Genetic linkage of snowflake vitreoretinal degeneration to chromosome 2q36

Purpose: To identify the chromosomal location of the gene causing snowflake vitreoretinal degeneration (SVD), an autosomal dominant retinal degeneration characterized by small yellow-white dots in the retina, fibrillar anomaly of the vitreous humor, and retinal detachment.

Methods: Clinical data were collected on 31 family members by history and examination. Thirteen family members underwent prospective examination. Genotyping was performed using microsatellite markers spaced at approximately 10 cM intervals. Two-point and multipoint linkage analysis was performed (FASTLINK version of the MLINK program and the VITESSE algorithm, both available at http://linkage.rockefeller.edu/soft/list.html). Direct DNA Sequencing of amplified genomic DNA and mRNA was performed for candidate gene analysis.

Results: The SVD locus was linked to markers in a region of chromosome 2q36 defined by D2S2158 and D2S2202, based on meiotic breakpoint mapping of affected individuals. A maximum two-point lod score of 5.5 was obtained with marker D2S172 at theta; = 0 within this region. Direct DNA Sequencing of all 52 exons of the COL4A3 gene revealed no potentially pathogenic coding sequence variation or evidence for deletion.

Conclusions: The genetic locus for SVD lies in a 9 Mb region flanked by D2S2158 and D2S2202. Localization of SVD to a genomic region distinct from both Wagner disease and the Stickler syndromes indicates that SVD is a distinct genetic entity. The absence of coding sequence variation in the only collagen gene within the disease-region, suggests a novel pathogenesis for vitreoretinal degeneration. Snowflake vitreoretinal degeneration should be considered in the differential diagnosis of families with fibrillar anomaly of the vitreous.