Autosomal Dominant Vitreoretinopathy of the Dajabòn: Report of a Novel COL2A1 c.3925G>A Mutation

Abstract

Purpose : To present the genotype and phenotype of a family originating from the Dajabòn, Dominican Republic, with a hereditary vitreoretinopathy.

Methods : Family members spanning five generations related to our proband underwent detailed medical histories and complete ophthalmic examinations at two different time points spanning approximately 10 years. The proband suffered from high myopia, retinal detachment, and hip dysplasia as a teenager. A total of 128 family members were studied of whom 26 had clinical findings of a vitreoretinopathy. Genetic testing was performed on the proband and 49 family members (13 clinically affected, 36 unaffected) at the second time point. Analysis of the genes for type ll collagen using PCR amplification of the exons and the exon-intron boundaries of the 54 exons of the COL2A1 gene were performed. Fragments were sequenced using an ABI PRISM ^TM 3130XL Sequencer. Hierarchical, linear and logistic mixed effects models were used to quantify trends in disease sequelae. Statistical significance was set at p < 0.05.

Results : The proband and the 13 tested, affected family members had a COL2A1 c.3925G>A mutation. A nucleotide G to A substitution converted a codon for aspartic acid-1309 (GAC) to a codon for asparagine (AAC) at exon 52 in the COL2A1 gene (transcript: NM_001844.4). This novel substitution resulted in the formation of Asparagine in lieu of Aspartate in the alpha-1(ii) chains. All 39 tested, unaffected subjects were negative for the mutation. Of the total 26 affected subjects, 4 (15.4%) developed retinal detachments, 17 (65.4%) had lattice degeneration, 17 (65.4%) had premature vitreous degeneration, and 16 (61.5%) had joint disease (predominantly hip). Mean height was significantly less in affected subjects (3rd percentile) vs. unaffected relatives (15th percentile) for both males (156 cm vs. 167 cm) and females (150 cm vs. 155 cm). Age-adjusted mean height in affected subjects was approximately 1 SD greater than the reported mean maximal height of patients with the most common glycine-substitution COL2A1 dysplasias.

Conclusions : Autosomal Dominant Vitreoretinopathy of the Dajabòn results from a novel COL2A1 c.3925G>A mutation. Affected individuals are shorter than unaffected family members and are predisposed to retinal detachments with lattice degeneration, premature vitreous degeneration, and joint disease.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.