A number sign (#) is used with this entry because of evidence that exudative vitreoretinopathy-6 (EVR6) is caused by heterozygous mutation in the ZNF408 gene (616454) on chromosome 11p11. One such family has been reported.

Homozygous mutation in the ZNF408 gene has been reported to cause retinitis pigmentosa (see RP72, 616469).

For a general phenotypic description and discussion of genetic heterogeneity of exudative vitreoretinopathy, see EVR1 (133780).

Van Nouhuys (1982) described a large 6-generation Dutch pedigree (family D) with exudative vitreoretinopathy (EVR) and provided detailed descriptions of 16 affected individuals. Visual acuity varied widely, with some patients reporting reduced vision from early childhood, whereas others had 20/20 vision on examination. Temporal stretching of retinal vessels was consistently observed, with temporal ectopia of the macula and/or optic disc in some patients. Terminal ramifications of retinal vessels at the temporal equator were present, with avascularity of the temporal fundus peripherally. Some patients exhibited vitreous membranes, and others had complete vitreous detachment, sometimes with tractional retinal detachment as well. Exudates were observed in 3 of the 16 patients.

Collin et al. (2013) studied 2 patients from the large Dutch pedigree with EVR that was originally reported by van Nouhuys (1982) as family D. The first was a 47-year-old man (patient IV-15 of van Nouhuys (1982)) with a history of school-age myopia who was treated for retinal detachment at age 20 years. Examination revealed visual acuities of 20/100 and 20/125 in the right and left eyes, respectively, with minimal cortical cataract present in both eyes. On funduscopy, the temporal retinal vessels showed a stretched course, with some temporal ectopia of the macula. There were local areas of choroid and retinal pigment epithelium (RPE) atrophy in the posterior pole, with avascularity of the peripheral retina temporally. The second patient was a 26-year-old woman (daughter of patient V-12 of van Nouhuys (1982)) who was diagnosed with EVR at 3 years of age. Examination at age 15 years revealed visual acuity in the right eye of finger counting only, with poor fixation, and in the left eye of 20/100. Funduscopy of the right eye showed a prominent falciform retinal fold traversing the posterior pole inferotemporally from the optic nerve head, with marked chorioretinal atrophy and retinal pigmentation on both sides of the fold. The left eye showed a dragged disc and marked deformation of the retina at the posterior pole; there were retinal vessels with an abnormally stretched course to the inferotemporal area, and a whitish mass of fibrous tissue was noted as well as several retinal exudates central to the mass. Fluorescein angiography revealed a deformed retinal network bilaterally, with leakage of dye from dilated capillaries in the left posterior pole. Beginning at age 19, the patient underwent treatment for slowly extending retinal exudates and progressive posterior vitreous detachment and tractional retinal detachment. By age 26, visual acuity in her left eye had deteriorated to finger counting, with an attached retina; the retinal fold and low visual function of the right eye remained unchanged.

In a large Dutch pedigree with EVR, originally described by van Nouhuys (1982) and in which mutations in the LRP5 (603506) and FZD4 (604579) genes had been excluded by Boonstra et al. (2009), Collin et al. (2013) performed SNP genotyping and linkage analysis. They obtained a maximum multipoint lod score of 2.7 at both a 13.6-Mb interval on chromosome 2q, between rs1403970 and rs1995496, and at a 41.7-Mb interval on chromosome 11q, between rs8929 and rs1986778. Reanalysis after the discovery of a second Dutch EVR family sharing a common ancestor with family D yielded a 2-point lod score of 3.05 at marker D11S1395 on chromosome 11q.

In 2 distantly related affected individuals from a large Dutch pedigree with EVR mapping to chromosome 11q, originally described by van Nouhuys (1982) as family D, Collin et al. (2013) performed exome sequencing and identified heterozygosity for a missense mutation in the ZNF408 gene (H455Y; 616454.0001) on chromosome 11p11. The mutation, which was present in all affected individuals as well as 2 unaffected family members, was not found in 220 ethnically matched controls or 1,154 in-house ethnically matched exomes. Analysis of 9 additional Dutch families with EVR revealed the same H455Y mutation in 1 proband and his affected grand-nephew. Microsatellite and SNP analysis revealed a 9.9-Mb shared haplotype between the 2 families, and genealogic analysis revealed a common ancestor 5 generations previously. Analysis of ZNF408 in another 77 European and 55 Japanese EVR probands revealed heterozygosity for a different missense mutation (S126N; 616454.0002) in a Japanese man; the S126N mutation was also present in his father, who had an erosive vitreoretinopathy phenotype, but it was not found in 191 Japanese controls or in an in-house exome variant database. Functional analysis in COS-1 cells demonstrated that, like wildtype ZNF408, the S126N variant, which involved a moderately conserved residue, localized almost exclusively to the nucleus, whereas the H455Y mutant was present predominantly in the cytoplasm.