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

Geert Mortier (1) , Kristien P Hoornaert (1) , Inge Vereecke (1) , Chantal Dewinter (1) , Thomas Rosenberg (1) , Frits A Beemer (1) , Jules G Leroy (1) , Laila Bendix (1) , Erik Björck (1) , Dr. Bonduelle (1) , Odile Boute (1) , Valérie Cormier-Daire (1) , Christine E.M. de Die-Smulders (1) , Anne Dieux-Coeslier (1) , Hélène Dollfus (1) , Mariet Elting (1) , Andrew Green (1) , Veronica Ileana Guerci (1) , Raoul Cm Hennekam (1) , Yvonne Hilhorst-Hofstee (1) , Muriel Holder (1) , Carel B Hoyng (1) , Kristi J Jones (1) , Dragana Josifova (1) , Ilkka Kaitila (1) , Suzanne Kjaergaard (1) , Yolande H Kroes (1) , Kristina Lagerstedt (1) , Melissa Lees (1) , Martine Lemerrer (1) , Cinzia Magnani (1) , Carlo Marcelis (1) , Loreto Martorell (1) , Michèle Mathieu (1) , Meriel Mcentagart (1) , Angela Mendicino (1) , Jenny Elizabeth Morton (1) , Gabrielli Orazio (1)

1 Head of the Department of Medical Genetics

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 analysed by either a mutation scanning technique or bidirectional fluorescent DNA sequencing. The effect of splice site alterations was investigated by analysing mRNA. MLPA 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 revealed 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 to the mutation negative group (p<0.01). 20 of the 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 since more than 90% of the mutations were predicted to result in nonsense mediated decay. Based on binary regression analysis we developed a scoring system that may be useful when evaluating patients with Stickler syndrome.

Mots clés: COL2A1; Stickler syndrome; genotype-phenotype correlation

Geert Mortier, Kristien P Hoornaert, Inge Vereecke, Chantal Dewinter, Thomas Rosenberg, et al.. Stickler syndrome caused by COL2A1 mutations: genotype-phenotype correlation in a series of 100 patients. European Journal of Human Genetics, 2010, n/a (n/a), pp.n/a-n/a. ⟨10.1038/ejhg.2010.23⟩. ⟨hal-00511182⟩