Vitreoretinal Degeneration, Snowflake Type

A number sign (#) is used with this entry because of evidence that snowflake vitreoretinal degeneration (SVD) is caused by heterozygous mutation in the KCNJ13 gene (603208) on chromosome 2q37.

Clinical Features

Hirose et al. (1974) first described this disorder. Gheiler et al. (1982) observed it in 3 generations of an Algerian Jewish kindred, with several instances of male-to-male transmission. The characteristic that suggested the name was the presence of very small, yellow-white dots in the retina. All the affected persons had vitreous abnormalities, including fibrillar degeneration, gel liquefaction, and marked thickening of the cortical vitreous. Some showed an optically empty vitreous cavity. Cataracts developed in several. Differentiation from Wagner disease (143200), the vitreoretinal degeneration it resembles most closely, was considered possible: in snowflake degeneration, the earliest change is in the superficial retinal layers and cortical vitreous, whereas Wagner disease begins in the deep retinal layers and choroid, with atrophy of the choriocapillaris and pigment epithelium. Furthermore, snowflake degeneration shows not the membranous degeneration of the vitreous typical of Wagner disease but fibrillar degeneration of the vitreous.

Lee et al. (2003) reported the ocular and systemic findings of the family originally described by Hirose et al. (1974) and studied the genetic loci distinguishing known genetic causes of vitreoretinal degenerations--COL2A1 (120140), COL11A1 (120280), and the Wagner syndrome locus--in this family. Ocular features included corneal guttae (80%), early-onset cataract (83%), fibrillar vitreous degeneration (100%), and peripheral retinal abnormalities (83%), including minute crystalline deposits called snowflakes (67%). Retinal detachment was seen in 1 (17%) of 6 patients. Orofacial features (e.g., cleft palate, cleft lip, Pierre-Robin sequence), early-onset hearing loss, and arthritis typical of Stickler syndrome (see 108300) were absent. The absence of vitreous gel in the retrolental space and the presence of fibrillar vitreous degeneration were consistent with the vitreous structure reported for COL11A1, but not COL2A1, mutations. The absence of systemic features was characteristic of the vitreoretinopathies linked to chromosome 5q13 (Wagner syndrome and erosive vitreoretinopathy) and mutations in exon 2 of the COL2A1 gene. Snowflakes in the peripheral retina and the absence of nyctalopia, posterior chorioretinal atrophy, and tractional retinal detachment were inconsistent with the chromosome 5q13 vitreoretinopathies. The association of Fuchs corneal endothelial dystrophy (610158) found in this family had not been previously reported in other vitreoretinal degenerations. Lee et al. (2003) concluded that these findings and the exclusion of known genetic loci suggested that snowflake is a distinct vitreoretinal degeneration.

Mapping

Jiao et al. (2004) identified the chromosomal location of the gene causing snowflake vitreoretinal degeneration (SVD). The SVD locus was linked to markers in a region of chromosome 2q36 defined by D2S2158 and D2S2202. A maximum 2-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 (120070), part of which mapped to the SVD critical region, revealed no potentially pathogenic coding sequence variation or evidence for deletion. Localization of SVD to a 9-Mb region flanked by D2S2158 and D2S2202 distinct from both Wagner syndrome and the Stickler syndromes indicated that SVD is a distinct genetic entity. The absence of a coding sequence variation in the only collagen gene within the disease region suggested a novel pathogenesis for this vitreoretinal degeneration. Jiao et al. (2004) concluded that snowflake vitreoretinal degeneration should be considered in the differential diagnosis of families with fibrillar anomaly of the vitreous.

Molecular Genetics

Hejtmancik et al. (2008) sequenced 20 of the 59 genes within the critical linkage region defined by Jiao et al. (2004) on the long arm of chromosome 2 in affected members of the original family (Hirose et al., 1974) and demonstrated a missense mutation in the KCNJ13 gene (603208.0001).