Autosomal Recessive Stickler Syndrome in Two Families Caused by Mutations in the COL9A1 Gene

Abstract

Purpose: : To study the occurrence of COL9A1 mutations in 11 families with autosomal recessive (ar)Stickler syndrome and to delineate the associated phenotypes.

Methods: : Six consanguineous arStickler families were evaluated for possible homozygosity by means of haplotype analysis in a region of 2cM encompassing COL9A1. In the proband of another consanguineous family, a genome wide SNP array analysis was performed. One affected individual from each of the 11 pedigrees was screened for mutations in the entire COL9A1 ORF. All family members were investigated for dysmorphic features additionally to ophthalmologic, audiologic, and radiologic abnormalities.

Results: : We identified a novel homozygous COL9A1 mutation (p.R507X), in two affected Turkish sisters, and one previously published homozygous mutation (p.R295X) in a Moroccan boy. Ophthalmic examination in these three patients (age ranging from 15 to 43 years) revealed moderate to high myopia, reduced visual acuity, and cataracts. The vitreous body showed liquefaction with membranous structures and vitreo-retinal adhesions, leading to bilateral retinal detachment in two patients. Progressive retinal degeneration with reduced electroretinographic responses and visual field defects was evident in the two siblings. All three had a sensorineural hearing deficit and mild signs of epiphyseal dysplasia. Midfacial hypoplasia with malocclusion was found in one patient. In two heterozygotes, intervertebral disk bulging was observed, with hypermobile joints in one of them.

Conclusions: : We identified a second novel mutation in COL9A1 causing arStickler syndrome and the previously described change, in two families. Their phenotype seems comparable to those of other Stickler genes. COL9A1 should be routinely tested in cases with features suggestive of arStickler for accurate clinical diagnostics.

Keywords: retinal degenerations: hereditary • mutations • genetics