A New Autosomal Recessive Form of Stickler Syndrome Is Caused by a Mutation in the COL9A1 Gene

Abstract

Stickler syndrome is characterized by ophthalmic, articular, orofacial, and auditory manifestations. It has an autosomal dominant inheritance pattern and is caused by mutations in COL2A1, COL11A1, and COL11A2. We describe a family of Moroccan origin that consists of four children with Stickler syndrome, six unaffected children, and two unaffected parents who are distant relatives (fifth degree). All family members were clinically investigated for ear, nose, and throat; ophthalmologic; and radiological abnormalities. Four children showed symptoms characteristic of Stickler syndrome, including moderate-to-severe sensorineural hearing loss, moderate-to-high myopia with vitreoretinopathy, and epiphyseal dysplasia. We considered the COL9A1 gene, located on chromosome 6q13, to be a candidate gene on the basis of the structural association with collagen types II and XI and because of the high expression in the human inner ear indicated by cDNA microarray. Mutation analysis of the coding region of the COL9A1 gene showed a homozygous R295X mutation in the four affected children. The parents and four unaffected children were heterozygous carriers of the R295X mutation. Two unaffected children were homozygous for the wild-type allele. None of the family members except the homozygous R295X carriers had any signs of Stickler syndrome. Therefore, COL9A1 is the fourth identified gene that can cause Stickler syndrome. In contrast to the three previously reported Stickler syndrome-causing genes, this gene causes a form of Stickler syndrome with an autosomal recessive inheritance pattern. This finding will have a major impact on the genetic counseling of patients with Stickler syndrome and on the understanding of the pathophysiology of collagens. Mutation analysis of this gene is recommended in patients with Stickler syndrome with possible autosomal recessive inheritance.

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

“…120210). 9 Stickler syndrome type 1 is the most common form. The majority of COL2A1 mutations identified in patients with Stickler syndrome type 1 are predicted to result in nonsense-mediated decay (NMD).…”

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

“…First described in 1965, 1,2 hereditary arthroophthalmopathy (Stickler syndrome) is now known to encompass at least five clinically different subgroups, [5][6][7][8][9][10][11] which are summarised in Table 1, and in addition there is still further genetic heterogeneity to be resolved. 12,13 The group forms one of the most prevalent of the connective tissue disordersFthe service in Cambridge now seeing an average of one and half new families per week and with nearly 1000 Stickler syndrome patients registered on the Vitreoretinal Service database.…”

“…In most instances, of MED the ocular phenotype is reported as normal. As type IX collagen is normally expressed in vitreous and there have been recent reports of autosomal recessive Stickler syndrome secondary to compound heterozygote mutations in COL9A1, 8,9 the clinician should be alert to the theoretical possibility of ocular involvement with MED.…”

Evaluation and management of pediatric rhegmatogenous retinal detachment

“…31,32 A rare autosomal recessive form Stickler syndrome that does have ocular involvement has also recently been described and is associated with mutations in the COL9A1 gene. 33 …”