Stickler syndrome and the vitreous phenotype: mutations in COL2A1 and COL11A1

Abstract

Stickler syndrome is a dominantly inherited disorder affecting the fibrillar type II/XI collagen molecules expressed in vitreous and cartilage. Mutations have been found in COL2A1, COL11A1 and COL11A2. It has a highly variable phenotype that can include midline clefting, hearing loss, premature osteoarthritis, congenital high myopia and blindness through retinal detachment. Although the systemic phenotype is highly variable, the vitreous phenotype has been used successfully to differentiate between patients with mutations in these different genes. Mutations in COL2A1 usually result in a congenital membranous vitreous anomaly. In contrast mutations in COL11A1 result in a different vitreous phenotype where the lamellae have an irregular and beaded appearance. However, it is now apparent that a new sub-group of COL2A1 mutations is emerging that result in a different phenotype with a hypoplastic vitreous that fills the posterior chamber of the eye, and is either optically empty or has sparse irregular lamellae. Here we characterise a further 89 families with Stickler syndrome or a type II collagenopathy, and correlate the mutations with the vitreous phenotype. We have identified 57 novel mutations including missense changes in both COL2A1 and COL11A1 and have also detected two cases of complete COL2A1 gene deletions using MLPA.

Stickler syndrome, ocular-only variants and a key diagnostic role for the ophthalmologist

“…14 Clinical assessment continues to have a vital role as an indicator of clinical suspicion and also to assist in indicating which genes to screen. 15 For the ophthalmologist, combining clinical and molecular genetic analysis is particularly important given the emerging array of ocular-only variants 10,11 (see below) with a high risk of retinal detachment, but Other Unknown Hypoplastic vitreous, deafness, arthropathy, cleft palate.…”

“…38 In addition to assisting the clinical diagnosis, the diagnostic protocol depicted in Figure 2 assists and directs mutation analysis substantially improving COL2A1 analysis resulting in a 95% positive pick-up rate. 15,39 The advances currently being made in sequencing technologies, so-called next-generation sequencing, may in future make it more economically viable to sequence and analyse all candidate genes simultaneously; however, at present, the vitreous phenotyping before molecular analysis greatly increases the efficiency of mutation detection.…”

Splicing analysis of unclassified variants in COL2A1 and COL11A1 identifies deep intronic pathogenic mutations

“…7,8 Both are multi-exon genes with a large number of characterised mutations, many of which affect consensus splice sites. [9][10][11][12] Stickler syndrome can present with high myopia, midline clefting, midfacial hypoplasia, hearing loss, premature osteoarthritis and a high incidence of retinal detachment. 13 With an incidence of between 1 in 7500-1 in 9000 newborns, 14 it is phenotypically highly variable both between and within families, and patients often remain undiagnosed for many years, until the suggestion of the condition is raised clinically and later confirmed by genetic testing.…”

The expanding spectrum of COL2A1 gene variants IN 136 patients with a skeletal dysplasia phenotype

“…This variant was already observed in several Stickler cases. 9,[12][13][14] Finally, p.(Arg989Cys), c.2965C4T was carried by one of our SEMD Strudwick patients, and this variant has been previously reported in several SEDC cases. 9,[15][16][17] In accordance with the literature, we observed that arginine to cysteine changes were associated with a broad spectrum of diseases, but they were more often encountered in the moderate phenotypes.…”

“…Molecular defects in the COL2A1 gene (MIM#108300), which encodes the alpha 1 chain of procollagen type II, result in skeletal, 12 Service de Génétique, CHU Félix Guyon, Saint-Denis, La Réunion, France; 13 Service de Génétique, CHU de Nancy, Nancy, France; 14 Génétique Médicale, CHU, Nantes, France; 15 Service de Biologie du Développement, Hôpital Robert Debré, Paris, France; 16 Centre de Génétique, CHU Dijon -Hôpital d'Enfants, Dijon, France; 17 Département de Génétique Médicale, CHU de Nice -Hôpital de l'Archet II, Nice, France; 18 Unité de Génétique Clinique, CHU de Rouen -Hôpital Charles Nicolle, Rouen, France; 19 Génétique Médicale, CHU de la Réunion, Saint Pierre, La Réunion, France; 20 orofacial, and ocular disorders. These dominantly inherited diseases are associated with various COL2A1 variants that include missense, nonsense, small indels or large deletions.…”