Abstract
Hereditary retinal dystrophies (RD) constitute a group of blinding diseases that are characterized by clinical variability and pronounced genetic heterogeneity. The different forms of RD can be caused by mutations in >100 genes, including >1600 exons. Consequently, next generation sequencing (NGS) technologies are among the most promising approaches to identify mutations in RD. So far, NGS is not routinely used in gene diagnostics. We developed a diagnostic NGS pipeline to identify mutations in 170 genetically and clinically unselected RD patients. NGS was applied to 105 RD-associated genes. Underrepresented regions were examined by Sanger sequencing. The NGS approach was successfully established using cases with known sequence alterations. Depending on the initial clinical diagnosis, we identified likely causative mutations in 55% of retinitis pigmentosa and 80% of Bardet–Biedl or Usher syndrome cases. Seventy-one novel mutations in 40 genes were newly associated with RD. The genes USH2A, EYS, ABCA4, and RHO were more frequently affected than others. Occasionally, cases carried mutations in more than one RD-associated gene. In addition, we found possible dominant de-novo mutations in cases with sporadic RD, which implies consequences for counseling of patients and families. NGS-based mutation analyses are reliable and cost-efficient approaches in gene diagnostics of genetically heterogeneous diseases like RD.
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Acknowledgements
We would like to thank all patients for participating in this study. We are grateful for technical assistance from Esther Glaus and Mariana Wittmer. We thank Detlef Boehm for his help in setting up the first versions of the panel. He was employed by CeGaT during that time. This work was in part supported by a grant of the BMBF (01GM1108A to BW and SK) and the Forschungskredit of the University of Zurich (to JN).
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Glöckle, N., Kohl, S., Mohr, J. et al. Panel-based next generation sequencing as a reliable and efficient technique to detect mutations in unselected patients with retinal dystrophies. Eur J Hum Genet 22, 99–104 (2014). https://doi.org/10.1038/ejhg.2013.72
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DOI: https://doi.org/10.1038/ejhg.2013.72
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