Frizzle Frazzled

Further ancillary testing was obtained while waiting for the confirmatory result. OCT showed a crowded posterior pole with distortion of the foveal contours (Figure 4). Optic nerve head volumes were 4.24 mm3 OD and 4.89 mm3 OS. Supranormal retinal nerve fiber layer thicknesses were measured in both eyes (Figure 5). B-scan ultrasound showed bilateral hyperechoic signals at the optic nerve heads (Figure 6). Ocular biometry revealed axial lengths of 16.35 mm OD and 16.28 mm OS with normal anterior chamber depths and white-to-white distances (Figure 7). Electroretinography showed reduced scotopic responses and normal photopic responses and implicit times (Figure 8). Similar testing results were obtained in the patient's sister, but with more clear electroretinographic abnormalities including prolonged implicit times OU. Next generation genetic sequencing revealed a novel homozygous variant in the Membrane-type Frizzled-Related Protein (MFRP) gene (MFRP) located on chromosome 11q23.3: NM_031433.3:c.1125G>T (p.Arg375Ser) (Table 1). The variant was found to have a profoundly low allele frequency at 8.88x10-6 at a highly evolutionarily conserved locus (GERP-RS 4.84). The nucleotide substitution disrupts the 3' acceptor splice site of exon 10 and was shown to be damaging to protein structure and function on multimodal in silico analyses (Table 2). These data combine with the highly specific clinical picture to provide definitive evidence for pathogenicity (Richards et al., Genet Med. 2015;17(5):405-24). The final diagnosis is posterior micro-ophthalmos-retinitis pigmentosa-foveoschisis-optic nerve drusen syndrome secondary to a novel mutation in MFRP. MFRP is a membrane protein highly expressed in retinal pigment and ciliary epithelial cells and plays roles in Wnt signaling, emmetropization and photoreceptor maintenance (Almoallem et al. Sci Rep. 2020;10(1):1289). Though the patient's parents denied a family history of consanguinity, homozygosity of this extremely rare autosomal variant implies shared ancestry.