September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Whole Genome Sequencing identifies a structural variant in the EYS gene in retinitis pigmentosa patients.
Author Affiliations & Notes
  • Katarina Cisarova
    Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
  • Nicola Bedoni
    Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
  • Rocio Sanchez-Alcudia
    Department of Genetics, IIS-Fundacion Jimenez Díaz University Hospital, Madrid, Spain
  • Beryl Royer-Bertrand
    Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
  • Almudena Avila-Fernandez
    Department of Genetics, IIS-Fundacion Jimenez Díaz University Hospital, Madrid, Spain
  • Marta Corton
    Department of Genetics, IIS-Fundacion Jimenez Díaz University Hospital, Madrid, Spain
  • Olga Zurita
    Department of Genetics, IIS-Fundacion Jimenez Díaz University Hospital, Madrid, Spain
  • Sara Balzano
    Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
  • Konstantinos Nikopoulos
    Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
  • Ayuso Carmen
    Department of Genetics, IIS-Fundacion Jimenez Díaz University Hospital, Madrid, Spain
  • Carlo Rivolta
    Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
  • Footnotes
    Commercial Relationships   Katarina Cisarova, None; Nicola Bedoni, None; Rocio Sanchez-Alcudia, None; Beryl Royer-Bertrand, None; Almudena Avila-Fernandez, None; Marta Corton, None; Olga Zurita, None; Sara Balzano, None; Konstantinos Nikopoulos, None; Ayuso Carmen, None; Carlo Rivolta, None
  • Footnotes
    Support  Swiss National Science Foundation Grant #310030-156260
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 673. doi:
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      Katarina Cisarova, Nicola Bedoni, Rocio Sanchez-Alcudia, Beryl Royer-Bertrand, Almudena Avila-Fernandez, Marta Corton, Olga Zurita, Sara Balzano, Konstantinos Nikopoulos, Ayuso Carmen, Carlo Rivolta; Whole Genome Sequencing identifies a structural variant in the EYS gene in retinitis pigmentosa patients.. Invest. Ophthalmol. Vis. Sci. 2016;57(12):673.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : To study the genetic basis of autosomal recessive Retinitis Pigmentosa (arRP) in a Spanish family negative for mutations, as investigated by Whole Exome Sequencing (WES), and to highlight the advantages of Whole Genome Sequencing (WGS) versus WES.

Methods :
WES was performed on the DNA of two siblings suffering from arRP, born from healthy and unrelated parents. Subsequently, one of the affected individuals was subjected to WGS analyses using the Complete Genomics platform. The generated genome data were processed using an expert in-house in silico pipeline.

Results : Following our analytical pipeline, the nearly 4 million DNA variants that were generated by WGS of the proband were reduced to 677 potential pathogenic mutations. Among those, we identified no biallelic single nucleotide variations that could be deemed responsible for a recessive disease among the coding regions of the genome. Thus, we focused on the analysis of structural variations. Adopting this strategy, we identified a ~56 kb heterozygous deletion in the EYS gene, a known cause of arRP. This deletion is depriving the transcript of two exons and is predicted to have a deleterious impact on the protein. In addition, we also identified a novel missense variant, p.Y2971D, affecting an evolutionarily conserved amino acid. Interestingly, this missense change was previously missed by WES analysis due to the low-depth coverage of the region in question. Both variants, segregating with the disease within the family, were further validated by Sanger sequencing and MLPA analysis.

Conclusions : With our study we emphasize the benefits of the use of WGS in unsolved cases of hereditary retinal disorders. Our work not only demonstrates that WGS enables the detection of structural events (e.g. deletions) that otherwise would have been unnoticed, but it also underscores that WGS performance is more reliable and uniform in terms of sequencing coverage. Furthermore, we also demonstrate that our analytic pipeline does reveal clinically relevant mutations, exploiting the full potential of WGS data. To date, the major focus of studies on Mendelian diseases, including RP, has been limited to exonic regions. However, non-coding variants in known or novel genes can also affect disease pathophysiology. WGS can indeed shed more light in the so called genomic 'dark matter' of the human genome and, and in particular of retinal degenerations.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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