Whole exome sequencing revealed 14 variants in NDP, FZD4, LRP5, and TSPAN12 genes for 20 families with familial exudative vitreoretinopathy

Abstract

Background Familial exudative vitreoretinopathy (FEVR) is a complex form of blindness-causing retinal degeneration. This study investigated the potential disease-causing variants in 20 Chinese families with FEVR. Methods All available family members underwent detailed ophthalmological examinations, including best-corrected visual acuity and fundus examination. All probands and most family members underwent fluorescein fundus angiography. Twenty probands underwent whole exome sequencing; 16 of them also underwent copy number variant and mitochondrial genome analysis. Bioinformatics analysis and Sanger sequencing of available family members were used to confirm the disease-causing gene variant. Results Twenty families were diagnosed with FEVR based on clinical symptoms, fundus manifestations, and fundus fluorescein angiography. Whole exome sequencing revealed 14 variants in NDP, FZD4, LRP5, and TSPAN12 genes among the 13 families. These variants were predicted to be damaging or deleterious according to multiple lines of prediction algorithms; they were not frequently found in multiple population databases. Seven variants had not previously been reported to cause FEVR: c.1039T>G p.(Phe347Val) in the FZD4 gene; c.1612C>T p.(Arg538Trp) and c.3237-2A>C in the LRP5 gene; and c.77T>A p.(Ile26Asn), c.170dupT p.(Leu57Phe fsTer60), c.236T>G p.(Met79Arg) and c.550dupA p.(Arg184Lys fsTer16) in the TSPAN12 gene. We did not detect any variants in the remaining seven families. Conclusions These results expand the spectrum of variants in the NDP, FZD4, LRP5, and TSPAN12 genes and provide insights regarding accurate diagnosis, family genetic counseling, and future gene therapy for FEVR.

Severe isolated exudative vitreoretinopathy caused by biallelic FZD4 variants

“…The variant has been found in three out of 251 156 alleles reported in gnomAD v.2.1.1. Several patients with FEVR have been reported to carry the variant, apparently as part of an autosomal dominant trait 12 . ClinVar includes an entry for the variant, interpreting it as likely pathogenic (Variation ID: 1068101).…”

“…Several patients with FEVR have been reported to carry the variant, apparently as part of an autosomal dominant trait. 12 ClinVar includes an entry for the variant, interpreting it as likely pathogenic (Variation ID: maintain normal WNT pathway activity. 13 The variant has not been reported in gnomAD, nor has it been described in the literature in relation to FZD4-related disease.…”

Congenital X-linked Retinoschisis and Familial Exudative Vitreoretinopathy: Pathogenesis, Diagnosis, and Treatment

“…Bu bulguların FEVR için doğru tanı, genetik danışmalık ve gelecekte mümkün olabilecek gen tedavileri için yararlı olacağını düşünmekteyiz. [44,45] Sonuç KXR klinik ve OKT görüntüleme ile tanı konulabilen ancak günümüzde etkin tedavisi olmayan bir kalıtsal fundus distrofisidir. Stabil seyreden ve makulaya ilerlemeyen periferik skizis bulunan olguların takibi önerilmekle birlikte, retina dekolmanı ve vitreus hemorajisi gibi komplikasyon gelişen olgular vitrektomiden fayda görebilir.…”

Decrease of FZD4 exon 1 methylation in probands from FZD4-associated FEVR family of phenotypic heterogeneity

“…The NDP gene encodes the extracellular ligand Norrin, which binds specifically to the receptor/coreceptor ( FZD4, LRP5 and TSPAN12 ) and forms a ligand-receptor complex. Upon activation of Norrin signaling, β-catenin translocates to the nucleus, binds to TCF/LEF (T cell factor/lymphoid-enhancing factor) and subsequently modulates gene expression ( 17 – 19 ). Mutations in CTNNA1 induce overactivation of Norrin/β-catenin signaling and interrupt cell junctions ( 20 , 21 ).…”