Next-generation genetic testing for retinitis pigmentosa

Kornelia Neveling, Rob W J Collin, Christian Gilissen, Ramon A C van Huet, Linda Visser, Michael P Kwint, Sabine J Gijsen, Marijke N Zonneveld, Nienke Wieskamp, Joep de Ligt, Anna M Siemiatkowska, Lies H Hoefsloot, Michael F Buckley, Ulrich Kellner, Kari E Branham, Anneke I den Hollander, Alexander Hoischen, Carel Hoyng, B Jeroen Klevering, L Ingeborgh van den BornJoris A Veltman, Frans P M Cremers, Hans Scheffer

Research output: Contribution to journalArticleResearchpeer-review


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.

Original languageEnglish
Pages (from-to)963-72
Number of pages10
JournalHuman Mutation
Issue number6
Publication statusPublished - Jun 2012


  • Alleles
  • Computational Biology/methods
  • Female
  • Genetic Variation
  • Genotype
  • High-Throughput Nucleotide Sequencing/methods
  • Humans
  • Male
  • Mutation
  • Pedigree
  • Phenotype
  • Quality Control
  • Reproducibility of Results
  • Retinitis Pigmentosa/diagnosis


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