Wagner - Stickler syndrome . gene in a family with Exclusion of COL 2 A 1 as a candidate

A large family with Wagner's vitreoretinal degeneration but none of the non-ocular features of Stickler's syndrome has been studied with gene probes for type II coliagen. Recombination has been observed, thus excluding type II collagen as the site of mutation in this family. This report supports other published evidence that the WagnerStickler syndrome is genetically heterogeneous. In 1938, Wagner' described a family where 13 members in three generations had a vitreoretinal degeneration associated with myopia and cataracts. The only non-ocular feature reported was hearing loss in a 17 year old patient. The pattern of inheritance was autosomal dominant. Jansen2 later reported a similar phenotype in two Dutch families, but in some ofthese cases retinal detachments and simple glaucoma occurred. In 1963, Delaney et a13 described a family where cleft palate was associated with the ocular changes and in 1965 Stickler et al4 noted an association with craniofacial abnormalities and a progressive arthropathy. In several subsequent studies, patients with Wagner's retinopathy were shown to have some of the non-ocular features of Stickler's syndrome. Liberfarb et a15 studied 22 probands with Wagner's retinopathy and 68 of their relatives and found, in total, 70 affected subjects. Of these, 86% had the facial features of Stickler's syndrome and 60% had musculoskeletal abnormalities. They termed the disInstitute of Medical Genetics, Universtty Hospital of Wales, Heath Park, Cardiff CF4 4XW. A E Fryer, M Upadhyaya, M Littler, P S Harper Department of Ophthalmology, University Hospital of Wales, Cardiff. P Bacon Department of Pediatrics, University of Connecticut Health Center, Farmington, CT 06032, USA. D Watkins, P Tsipouras Correspondence to Dr Fryer order the Wagner-Stickler syndrome, concluding that the two phenotypes were part of the same condition. An alternative approach was adopted by Maumenee6 who subdivided 'Wagner-like vitreoretinal degeneration' according to the associated clinical features. She first grouped families into those with and those without non-ocular manifestations. The first group included families like those described by Wagner' and Jansen.2 The second group contained several bone dysplasias and included Stickler's syndrome. Maumenee suggested that families in this latter group may result from mutations involving type II collagen as this is present in the secondary vitreous and cartilage. This view gained support when genetic linkage was shown to the structural gene for type II collagen (COL2A1) in two families with Stickler's syndrome.7 This discovery provides a means of determining whether all vitreoretinal degenerations result from mutations at the same locus or whether the clinical subdivision of Maumenee has a basis in non-allelic genetic heterogeneity. We have studied a family where the clinical features have been purely ocular and where several members have had retinal detachments. This family therefore most resembles that described by Jansen.2 We have looked for genetic linkage in this family to the collagen probe COL2A1. If recombination is detected then a mutation in the type II collagen gene is excluded as the cause for the disorder in this family. Families that have been reported with the WagnerStickler syndrome have shown considerable variability in the expression of the gene. Liberfarb et a15 found no evidence of skipped generations in 22 families and so penetrance appears to be nearly complete, but in view of the variability they recommended that routine eye examinations had to be performed into the third decade before the diagnosis of Wagner's syndrome could be ruled out with certainty.