A number sign (#) is used with this entry because familial exudative vitreoretinopathy-5 (EVR5) is caused by heterozygous mutations in the TSPAN12 gene (613138) on chromosome 7q31. Severely affected individuals with homozygous or compound heterozygous mutations in TSPAN12 have also been reported. In addition, 1 large multiply consanguineous Bedouin family segregating a homozygous TSPAN12 mutation has been reported.

Familial exudative vitreoretinopathy is an inherited blinding disorder caused by defects in the development of retinal vasculature. There is extensive variation in disease severity among patients, even between members of the same family. Severely affected individuals often are registered as blind during infancy and can present with a phenotype resembling retinal dysplasia. Conversely, mildly affected individuals frequently have few or no visual problems and may have just a small area of avascularity in their peripheral retina, detectable only by fluorescein angiography (summary by Poulter et al., 2012).

For a discussion of genetic heterogeneity of familial exudative vitreoretinopathy (FEVR), see EVR1 (133780).

Toomes et al. (2005) studied a large 4-generation Mexican family with FEVR. The proband and his paternal grandfather and a paternal great aunt had bilateral tractional retinal detachments in childhood, whereas 10 other family members were more mildly affected and predominantly exhibited retinal exudation: 7 adults, including the proband's father, had clusters of exudates throughout the retina, and 3 young patients had only isolated exudates. An additional 3 patients were of unclear status, 1 due to bilateral cataracts that obscured the view of the retina, as well as 2 young patients who had minimal abnormalities in the far retinal periphery. The proband had hand-motion vision in his right eye and 20/60 vision in his left eye following treatment; his affected grandfather and great aunt were totally blind. All other family members had 20/20 best-corrected vision except for the individual with cataracts. Slit-lamp examination of the proband and his father revealed nasally displaced pupils without well-defined collarettes and some shallowing of the anterior chambers; indocyanine-green angiography failed to demonstrate normal vascularization of the iris; and fluorescein angiography showed the typical exudates of FEVR and termination of the peripheral vessels before reaching the ora serrata in the proband and macular dragging with peripheral retinal atrophic areas in his father.

Nikopoulos et al. (2010) studied 2 large, unrelated Dutch families segregating autosomal dominant exudative vitreoretinopathy. Patients in both families invariably displayed the peripheral avascular area characteristic of FEVR. Visual acuity varied considerably, ranging from normal to light perception only, as a result of secondary defects such as retinal detachment and retinal exudates.

Gal et al. (2014) reported a large inbred Bedouin family segregating an autosomal recessive variable phenotype of abnormal vitreoretinal vasculature and mutation in the TSPAN12 gene. Of 13 affected family members, 11 were examined. Almost all were blind at birth, but 2 were reported as having low vision at birth, and 1 patient self-reported normal vision initially that deteriorated to complete blindness by the third decade. Of 11 patients examined, 8 had phthisis bulbi bilaterally with no light perception. In the 4 patients with a detailed examination, 1 had 'suspected' Norrie disease, 1 had a 'possible diagnosis' of persistent fetal vasculature, and in the remaining 2, who showed membranes arising from the optic nerve and crossing the vitreous, no definite clinical diagnosis could be made.

In the large 4-generation Mexican family with familial exudative vitreoretinopathy studied by Toomes et al. (2005), inheritance showed a clear autosomal dominant pattern, with male-to-male transmission excluding an X-linked locus.

By performing linkage analysis in a large 4-generation Mexican family with FEVR, Toomes et al. (2005) excluded the 3 known autosomal dominant FEVR loci.

Nikopoulos et al. (2010) performed genomewide linkage analysis in 2 large Dutch families ('A' and 'B') segregating autosomal dominant exudative vitreoretinopathy and obtained a suggestive lod score of 2.34 for a 40.5-Mb genomic region on chromosome 7 in family A and a significant lod score of 3.31 for a 16.7-Mb region on chromosome 7 in family B. SNP and microsatellite alleles in affected individuals defined a 10-Mb shared interval containing many genes. Using array-based sequence capture followed by next-generation sequencing, Nikopoulos et al. (2010) identified variants in 3 candidate genes that were detected in at least 4 nonduplicate reads and had a high score for evolutionary conservation.

Using conventional Sanger sequencing in 2 large Dutch families segregating autosomal dominant exudative vitreoretinopathy mapping to chromosome 7, Nikopoulos et al. (2010) confirmed that a variant detected in the candidate gene TSPAN12 (A237P; 613138.0001) was present in heterozygosity in the probands of both families and in their affected relatives. The variant, which was not found in 140 ethnically matched controls, was also detected in 3 relatives of uncertain clinical status and in 1 healthy individual, suggesting nonpenetrance. Analysis of the TSPAN12 gene in 9 additional Dutch FEVR probands in whom mutations in known FEVR genes had been excluded revealed that the A237P change segregated with the phenotype in 2 of the families, whereas a different missense mutation (G188R; 613138.0002) was found in 2 affected brothers from a third family.

Poulter et al. (2010) screened the TSPAN12 gene in 70 FEVR patients in whom mutations in known FEVR genes had been excluded, and identified 7 heterozygous mutations not present in controls (see, e.g., 613138.0003-613138.0006). The authors stated that there was no correlation between particular mutations or mutation types and phenotypes, and that the variation in eye phenotypes was similar to that reported with other FEVR-causing genes.

Kondo et al. (2011) screened for mutations in the TSPAN12 gene in 90 Japanese probands with FEVR and identified a heterozygous mutation in 3: a previously reported L140X mutation (613136.0004) in 2 and a novel L245P mutation (613136.0007) in 1. The clinical signs and symptoms varied among the patients, but the retinal findings were not different from patients with mutations in other known FEVR-causing genes. Kondo et al. (2011) concluded that mutant TSPAN12 is responsible for approximately 3% of FEVR patients in Japan.

In an affected member of a large 4-generation Mexican family segregating autosomal dominant FEVR, originally studied by Toomes et al. (2005), Poulter et al. (2012) analyzed the TSPAN12 gene and identified a missense mutation (Y138C; 613138.0008). Segregation analysis in the family showed that the 3 most severely affected individuals, the proband, his paternal grandfather, and a paternal great aunt, were homozygous for Y138C, whereas 9 more mildly affected individuals, including the proband's parents, were heterozygous for the missense mutation. Consanguinity was not known in the family, but the parents were from the same village in Mexico and believed that their grandparents might have been distantly related. The proband's 3 sibs, who were asymptomatic and showed no signs of FEVR on indirect ophthalmoscopy, were also heterozygous for Y138C; Poulter et al. (2012) noted that without fluorescein angiography, subtle defects might have been missed, and that the sibs might have been too young to exhibit visible signs of disease such as exudates. In addition, 2 family members previously classified as mildly affected did not carry the mutation; reexamination in their homes showed the presence of retinal exudates but no other features of FEVR. The authors suggested that these individuals represented misdiagnoses or phenocopies, or alternatively, that they might harbor mutations in other FEVR genes. Screening a panel of 10 severely affected FEVR/retinal dysplasia patients without mutations in known FEVR genes revealed a further 3 patients with homozygous or compound heterozygous mutations in TSPAN12 (see, e.g., 613138.0009-613138.0011). Noting the clinical variability seen in FEVR families, Poulter et al. (2012) suggested that patients with severe disease might actually harbor 2 mutant alleles, derived either from the same gene or potentially from other genes encoding components of the norrin (300658)-beta-catenin (116806) signaling pathway.

In a large inbred Bedouin family with variable abnormal vitreoretinal vasculature, Gal et al. (2014) performed exome sequencing in the proband and identified homozygosity for a missense mutation in the TSPAN12 gene (C181F; 613138.0012). The authors noted that the TSPAN12 gene was located within a shared 58-Mb homozygous region with a lod score peak in chromosome 7. Sanger sequencing validated the mutation and its segregation with disease. There were 10 unaffected heterozygotes in the family, 6 of whom had been examined and showed no abnormalities of eye structure or function. The variant was not found in the dbSNP, 1000 Genomes Project, and ESP databases or in 63 ethnically matched controls. The authors noted that the lack of evidence for subclinical symptoms in heterozygotes in this family contrasted with the findings of Poulter et al. (2012). Gal et al. (2014) suggested that this might be a direct reflection of allelic dosage effect, but that there might also be contributions from modifier genes or environmental cues associated with the pathogenesis.