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Novel COL11A1 mutations in Stickler syndrome detected by next-generation sequencing

Frederic Acke (UGent) , Fransiska Malfait (UGent) , Olivier Vanakker (UGent) , Wouter Steyaert (UGent) , Kim De Leeneer (UGent) , Geert Mortier (UGent) , Ingeborg Dhooge (UGent) , Anne De Paepe (UGent) , Els De Leenheer (UGent) and Paul Coucke (UGent)
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Abstract
Stickler syndrome is a connective tissue disorder with considerable phenotypic and genotypic variability, characterized by distinctive facial abnormalities, ocular problems, hearing loss, and joint problems. Up to now, mutations in 5 different collagen genes have been associated with the disease. Mutations in the COL11A1 gene may result in Stickler syndrome type 2, which can be differentiated clinically by a ‘beaded’ vitreous and a more severe hearing loss compared to the more prevalent type 1, caused by mutations in COL2A1. In literature, only a few dozen COL11A1 mutations have been reported. We selected 33 unrelated COL2A1 mutation-negative patients, based on their clinical features, for molecular COL11A1 analysis, by means of next-generation sequencing technology (MiSeq, Illumina). The bioinformatic pipeline included the CLC bio Workbench 6.0 followed by an in-house developed software package for variant interpretation. Assays lacking sufficient coverage as well as the mutations identified were verified by Sanger sequencing. Out of the 33 selected probands, disease-causing mutations could be identified in 14 independent patients. Half of these mutations are novel, of which most are missense mutations (including 2 glycine substitutions). The other half are previously reported mutations, mostly splice-site alterations. Moreover, additional SNPs were identified. All molecularly confirmed patients had a clinical presentation compatible with Stickler syndrome type 2. In conclusion, COL11A1 screening in selected Stickler syndrome patients, based on meticulous clinical evaluation, is rewarding. For large genes such as COL11A1, next-generation sequencing proves to be an efficient and cost-effective molecular tool.

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Chicago
Acke, Frederic, Fransiska Malfait, Olivier Vanakker, Wouter Steyaert, Kim De Leeneer, Geert Mortier, Ingeborg Dhooge, Anne De Paepe, Els De Leenheer, and Paul Coucke. 2013. “Novel COL11A1 Mutations in Stickler Syndrome Detected by Next-generation Sequencing.” In American Society of Human Genetics, 63rd Annual Meeting, Abstracts.
APA
Acke, F., Malfait, F., Vanakker, O., Steyaert, W., De Leeneer, K., Mortier, G., Dhooge, I., et al. (2013). Novel COL11A1 mutations in Stickler syndrome detected by next-generation sequencing. American Society of Human Genetics, 63rd Annual meeting, Abstracts. Presented at the 63rd Annual meeting of the American Society of Human Genetics (ASHG 2013).
Vancouver
1.
Acke F, Malfait F, Vanakker O, Steyaert W, De Leeneer K, Mortier G, et al. Novel COL11A1 mutations in Stickler syndrome detected by next-generation sequencing. American Society of Human Genetics, 63rd Annual meeting, Abstracts. 2013.
MLA
Acke, Frederic, Fransiska Malfait, Olivier Vanakker, et al. “Novel COL11A1 Mutations in Stickler Syndrome Detected by Next-generation Sequencing.” American Society of Human Genetics, 63rd Annual Meeting, Abstracts. 2013. Print.
@inproceedings{4182807,
  abstract     = {Stickler syndrome is a connective tissue disorder with considerable phenotypic and genotypic variability, characterized by distinctive facial abnormalities, ocular problems, hearing loss, and joint problems. Up to now, mutations in 5 different collagen genes have been associated with the disease. Mutations in the COL11A1 gene may result in Stickler syndrome type 2, which can be differentiated clinically by a ‘beaded’ vitreous and a more severe hearing loss compared to the more prevalent type 1, caused by mutations in COL2A1. In literature, only a few dozen COL11A1 mutations have been reported. We selected 33 unrelated COL2A1 mutation-negative patients, based on their clinical features, for molecular COL11A1 analysis, by means of next-generation sequencing technology (MiSeq, Illumina). The bioinformatic pipeline included the CLC bio Workbench 6.0 followed by an in-house developed software package for variant interpretation. Assays lacking sufficient coverage as well as the mutations identified were verified by Sanger sequencing. Out of the 33 selected probands, disease-causing mutations could be identified in 14 independent patients. Half of these mutations are novel, of which most are missense mutations (including 2 glycine substitutions). The other half are previously reported mutations, mostly splice-site alterations. Moreover, additional SNPs were identified. All molecularly confirmed patients had a clinical presentation compatible with Stickler syndrome type 2. In conclusion, COL11A1 screening in selected Stickler syndrome patients, based on meticulous clinical evaluation, is rewarding. For large genes such as COL11A1, next-generation sequencing proves to be an efficient and cost-effective molecular tool.},
  author       = {Acke, Frederic and Malfait, Fransiska and Vanakker, Olivier and Steyaert, Wouter and De Leeneer, Kim and Mortier, Geert and Dhooge, Ingeborg and De Paepe, Anne and De Leenheer, Els and Coucke, Paul},
  booktitle    = {American Society of Human Genetics, 63rd Annual meeting, Abstracts},
  language     = {eng},
  location     = {Boston, MA, USA},
  title        = {Novel COL11A1 mutations in Stickler syndrome detected by next-generation sequencing},
  year         = {2013},
}