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  Screening for single nucleotide variants, small indels and exon deletions with a next-generation sequencing based gene panel approach for Usher syndrome

Krawitz, P. M., Schiska, D., Krüger, U., Appelt, S., Heinrich, V., Parkhomchuk, D., et al. (2014). Screening for single nucleotide variants, small indels and exon deletions with a next-generation sequencing based gene panel approach for Usher syndrome. Molecular Genetics and Genomic Medicine, 2(5), 393-401. doi:10.1002/mgg3.92.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0025-7901-3 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0027-A89C-E
Genre: Journal Article

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 Creators:
Krawitz, P. M., Author
Schiska, D., Author
Krüger, U., Author
Appelt, S., Author
Heinrich, V., Author
Parkhomchuk, D.1, Author              
Timmermann, B.2, Author              
Millan, J. M., Author
Robinson, P. N., Author
Mundlos, S.3, Author              
Hecht, J.3, Author              
Gross, M., Author
Affiliations:
1Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433550              
2Sequencing (Head: Bernd Timmermann), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479670              
3Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              

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Free keywords: Gene panel diagnostics, next-generation sequencing, Usher syndrome
 Abstract: Usher syndrome is an autosomal recessive disorder characterized both by deafness and blindness. For the three clinical subtypes of Usher syndrome causal mutations in altogether 12 genes and a modifier gene have been identified. Due to the genetic heterogeneity of Usher syndrome, the molecular analysis is predestined for a comprehensive and parallelized analysis of all known genes by next-generation sequencing (NGS) approaches. We describe here the targeted enrichment and deep sequencing for exons of Usher genes and compare the costs and workload of this approach compared to Sanger sequencing. We also present a bioinformatics analysis pipeline that allows us to detect single-nucleotide variants, short insertions and deletions, as well as copy number variations of one or more exons on the same sequence data. Additionally, we present a flexible in silico gene panel for the analysis of sequence variants, in which newly identified genes can easily be included. We applied this approach to a cohort of 44 Usher patients and detected biallelic pathogenic mutations in 35 individuals and monoallelic mutations in eight individuals of our cohort. Thirty-nine of the sequence variants, including two heterozygous deletions comprising several exons of USH2A, have not been reported so far. Our NGS-based approach allowed us to assess single-nucleotide variants, small indels, and whole exon deletions in a single test. The described diagnostic approach is fast and cost-effective with a high molecular diagnostic yield.

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Language(s): eng - English
 Dates: 2014-06-152014-09
 Publication Status: Published in print
 Pages: -
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 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1002/mgg3.92
ISSN: 2324-9269 (Electronic)
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Title: Molecular Genetics and Genomic Medicine
Source Genre: Journal
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Publ. Info: National Center for Biotechnology Information, U.S. National Library of Medicine
Pages: - Volume / Issue: 2 (5) Sequence Number: - Start / End Page: 393 - 401 Identifier: -