in recovery of the MLSA tree topology less than half the time. Our reanalysis of a yeast dataset found that trees identical to established phylogeny were recovered only by pruning taxa - including the reference taxon - from the analysis.ConclusionOur results indicate that CGH data can be problematic for phylogenetic analysis. Success fluctuates based on the methods utilized to construct the tree and the taxa included. Selective pruning of the taxa improves the results - an impractical approach for normal phylogenetic analysis. From the more successful methods we make suggestions on the normalization and post-normalization methods that work best in estimating genetic distance between taxa.

Project description:Inherited retinal diseases (IRDs) are a genetically and phenotypically heterogeneous group of genetic eye disorders. There are more than 300 disease entities, and together this group of disorders affects millions of people globally and is a frequent cause of blindness or low-vision certification. However, each type is rare or ultra-rare. Characteristically, the impaired vision in IRDs is due to retinal photoreceptor dysfunction and loss resulting from mutation in a gene that codes for a retinal protein. Historically, IRDs have been considered incurable and individuals living with these blinding conditions could be offered only supportive care. However, the treatment landscape for IRDs is beginning to evolve. Progress is being made, driven by improvements in understanding of genotype-phenotype relationships, through advances in molecular genetic testing and retinal imaging. Alongside this expanding knowledge of IRDs, the current era of precision medicine is fueling a growth in targeted therapies. This has resulted in the first treatment for an IRD being approved. Several other therapies are currently in development in the IRD space, including RNA-based therapies, gene-based therapies (such as augmentation therapy and gene editing), cell therapy, visual prosthetics, and optogenetics. RNA-based therapies are a novel approach within precision medicine that have demonstrated success, particularly in rare diseases. Three antisense oligonucleotides (AONs) are currently in development for the treatment of specific IRD subtypes. These RNA-based therapies bring several key advantages in the setting of IRDs, and the potential to bring meaningful vision benefit to individuals living with inherited blinding disorders. This review will examine the increasing breadth and relevance of RNA-based therapies in clinical medicine, explore the key features that make AONs suitable for treating genetic eye diseases, and provide an overview of the three-leading investigational AONs in clinical trials.

Dataset Information

Genomic screening of ABCA4 and array CGH analysis underline the genetic variability of Greek patients with inherited retinal diseases.

Publications

Genomic screening of ABCA4 and array CGH analysis underline the genetic variability of Greek patients with inherited retinal diseases.

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