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Mapping the genomic landscape of inherited retinal disease genes prioritizes genes prone to coding and noncoding copy-number variations

Kristof Van Schil UGent, Sarah Naessens UGent, Stijn Van De Sompele UGent, Marjolein Carron UGent, Alexander Aslanidis, Caroline Van Cauwenbergh UGent, Anja Kathrin Mayer, Mattias Van Heetvelde UGent, Miriam Bauwens UGent, Hannah Verdin UGent, et al. (2018) GENETICS IN MEDICINE. 20(2). p.202-213
abstract
Purpose: Part of the hidden genetic variation in heterogeneous genetic conditions such as inherited retinal diseases (IRDs) can be explained by copy-number variations (CNVs). Here, we explored the genomic landscape of IRD genes listed in RetNet to identify and prioritize those genes susceptible to CNV formation. Methods: RetNet genes underwent an assessment of genomic features and of CNV occurrence in the Database of Genomic Variants and literature. CNVs identified in an IRD cohort were characterized using targeted locus amplification (TLA) on extracted genomic DNA. Results: Exhaustive literature mining revealed 1,345 reported CNVs in 81 different IRD genes. Correlation analysis between rankings of genomic features and CNV occurrence demonstrated the strongest correlation between gene size and CNV occurrence of IRD genes. Moreover, we identified and delineated 30 new CNVs in IRD cases, 13 of which are novel and three of which affect noncoding, putative cis-regulatory regions. Finally, the breakpoints of six complex CNVs were determined using TLA in a hypothesis-neutral manner. Conclusion: We propose a ranking of CNV-prone IRD genes and demonstrate the efficacy of TLA for the characterization of CNVs on extracted DNA. Finally, this IRD-oriented CNV study can serve as a paradigm for other genetically heterogeneous Mendelian diseases with hidden genetic variation.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
copy-number variations, genomic features, inherited retinal disease genes, predisposition, targeted locus amplification (TLA), EXOME SEQUENCING DATA, RETINITIS-PIGMENTOSA, MEDIATED DELETION, DIAGNOSTIC YIELD, MUTATIONS, DYSTROPHY, DEGENERATIONS, TRANSCRIPTION, ENHANCERS, VARIANTS
journal title
GENETICS IN MEDICINE
Genet. Med.
volume
20
issue
2
pages
202 - 213
Web of Science type
Article
Web of Science id
000425939300005
ISSN
1098-3600
1530-0366
DOI
10.1038/gim.2017.97
language
English
UGent publication?
yes
classification
A1
copyright statement
Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
id
8529931
handle
http://hdl.handle.net/1854/LU-8529931
date created
2017-08-30 14:07:39
date last changed
2018-03-14 09:30:16
@article{8529931,
  abstract     = {Purpose: Part of the hidden genetic variation in heterogeneous genetic conditions such as inherited retinal diseases (IRDs) can be explained by copy-number variations (CNVs). Here, we explored the genomic landscape of IRD genes listed in RetNet to identify and prioritize those genes susceptible to CNV formation. 
Methods: RetNet genes underwent an assessment of genomic features and of CNV occurrence in the Database of Genomic Variants and literature. CNVs identified in an IRD cohort were characterized using targeted locus amplification (TLA) on extracted genomic DNA. 
Results: Exhaustive literature mining revealed 1,345 reported CNVs in 81 different IRD genes. Correlation analysis between rankings of genomic features and CNV occurrence demonstrated the strongest correlation between gene size and CNV occurrence of IRD genes. Moreover, we identified and delineated 30 new CNVs in IRD cases, 13 of which are novel and three of which affect noncoding, putative cis-regulatory regions. Finally, the breakpoints of six complex CNVs were determined using TLA in a hypothesis-neutral manner. 
Conclusion: We propose a ranking of CNV-prone IRD genes and demonstrate the efficacy of TLA for the characterization of CNVs on extracted DNA. Finally, this IRD-oriented CNV study can serve as a paradigm for other genetically heterogeneous Mendelian diseases with hidden genetic variation.},
  author       = {Van Schil, Kristof and Naessens, Sarah and Van De Sompele, Stijn and Carron, Marjolein and Aslanidis, Alexander and Van Cauwenbergh, Caroline and Mayer, Anja Kathrin and Van Heetvelde, Mattias and Bauwens, Miriam and Verdin, Hannah and Coppieters, Frauke and Greenberg, Michael E and Yang, Marty G and Karlstetter, Marcus and Langmann, Thomas and De Preter, Katleen and Kohl, Susanne and Cherry, Timothy J and Leroy, Bart and De Baere, Elfride},
  issn         = {1098-3600},
  journal      = {GENETICS IN MEDICINE},
  keyword      = {copy-number variations,genomic features,inherited retinal disease genes,predisposition,targeted locus amplification (TLA),EXOME SEQUENCING DATA,RETINITIS-PIGMENTOSA,MEDIATED DELETION,DIAGNOSTIC YIELD,MUTATIONS,DYSTROPHY,DEGENERATIONS,TRANSCRIPTION,ENHANCERS,VARIANTS},
  language     = {eng},
  number       = {2},
  pages        = {202--213},
  title        = {Mapping the genomic landscape of inherited retinal disease genes prioritizes genes prone to coding and noncoding copy-number variations},
  url          = {http://dx.doi.org/10.1038/gim.2017.97},
  volume       = {20},
  year         = {2018},
}

Chicago
Van Schil, Kristof, Sarah Naessens, Stijn Van De Sompele, Marjolein Carron, Alexander Aslanidis, Caroline Van Cauwenbergh, Anja Kathrin Mayer, et al. 2018. “Mapping the Genomic Landscape of Inherited Retinal Disease Genes Prioritizes Genes Prone to Coding and Noncoding Copy-number Variations.” Genetics in Medicine 20 (2): 202–213.
APA
Van Schil, K., Naessens, S., Van De Sompele, S., Carron, M., Aslanidis, A., Van Cauwenbergh, C., Mayer, A. K., et al. (2018). Mapping the genomic landscape of inherited retinal disease genes prioritizes genes prone to coding and noncoding copy-number variations. GENETICS IN MEDICINE, 20(2), 202–213.
Vancouver
1.
Van Schil K, Naessens S, Van De Sompele S, Carron M, Aslanidis A, Van Cauwenbergh C, et al. Mapping the genomic landscape of inherited retinal disease genes prioritizes genes prone to coding and noncoding copy-number variations. GENETICS IN MEDICINE. 2018;20(2):202–13.
MLA
Van Schil, Kristof, Sarah Naessens, Stijn Van De Sompele, et al. “Mapping the Genomic Landscape of Inherited Retinal Disease Genes Prioritizes Genes Prone to Coding and Noncoding Copy-number Variations.” GENETICS IN MEDICINE 20.2 (2018): 202–213. Print.