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Stickler syndrome caused by COL2A1 mutations: genotype-phenotype correlation in a series of 100 patients

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Abstract
Stickler syndrome is an autosomal dominant connective tissue disorder caused by mutations in different collagen genes. The aim of our study was to define more precisely the phenotype and genotype of Stickler syndrome type 1 by investigating a large series of patients with a heterozygous mutation in COL2A1. In 188 probands with the clinical diagnosis of Stickler syndrome, the COL2A1 gene was analyzed by either a mutation scanning technique or bidirectional fluorescent DNA sequencing. The effect of splice site alterations was investigated by analyzing mRNA. Multiplex ligation-dependent amplification analysis was used for the detection of intragenic deletions. We identified 77 different COL2A1 mutations in 100 affected individuals. Analysis of the splice site mutations showed unusual RNA isoforms, most of which contained a premature stop codon. Vitreous anomalies and retinal detachments were found more frequently in patients with a COL2A1 mutation compared with the mutation-negative group (P<0.01). Overall, 20 of 23 sporadic patients with a COL2A1 mutation had either a cleft palate or retinal detachment with vitreous anomalies. The presence of vitreous anomalies, retinal tears or detachments, cleft palate and a positive family history were shown to be good indicators for a COL2A1 defect. In conclusion, we confirm that Stickler syndrome type 1 is predominantly caused by loss-of-function mutations in the COL2A1 gene as >90% of the mutations were predicted to result in nonsense-mediated decay. On the basis of binary regression analysis, we developed a scoring system that may be useful when evaluating patients with Stickler syndrome.
Keywords
GEL-ELECTROPHORESIS, SITE MUTATION, splice site mutation, type II collagenopathies, genotype-phenotype correlation, Stickler syndrome, COL2A1, DYSPLASIA, DOMINANT, SUBSTITUTION, ARTHROOPHTHALMOPATHY, TRIPLE-HELIX, COL11A1 GENE, COLLAGEN, EXON-2

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Chicago
Hoornaert, Kristien, INGE VEREECKE, CHANTAL DEWINTER, Thomas Rosenberg, Frits A Beemer, Juliaan Leroy, Laila Bendix, et al. 2010. “Stickler Syndrome Caused by COL2A1 Mutations: Genotype-phenotype Correlation in a Series of 100 Patients.” European Journal of Human Genetics 18 (8): 872–880.
APA
Hoornaert, K., VEREECKE, I., DEWINTER, C., Rosenberg, T., Beemer, F. A., Leroy, J., Bendix, L., et al. (2010). Stickler syndrome caused by COL2A1 mutations: genotype-phenotype correlation in a series of 100 patients. EUROPEAN JOURNAL OF HUMAN GENETICS, 18(8), 872–880.
Vancouver
1.
Hoornaert K, VEREECKE I, DEWINTER C, Rosenberg T, Beemer FA, Leroy J, et al. Stickler syndrome caused by COL2A1 mutations: genotype-phenotype correlation in a series of 100 patients. EUROPEAN JOURNAL OF HUMAN GENETICS. 2010;18(8):872–80.
MLA
Hoornaert, Kristien, INGE VEREECKE, CHANTAL DEWINTER, et al. “Stickler Syndrome Caused by COL2A1 Mutations: Genotype-phenotype Correlation in a Series of 100 Patients.” EUROPEAN JOURNAL OF HUMAN GENETICS 18.8 (2010): 872–880. Print.
@article{953420,
  abstract     = {Stickler syndrome is an autosomal dominant connective tissue disorder caused by mutations in different collagen genes. The aim of our study was to define more precisely the phenotype and genotype of Stickler syndrome type 1 by investigating a large series of patients with a heterozygous mutation in COL2A1. In 188 probands with the clinical diagnosis of Stickler syndrome, the COL2A1 gene was analyzed by either a mutation scanning technique or bidirectional fluorescent DNA sequencing. The effect of splice site alterations was investigated by analyzing mRNA. Multiplex ligation-dependent amplification analysis was used for the detection of intragenic deletions. We identified 77 different COL2A1 mutations in 100 affected individuals. Analysis of the splice site mutations showed unusual RNA isoforms, most of which contained a premature stop codon. Vitreous anomalies and retinal detachments were found more frequently in patients with a COL2A1 mutation compared with the mutation-negative group (P{\textlangle}0.01). Overall, 20 of 23 sporadic patients with a COL2A1 mutation had either a cleft palate or retinal detachment with vitreous anomalies. The presence of vitreous anomalies, retinal tears or detachments, cleft palate and a positive family history were shown to be good indicators for a COL2A1 defect. In conclusion, we confirm that Stickler syndrome type 1 is predominantly caused by loss-of-function mutations in the COL2A1 gene as {\textrangle}90\% of the mutations were predicted to result in nonsense-mediated decay. On the basis of binary regression analysis, we developed a scoring system that may be useful when evaluating patients with Stickler syndrome.},
  author       = {Hoornaert, Kristien and Vereecke, Inge and Dewinter, Chantal and Rosenberg, Thomas and Beemer, Frits A and Leroy, Juliaan and Bendix, Laila and Bj{\"o}rck, Erik and Bonduelle, Maryse and Boute, Odile and Cormier-Daire, Valerie and De Die-Smulders, Christine and Dieux-Coeselier, Anne and Dollfus, H{\'e}l{\`e}ne and Eting, Mariet and Green, Andrew and Guerci, Veronica I and Hennekam, Raoul CM and Hillhorts-Hofstee, Yvonne and Holder, Muriel and Hyong, Carel and Jones, Kristi J and Josifova, Dragana and Kaittila, Ilkka and Kjaergaard, Suzanne and Kroes, Yolande H and Lagerstedt, Kristina and Lees, Melissa and LeMerrer, Martine and Magnani, Cinzia and Marcelis, Carlo and Martorell, Loreto and Mathieu, Mich{\`e}le and McEntagart, Meriel and Mendicino, Angela and Morton, Jenney and Orazio, Gabrielli and Paquis, V{\'e}ronique and Reish, Orit and Simola, Kalle OJ and Smithson, Sarah F and Temple, Karen I and Van Aken, Elisabeth and Van Bever, Yolande and van den Ende, Jenneke and Van Hagen, Johanna M and Zelante, Leopoldo and Zordiania, Riina and De Paepe, Anne and Leroy, Bart and De Buyzere, Marc and Coucke, Paul and Mortier, Geert},
  issn         = {1018-4813},
  journal      = {EUROPEAN JOURNAL OF HUMAN GENETICS},
  keyword      = {GEL-ELECTROPHORESIS,SITE MUTATION,splice site mutation,type II collagenopathies,genotype-phenotype correlation,Stickler syndrome,COL2A1,DYSPLASIA,DOMINANT,SUBSTITUTION,ARTHROOPHTHALMOPATHY,TRIPLE-HELIX,COL11A1 GENE,COLLAGEN,EXON-2},
  language     = {eng},
  number       = {8},
  pages        = {872--880},
  title        = {Stickler syndrome caused by COL2A1 mutations: genotype-phenotype correlation in a series of 100 patients},
  url          = {http://dx.doi.org/10.1038/ejhg.2010.23},
  volume       = {18},
  year         = {2010},
}

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