Submission Details

FZD4 was first reported in relation to autosomal dominant familial exudative vitreoretinopathy (FEVR) in 2002 (Robitaille et al., PMID: 12172548). FEVR is characterized by abnormal development of the retinal blood vessels, leading to incomplete vascularization of the peripheral retina. Features can include retinal detachment, vascular leakage, vitreoretinal traction, macular folds, peripheral avascular zones, retinal exudates, and vision loss/blindness. FEVR is known to have a high degree of inter- and intra-familial clinical variability as well as reduced penetrance. FZD4 is one of multiple FEVR genes, and FZD4 is associated with the disease entity exudative vitreoretinopathy 1 (MIM# 133780). FZD4 has also been associated with retinopathy of prematurity (ROP) (MIM# 133780, described in MacDonald et al., 2005. PMID:15733276), however FEVR and ROP have great deal of clinical overlap, and these conditions can co-occur. Studies suggest that a portion of severe ROP cases harbor disease-causing FZD4 variants and represent cases of FEVR in the setting of prematurity (PMID: 26731204). Therefore, this curation has been performed under the disease entity FZD4-related exudative vitreoretinopathy.

Twelve heterozygous variants (missense, in-frame indel, nonsense, frameshift, deletion) that have been reported in fifteen probands in seven publications (PMIDs: 12172548, 14507768, 15035989, 15223780, 15488808, 21177847, 23077402) are included in this curation. The mechanism of pathogenicity is reported to be loss of function. Given the reported variable expressivity and reduced penetrance of FEVR, probands were not excluded from the curation if they had family members who were mutation positive but asymptomatic. Three studies showing linkage of the clinical phenotypes to the FZD4 locus in large pedigrees were available in these publications (PMID:12172548, 15035989, 21177847), and contributed to the scoring of the gene-disease relationship. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Of note, there are limited reports of individuals with biallelic FZD4 variants with severe FEVR (PMIDs: 18161623, 38361102) or syndromic FEVR with hearing loss and developmental delay (PMID: 35951321). In some cases, the parents are reported to have mild ocular features of FEVR (PMID: 18161623), suggesting that semidominant inheritance can occur. These biallelic cases were not included in the present curation. There is not sufficient evidence in the literature at this time to determine if autosomal recessive syndromic FEVR is a separate disease entity related to FZD4.

This gene-disease relationship is also supported by experimental evidence, including animal models, protein interactions, expression studies, and in vitro functional assays (PMIDs: 15035989, 19837032, 21177847, 27489958). FZD4 encodes Frizzled-4 (Fz4), a receptor that plays a crucial role in the Norrin/Fz4/Lrp signaling pathway that is essential for normal vascular development. The biochemical function of Fz4 matches that of the LRP5 co-receptor, which is encoded by a gene in which biallelic and monoallelic variants have been reported to cause FEVR (PMID: 15035989). In the mouse retina, Fz4 (Frizzled4) is expressed in vascular cells (endothelial cells & mural cells), photoreceptors, and some inner retinal neurons (PMID:19837032). Mice with biallelic loss of function mutations in Fzd4 recapitulate human patient phenotypes including abnormal retinal vasculature, impaired vision, and abnormal electroretinogram (PMIDs:15035989, 19837032). In addition, studies with Fzd4 heterozygous mice indicate that haploinsufficiency results in abnormal retinal vasculature development (PMID: 27489958). More evidence is available in the literature, but the maximum score for experimental evidence (6 pts.) has been reached.

In summary, there is definitive evidence supporting the relationship between FZD4 and autosomal dominant FZD4-related exudative vitreoretinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Retina GCEP on April 4th, 2024 (SOP Version 10).