These authors contributed equally to this work
Next-generation genetic testing for retinitis pigmentosa†
Article first published online: 19 MAR 2012
© 2012 Wiley Periodicals, Inc.
Special Issue: Focus on CNV Detection with Diagnostic Arrays
Volume 33, Issue 6, pages 963–972, June 2012
How to Cite
Neveling, K., Collin, R. W.J., Gilissen, C., van Huet, R. A.C., Visser, L., Kwint, M. P., Gijsen, S. J., Zonneveld, M. N., Wieskamp, N., de Ligt, J., Siemiatkowska, A. M., Hoefsloot, L. H., Buckley, M. F., Kellner, U., Branham, K. E., den Hollander, A. I., Hoischen, A., Hoyng, C., Klevering, B. J., van den Born, L. I., Veltman, J. A., Cremers, F. P.M. and Scheffer, H. (2012), Next-generation genetic testing for retinitis pigmentosa. Hum. Mutat., 33: 963–972. doi: 10.1002/humu.22045
Communicated by Paolo M. Fortina
- Issue published online: 7 MAY 2012
- Article first published online: 19 MAR 2012
- Accepted manuscript online: 14 FEB 2012 04:38PM EST
- Manuscript Accepted: 18 JAN 2012
- Manuscript Received: 19 OCT 2011
- European Community's Seventh Framework Program FP7/2007-2013. Grant Number: #223143; TECHGENE
- The Netherlands Organization for Health Research and Development. Grant Number: ZonMW grants 917-66-363 and 911-08-025
- TOP-grant. Grant Number: 40-00812-98-09047
- Algemene Nederlandse Vereniging ter Voorkoming van Blindheid; Gelderse Blinden Stichting; Landelijke Stichting voor Blinden en Slechtzienden; Retina Nederland; Stichting Oogfonds Nederland; Rotterdamse Stichting Blindenbelangen; Foundation Fighting Blindness.
Vol. 34, Issue 8, 1181, Article first published online: 12 JUN 2013
- DNA diagnostics;
- clinical molecular diagnostics;
- retinitis pigmentosa;
Molecular diagnostics for patients with retinitis pigmentosa (RP) has been hampered by extreme genetic and clinical heterogeneity, with 52 causative genes known to date. Here, we developed a comprehensive next-generation sequencing (NGS) approach for the clinical molecular diagnostics of RP. All known inherited retinal disease genes (n = 111) were captured and simultaneously analyzed using NGS in 100 RP patients without a molecular diagnosis. A systematic data analysis pipeline was developed and validated to prioritize and predict the pathogenicity of all genetic variants identified in each patient, which enabled us to reduce the number of potential pathogenic variants from approximately 1,200 to zero to nine per patient. Subsequent segregation analysis and in silico predictions of pathogenicity resulted in a molecular diagnosis in 36 RP patients, comprising 27 recessive, six dominant, and three X-linked cases. Intriguingly, De novo mutations were present in at least three out of 28 isolated cases with causative mutations. This study demonstrates the enormous potential and clinical utility of NGS in molecular diagnosis of genetically heterogeneous diseases such as RP. De novo dominant mutations appear to play a significant role in patients with isolated RP, having major implications for genetic counselling. Hum Mutat 33:963–972, 2012. © 2012 Wiley Periodicals, Inc.