Exudative Vitreoretinopathy, Rare Genetic Variant May Represent New Syndrome

Extraocular syndromic familial exudative vitreoretinopathy (FEVR) is associated with variants in the frizzled class receptor 4 (FZD4) gene, which result in decreased FZD4 signaling, a case series published in JAMA Ophthalmology shows.

This study was conducted at the Dalhousie University in Canada. A patient with FEVR and her parents underwent DNA testing and phenotyping. A combined signaling assay was performed to assess the role of FZD4 variants in FEVR.

The patient with FEVR was a 2-year-old girl who was born at full term after an uncomplicated pregnancy. The patient failed the newborn screening and at 6 months, was found to have congenital bilateral mild to moderate high-frequency sensorineural hearing loss. In addition, at 3 days old, she did not have a right red reflex and was diagnosed with bilateral complete tractional retinal detachment. At 2 years of age after undergoing surgery, the patient had no light perception in the left eye. She was found to have total retinal detachments with aphakic eyes.

The genetic testing revealed two heterozygous FZD4 variants each from 1 parent. The paternal variant was a missense single nucleotide polymorphism (SNP) in exon 2 (c.313A>G) and the maternal variant was a nonsense SNP also in exon 2 (c.1350T>A). The paternal variant has been associated with reduced Norrin-FZD4 signaling and the maternal variant truncates the protein in the middle of the sixth transmembrane domain, completely removing the intracellular tail which is key to Norrin signaling.

In an expression assay, homozygous expression of the paternal variant resulted in a 50% decrease in Norrin-FZD4 signaling and the maternal variant caused a complete loss of signaling. Co-expression of the 2 variants resulted in expression 4-times lower than wild type.

These findings were based on a single patient and may not be generalizable.

“In this case series investigation, a syndrome was presented that was associated with biallelic variants in the FZD4 gene and early-onset severe FEVR accompanied by hearing loss and developmental delay. A very severe defect in Norrin-FZD4 signaling may be the mechanism by which the extraocular phenotypes may manifest,” the investigators report.