Variable Familial Exudative Vitreoretinopathy in a family harbouring variants in both FZD4 and TSPAN12

To report a family affected by familial exudative vitreoretinopathy (FEVR) in which more severe disease phenotypes segregated with digenic rather than monogenic variants in FEVR-related genes.

Phenotype was documented with high-resolution imaging of retinal structure and wide-field fundus photography. Next-generation sequencing (NGS) of known genes involved in FEVR was performed.

Three affected individuals within a family with FEVR presented with variable disease severity. All three affected family members harboured mutation c.349T>C (p.Cys117Arg) in FZD4. In addition, the youngest family member, a 9-year-old boy, who presented with bilateral tractional retinal detachment, and his mother, who presented with retinal pigmentary alterations and bilateral dragging of the macula and atrophy, both harboured the variant c.565T>C (p.Cys189Arg) in TSPAN12. Both suffered from bilateral severe visual loss. On the other hand, the older sister who presented with mild visual loss, temporal avascularity in the right eye and dragging of the blood vessels over the disc and macula in the left eye did not harbour the variant p.Cys189Arg in TSPAN12.

These data suggest variants in more than one FEVR-related gene can underlie variable expressivity for FEVR phenotypes in a single family. Further studies of phenotype-genotype correlation, including next-generation sequencing, in larger cohorts of patients with FEVR are needed to investigate whether changes in more than one gene coding for proteins in the Norrin-β-catenin pathway are a recurrent cause for variable expressivity in the disease.