Severe isolated exudative vitreoretinopathy caused by biallelic FZD4 variants

Familial exudative vitreoretinopathy (FEVR) is linked to disruption of the Norrin/Frizzled‐4 signaling pathway, which plays an important role in retinal angiogenesis. Severe or complete knock‐down of proteins in the pathway also causes syndromic forms of the condition. Both heterozygous and biallelic pathogenic variants in the FZD4 gene, encoding the pathway's key protein frizzled‐4, are known to cause FEVR. However, it is not clear what effect different FZD4 variants have, and whether extraocular features should be expected in those with biallelic pathogenic FZD4 variants. Biallelic FZD4 variants were found in a young boy with isolated, severe FEVR. His parents were heterozygous for one variant each and reported normal vision. In‐vitro studies of the two variants, demonstrated that it was the combination of the two which led to severe inhibition of the Norrin/Frizzled‐4 pathway. Our observations demonstrate that biallelic FZD4‐variants are associated with a severe form of FEVR, which does not necessarily include extraocular features. In addition, variants causing severe FEVR in combination, may have no or minimal effect in heterozygous parents as non‐penetrance is also a major feature in dominant FZD4‐FEVR disease. This underscores the importance of genetic testing of individuals and families with FEVR. Here, we describe a young boy with isolated severe familial exudative vitreoretinopathy (FEVR) and biallelic FZD4‐variants. While FEVR caused by FZD4 variants is considered a dominant disorder, heterozygous family members were asymptomatic. Functional assays demonstrated that it was the combination of the two variants which caused a severe biological effect.