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

Kristien P. Hoornaert, Inge Vereecke, Chantal Dewinter, Thomas Rosenberg, Frits A. Beemer, Jules G. Leroy, Laila Bendix, Erik Björck, Maryse Bonduelle, Odile Boute, Valerie Cormier-Daire, Christine de Die-Smulders, Anne Dieux-Coeslier, Hélène Dollfus, Mariet Elting, Andrew Green, Veronica I. Guerci, Raoul C. M. Hennekam, Yvonne Hilhorts-Hofstee, Muriel HolderCarel Hoyng, Kristi J. Jones, Dragana Josifova, Ilkka Kaitila, Suzanne Kjaergaard, Yolande H. Kroes, Kristina Lagerstedt, Melissa Lees, Martine Lemerrer, Cinzia Magnani, Carlo Marcelis, Loreto Martorell, Michèle Mathieu, Meriel McEntagart, Angela Mendicino, Jenny Morton, Gabrielli Orazio, Véronique Paquis, Orit Reish, Kalle O. J. Simola, Sarah F. Smithson, Karen I. Temple, Elisabeth van Aken, Yolande van Bever, Jenneke van den Ende, Johanna M. van Hagen, Leopoldo Zelante, Riina Zordania, Anne de Paepe, Bart P. Leroy, Marc de Buyzere, Paul J. Coucke, Geert R. Mortier, E. Bjorck, J. van der Ende

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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. European Journal of Human Genetics (2010) 18, 872-880; doi:10.1038/ejhg.2010.23; published online 24 February 2010
Original languageEnglish
Pages (from-to)872-880
JournalEuropean journal of human genetics
Issue number8
Publication statusPublished - 2010

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