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Increasing the Yield in Targeted Sequencing by Implicating CNV Analysis, Exons and the Overall Variant The Example of Retinal Dystrophies


Affiliation: Bioscientia for Human Genetics, Ingelheim,

Arif O. Khan,


pigmentosa (RP) and Leber amaurosis (LCA) are major of blindness. They result mutations in many genes has long hampered comprehensive analysis. Recently, targeted sequencing (NGS) has proven to overcome this limitation. To “hidden mutations” such as number variations (CNVs) and in non-coding regions, we extended the use of NGS by quantitative readout for the exons of 55 RP and LCA in 126 patients, and by including non-coding 5′ We detected several causative which were key to the diagnosis in unsolved constellations, e.g. point mutations in consanguineous and CNVs complemented apparently recessive alleles. Mutations of exon 1 of EYS revealed its contribution to In view of the high carrier for retinal disease gene in the general population, we considered the variant load in each to assess if a mutation was causative or accidental carriership in patients mutations in several genes or single recessive alleles. For truncating mutations in RP1 . a gene in both recessive and dominant RP, causative in biallelic constellations, to disease when heterozygous on a mutation background of another or even non-pathogenic if close to the Patients with mutations in loci were common, but evidence for di- or oligogenic inheritance. the number of targeted genes

was low compared to previous studies, the detection rate was highest which likely results completeness and depth of coverage, and data analysis. CNV analysis routinely be applied in targeted and mutations in non-coding exons reason to systematically include in disease gene or exome Consideration of all variants is indispensable even truncating mutations may be

Citation: Eisenberger T, Neuhaus C, AO, Decker C, Preising MN, et al. (2013) the Yield in Targeted Next-Generation by Implicating CNV Analysis, Non-Coding and the Overall Variant Load: The of Retinal Dystrophies. PLoS ONE e78496. doi:10.1371/journal.pone.0078496

Editor: Li, National Eye Institute, United of America

Received: July 15, Accepted: September 12, 2013; November 12, 2013

Copyright: © Eisenberger et al. This is an open-access distributed under the terms of the Commons Attribution License, permits unrestricted use, and reproduction in any medium, provided the author and source are credited.

Funding: The authors received no funding for this study.

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interests: TE, CN, CD, AB, CB and HJB are employees of Bioscientia, is part of a publicly traded company. There are no patents, in development or marketed products to This does not alter the adherence to all the PLOS ONE policies on data and materials, as detailed in the guide for authors.


dystrophies result from of photoreceptor and retinal pigment cells. With a prevalence of

1 in they represent the major of hereditary blindness in developed [1]. Apart from the burden, retinal dystrophies contribute to healthcare costs Retinal dystrophies are characterized by genetic heterogeneity, with than 60 genes currently to underlie retinitis pigmentosa the most prevalent subtype affects more than 1.5 people worldwide [3]. Knowing the causative mutation is for several reasons: It provides the for personalized genetic counseling and of the recurrence risk, and it may predict the clinical course (including the of a genetic syndrome). In clinically presentations or ambiguous family the genotype may specify or even the previous diagnosis or the assumed of inheritance. Regarding the progress of therapy approaches for several dystrophies, the genetic diagnosis be an essential prerequisite for gene-specific [3]. [5]. However, from the c.2991+1655AG mutation in previously reported to be present in 20% of with Leber congenital (LCA) and RPGR in male RP [6]. [7].

there is no major mutation or gene for RP and LCA, and clear-cut correlations are largely lacking, prevents efficient targeted sequencing. Because chip-based for previously reported mutations only a fraction of the causative [8]. and gene-by-gene analysis by sequencing is too laborious and expensive, testing has been the exception recently. Now, next-generation (NGS) allows for simultaneous and analysis of all known disease for a given trait.

NGS of 55 genes involved in RP and LCA (the “LCA” was applied for early-onset dystrophies, including infant RP and cone-rod dystrophies, CRD; Data File S1 ) in 126 patients. mutations, including CNVs one to multiple exons, were in the majority of patients and confirmed the genetic heterogeneity. Our findings the immense potential of NGS for diagnostics of dystrophies and shed light on the complexity of this disease

Results and Discussion

Performance of Two NGS in RD Gene Panel Analysis

Volkswagen 412 Variant
Volkswagen 412 Variant
Volkswagen 412 Variant
Volkswagen 412 Variant


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