Universität zu Köln

Birtel, Johannes, Gliem, Martin, Mangold, Elisabeth, Mueller, Philipp L., Holz, Frank G., Neuhaus, Christine, Lenzner, Steffen, Zahnleiter, Diana, Betz, Christian, Eisenberger, Tobias, Bolz, Hanno J. and Issa, Peter Charbel ORCID: 0000-0002-0351-6673 (2018). Next-generation sequencing identifies unexpected genotype-phenotype correlations in patients with retinitis pigmentosa. PLoS One, 13 (12). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1932-6203

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Abstract

Retinitis pigmentosa (RP) is an inherited degenerative disease causing severe retinal dystrophy and visual impairment mainly with onset in infancy or adolescence. Targeted next-generation sequencing (NGS) has become an efficient tool to encounter the enormous genetic heterogeneity of diverse retinal dystrophies, including RP. To identify disease-causing mutations in unselected, consecutive RP patients, we conducted Sanger sequencing of genes commonly involved in the suspected genetic RP subtype, followed by targeted large-panel NGS if no mutation was identified, or NGS as primary analysis. A high (70%) detection rate of disease-causing mutations was achieved in a large cohort of 116 unrelated patients. About half (48%) of the solved RP cases were explained by mutations in four genes: RPGR, EYS, PRPF31 and USH2A. Overall, 110 different mutations distributed across 30 different genes were detected, and 46 of these mutations were novel. A molecular diagnosis was achieved in the majority (82-100%) of patients if the family history was suggestive for a particular mode of inheritance, but only in 60% in cases of sporadic RP. The diagnostic potential of extensive molecular analysis in a routine setting is also illustrated by the identification of unexpected genotype-phenotype correlations for RP patients with mutations in CRX, CEP290, RPGRIP1, MFSD8. Furthermore, we identified numerous mutations in autosomal dominant (PRPF31, PRPH2, CRX) and X-linked (RPGR) RP genes in patients with sporadic RP. Variants in RP2 and RPGR were also found in female RP patients with apparently sporadic or dominant disease. In summary, this study demonstrates that massively parallel sequencing of all known retinal dystrophy genes is a valuable diagnostic approach for RP patients.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Birtel, Johannes UNSPECIFIED UNSPECIFIED UNSPECIFIED Gliem, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Mangold, Elisabeth UNSPECIFIED UNSPECIFIED UNSPECIFIED Mueller, Philipp L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Holz, Frank G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Neuhaus, Christine UNSPECIFIED UNSPECIFIED UNSPECIFIED Lenzner, Steffen UNSPECIFIED UNSPECIFIED UNSPECIFIED Zahnleiter, Diana UNSPECIFIED UNSPECIFIED UNSPECIFIED Betz, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Eisenberger, Tobias UNSPECIFIED UNSPECIFIED UNSPECIFIED Bolz, Hanno J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Issa, Peter Charbel UNSPECIFIED orcid.org/0000-0002-0351-6673 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-162138
DOI:	10.1371/journal.pone.0207958
Journal or Publication Title:	PLoS One
Volume:	13
Number:	12
Date:	2018
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 LEBER CONGENITAL AMAUROSIS; COMPREHENSIVE MOLECULAR DIAGNOSIS; CONE-ROD DYSTROPHY; FUNDUS AUTOFLUORESCENCE; INCOMPLETE PENETRANCE; VISUAL FUNCTION; FREQUENT CAUSE; MUTATIONS; GENE; RPGR Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/16213