Eisenberger, Tobias, Neuhaus, Christine, Khan, Arif O., Decker, Christian, Preising, Markus N., Friedburg, Christoph, Bieg, Anika, Gliem, Martin, Issa, Peter Charbel ORCID: 0000-0002-0351-6673, Holz, Frank G., Baig, Shahid M., Hellenbroich, Yorck, Galvez, Alberto, Platzer, Konrad ORCID: 0000-0001-6127-6308, Wollnik, Bernd, Laddach, Nadja, Ghaffari, Saeed Reza, Rafati, Maryam, Botzenhart, Elke, Tinschert, Sigrid, Boerger, Doris, Bohring, Axel, Schreml, Julia, Koertge-Jung, Stefani, Schell-Apacik, Chayim, Bakur, Khadijah ORCID: 0000-0002-0668-1762, Al-Aama, Jumana Y., Neuhann, Teresa, Herkenrath, Peter, Nuernberg, Gudrun, Nuernburg, Peter, Davis, John S., Gal, Andreas, Bergmann, Carsten, Lorenz, Birgit and Bolz, Hanno J. (2013). Increasing the Yield in Targeted Next-Generation Sequencing by Implicating CNV Analysis, Non-Coding Exons and the Overall Variant Load: The Example of Retinal Dystrophies. PLoS One, 8 (11). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1932-6203

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Abstract

Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are major causes of blindness. They result from mutations in many genes which has long hampered comprehensive genetic analysis. Recently, targeted next-generation sequencing (NGS) has proven useful to overcome this limitation. To uncover hidden mutations such as copy number variations (CNVs) and mutations in non-coding regions, we extended the use of NGS data by quantitative readout for the exons of 55 RP and LCA genes in 126 patients, and by including non-coding 59 exons. We detected several causative CNVs which were key to the diagnosis in hitherto unsolved constellations, e. g. hemizygous point mutations in consanguineous families, and CNVs complemented apparently monoallelic recessive alleles. Mutations of non-coding exon 1 of EYS revealed its contribution to disease. In view of the high carrier frequency for retinal disease gene mutations in the general population, we considered the overall variant load in each patient to assess if a mutation was causative or reflected accidental carriership in patients with mutations in several genes or with single recessive alleles. For example, truncating mutations in RP1, a gene implicated in both recessive and dominant RP, were causative in biallelic constellations, unrelated to disease when heterozygous on a biallelic mutation background of another gene, or even non-pathogenic if close to the C-terminus. Patients with mutations in several loci were common, but without evidence for di- or oligogenic inheritance. Although the number of targeted genes was low compared to previous studies, the mutation detection rate was highest (70%) which likely results from completeness and depth of coverage, and quantitative data analysis. CNV analysis should routinely be applied in targeted NGS, and mutations in non-coding exons give reason to systematically include 5'-UTRs in disease gene or exome panels. Consideration of all variants is indispensable because even truncating mutations may be misleading.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Eisenberger, TobiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neuhaus, ChristineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Khan, Arif O.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Decker, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Preising, Markus N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Friedburg, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bieg, AnikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gliem, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Issa, Peter CharbelUNSPECIFIEDorcid.org/0000-0002-0351-6673UNSPECIFIED
Holz, Frank G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baig, Shahid M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hellenbroich, YorckUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Galvez, AlbertoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Platzer, KonradUNSPECIFIEDorcid.org/0000-0001-6127-6308UNSPECIFIED
Wollnik, BerndUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Laddach, NadjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ghaffari, Saeed RezaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rafati, MaryamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Botzenhart, ElkeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tinschert, SigridUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boerger, DorisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bohring, AxelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schreml, JuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koertge-Jung, StefaniUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schell-Apacik, ChayimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bakur, KhadijahUNSPECIFIEDorcid.org/0000-0002-0668-1762UNSPECIFIED
Al-Aama, Jumana Y.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neuhann, TeresaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herkenrath, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, GudrunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernburg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Davis, John S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gal, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bergmann, CarstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lorenz, BirgitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bolz, Hanno J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-472026
DOI: 10.1371/journal.pone.0078496
Journal or Publication Title: PLoS One
Volume: 8
Number: 11
Date: 2013
Publisher: PUBLIC LIBRARY SCIENCE
Place of Publication: SAN FRANCISCO
ISSN: 1932-6203
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
DOMINANT RETINITIS-PIGMENTOSA; LEBER CONGENITAL AMAUROSIS; IMPERFECTA TYPE-V; LINKAGE ANALYSIS; MISSENSE MUTATIONS; MESSENGER-RNA; RP1 MUTATIONS; GENE ACCOUNT; DISEASE; GENOMEMultiple languages
Multidisciplinary SciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/47202

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