Universität zu Köln

Tiwari, Amit, Lemke, Johannes, Altmueller, Janine, Thiele, Holger, Glaus, Esther, Fleischhauer, Johannes, Nuernberg, Peter, Neidhardt, John and Berger, Wolfgang (2016). Identification of Novel and Recurrent Disease-Causing Mutations in Retinal Dystrophies Using Whole Exome Sequencing (WES): Benefits and Limitations. PLoS One, 11 (7). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1932-6203

Full text not available from this repository.

Abstract

Inherited retinal dystrophies (IRDs) are Mendelian diseases with tremendous genetic and phenotypic heterogeneity. Identification of the underlying genetic basis of these dystrophies is therefore challenging. In this study we employed whole exome sequencing (WES) in 11 families with IRDs and identified disease-causing variants in 8 of them. Sequence analysis of about 250 IRD-associated genes revealed 3 previously reported disease-associated variants in RHO, BEST1 and RP1. We further identified 5 novel pathogenic variants in RPGRIP1 (p.Ser964Profs*37), PRPF8 (p.Tyr2334Leufs*51), CDHR1 (p.Pro133Arg and c.439-17G>A) and PRPF31 (p.Glu183_Met193dup). In addition to confirming the power of WES in genetic diagnosis of IRDs, we document challenges in data analysis and show cases where the underlying genetic causes of IRDs were missed by WES and required additional techniques. For example, the mutation c.439-17G>A in CDHR1 would be rated unlikely applying the standardWES analysis. Only transcript analysis in patient fibroblasts confirmed the pathogenic nature of this variant that affected splicing of CDHR1 by activating a cryptic splice-acceptor site. In another example, a 33-base pair duplication in PRPF31 missed by WES could be identified only via targeted analysis by Sanger sequencing. We discuss the advantages and challenges of using WES to identify mutations in heterogeneous diseases like IRDs.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Tiwari, Amit UNSPECIFIED UNSPECIFIED UNSPECIFIED Lemke, Johannes UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Thiele, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Glaus, Esther UNSPECIFIED UNSPECIFIED UNSPECIFIED Fleischhauer, Johannes UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Neidhardt, John UNSPECIFIED UNSPECIFIED UNSPECIFIED Berger, Wolfgang UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-269980
DOI:	10.1371/journal.pone.0158692
Journal or Publication Title:	PLoS One
Volume:	11
Number:	7
Date:	2016
Publisher:	PUBLIC LIBRARY SCIENCE
Place of Publication:	SAN FRANCISCO
ISSN:	1932-6203
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language AUTOSOMAL RECESSIVE BESTROPHINOPATHY; DOMINANT RETINITIS-PIGMENTOSA; SPLICING FACTOR PRP8; MISSENSE SUBSTITUTIONS; MACULAR DEGENERATION; PROTEIN FUNCTION; DOMAIN; VARIANTS; GENES; BRR2 Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/26998