Identification of a stop codon mutation in exon 2 of the collagen 2A1 gene in a large stickler syndrome family.

ABSTRACT

PURPOSE: To describe the clinical features and identify the mutation responsible for an autosomal dominant vitreoretinal degeneration occurring in a previously unreported large family. DESIGN: Cohort study. METHODS: Family members were evaluated clinically over a 30-year period. Genealogical investigation, genetic linkage to known vitreoretinal degenerations, and mutation screening of the COL2A1 gene were performed. RESULTS: We identified a single large family (2,384 total family members) with vitreoretinal degeneration spanning 12 generations. We reviewed the clinical records of 165 family members (95 affected and 70 unaffected). The common clinical findings in affected individuals included early-onset posterior perivascular retinal degeneration, vitreous degeneration, and retinal detachment. The incidence of retinal detachment was 57% (95/165) and the mean age of onset was 15.2 years. Orofacial, skeletal, and auditory abnormalities were seen in 0%, 5%, and 7.5%, respectively, in a subset of 28 affected subjects. Linkage to the collagen COL2A1 locus was demonstrated and a cytosine to adenosine transition identified within exon 2, leading to the creation of a stop codon at position 86 (Cys86Stop). CONCLUSIONS: Identification of the mutation in this family enables diagnosis of individuals at risk for potentially blinding complications in this condition at an early age. Given the variability of the Stickler phenotype, mutation detection allows for more comprehensive genetic counseling and directs clinical monitoring to family members inheriting the disease gene.