A loss of function mutation in the COL9A2 gene causes autosomal recessive Stickler syndrome

Abstract

Stickler syndrome is characterized by ocular, auditory, skeletal, and orofacial abnormalities. We describe a family with autosomal recessive Stickler syndrome. The main clinical findings consisted of high myopia, vitreoretinal degeneration, retinal detachment, hearing loss, and short stature. Affected family members were found to have a homozygous loss-of-function mutation in COL9A2, c.843_c.846 + 4del8. A family with autosomal recessive Stickler syndrome was previously described and found to have a homozygous loss-of-function mutation in COL9A1. COL9A1, COL9A2, and COL9A3 code for collagen IX. All three collagen IX α chains, α1, α2, and α3, are needed for formation of functional collagen IX molecule. In dogs, two causative loci have been identified in autosomal recessive oculoskeletal dysplasia. This dysplasia resembles Stickler syndrome. Recently, homozygous loss-of-function mutations in COL9A2 and COL9A3 were found to co-segregate with the loci. Together the data from the present study and the previous studies suggest that loss-of-function mutations in any of the collagen IX genes can cause autosomal recessive Stickler syndrome.

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.…”

Alternative splicing modifies the effect of mutations in COL11A1 and results in recessive type 2 Stickler syndrome with profound hearing loss

“…The COL11A2 gene is not expressed in the eye and mutations in that gene do not result in an eye phenotype 13. A recessive form of Stickler syndrome (MIM 614134, 614284)14 15 has been reported in association with null alleles of type IX collagen genes ( COL9A1 MIM 120210 and COL9A2 MIM 120260). Type IX collagen connects heterotypic type II/XI collagen fibrils to other components of the extracellular matrix 16 17…”

Novel pathogenic COL11A1/COL11A2 variants in Stickler syndrome detected by targeted NGS and exome sequencing

“…Third, the involvement of other, perhaps still unidentified genes for Stickler syndrome cannot be excluded. Mutations in the genes encoding type IX collagen have been identified in a few families exhibiting an autosomal recessive form of Stickler syndrome with clinical features partly distinct from the three main Stickler types [31][32][33]. Moreover, considerable phenotypical overlap between Stickler syndrome and other connective tissue dysplasias, such as Marfan, Ehlers-Danlos and Loeys-Dietz syndrome, exists.…”