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. 2021 Jun 27;12(7):980.
doi: 10.3390/genes12070980.

Whole-Gene Deletions of FZD4 Cause Familial Exudative Vitreoretinopathy

Li Huang  1 , Jinglin Lu  1 , Linyan Zhang  1 , Zhaotian Zhang  1 , Limei Sun  1 , Songshan Li  1 , Ting Zhang  1 , Limei Chen  1 , Liming Cao  1 , Xiaoyan Ding  1
Affiliations

Whole-Gene Deletions of FZD4 Cause Familial Exudative Vitreoretinopathy

Li Huang et al. Genes (Basel). .

Abstract

Familial exudative vitreoretinopathy (FEVR) is an inherited disorder characterized by abnormalities in the retinal vasculature. The FZD4 gene is associated with FEVR, but the prevalence and impact of FZD4 copy number variation (CNV) on FEVR patients are unknown. The aim of this study was to better understand the genetic features and clinical manifestations of patients with FZD4 CNVs. A total of 651 FEVR families were recruited. Families negative for mutations in FEVR-associated genes were selected for CNV analysis using SeqCNV. Semiquantitative multiplex polymerase chain reaction and multiplex ligation-dependent probe amplification were conducted to verify the CNVs. Four probands were found to carry whole-gene deletions of FZD4, accounting for 5% (4/80) of probands with FZD4 mutations and 0.6% (4/651) of all FEVR probands. The four probands exhibited similar phenotypes of unilateral retinal folds. FEVR in probands with CNVs was not more severe than in probands with FZD4 missense mutations (p = 1.000). Although this is the first report of FZD4 CNVs and the associated phenotypes, the interpretation of FZD4 CNVs should be emphasized when analyzing the next-generation sequencing data of FEVR patients because of their high prevalence.

Keywords: FZD4; copy number variation; familial exudative vitreoretinopathy; retinal fold; whole-gene deletion.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Fundus fluorescein angiography (FFA) of XDW248. FFA showed macular dragging and supernumerary branching in the right eye (A) and vitreous opacity and a retinal fold in the left eye (B).
Figure 2
Figure 2
Clinical features of DX1344. B-scan ultrasonography showed vitreous opacity in the right eye (A) and retinal folds in the left eye (B). Scanning laser ophthalmoscopy showed pigmentation on the nasal retina of the right eye (C) and retinal folds in the left eye (D).
Figure 3
Figure 3
Clinical features of DX1561. B-scan ultrasonography showed a normal retina and vitreous in the right eye (A) and retinal folds in the left eye (B). Scanning laser ophthalmoscopy showed a normal retinal anatomy of the right eye (C) and retinal folds in the left eye (D).
Figure 4
Figure 4
Clinical features of DX1988. RetCam showed avascular area in the temporal part in the right eye (A) and retinal folds in the left eye (B). Fundus fluorescein angiography showed supernumerary branching in the right eye (C) and retinal folds in the left eye with leakage (D).
Figure 5
Figure 5
FZD4 CNVs detected by SeqCNV. (A) A 0.51 Mb deletion was detected in XDW248. (B) A 4.5 Mb deletion was detected in DX1344. (C) A 0.51 Mb deletion was detected in DX1561. (D) A 0.15 Mb deletion was detected in DX1988. (E) Normal control without a deletion within the same region as (A,C,D). (F) Normal control without a deletion within the same region as (B).
Figure 6
Figure 6
Confirmation of whole-gene deletions of FZD4 using semiquantitative multiplex PCR. (A) The pedigrees of the four families with FZD4 CNVs. (B) Representative histograms of FZD4 exons 1 and 2 compared to other family members. TTLL5 exon 14 and SPATA7 exon 6 were used as controls. XDW248 and XDW248F were affected in family XDW248. DX1344 was affected in family DX1344. DX1561, DX1561F, DX1561A, and DX1561C were affected, and DX1561M was unaffected in family DX1561. DX1988, DX1988F, and DX1988S were affected, and DX1988M was unaffected in family DX1988. (C) The structure of FZD4 which contains two exons. The blue arrow indicated where the PCR primers located.
Figure 7
Figure 7
Confirmation of whole-gene deletions of FZD4 using MLPA. The MLPA analysis of XDW248 (A), DX1344 (B), DX1561 (C), DX1988 (D), and XDW248F (E). The arrows indicate a half-reduced relative peak height corresponding to FZD4 gene exon 1 and exon 2 probes. E. DX1344M is normal with no signal alterations in any FZD4 probes. *NDP is a gene on the X chromosome; the males (B,D,E) had half-reduced relative peak in NDP probes, which is normal compared to the females (A,C,F). (G) The MLPA probes ligation sites were listed. Probe 1 (blue arrow) and probe 2 (red arrow) were ligated to FZD4 exon 1. Probe 3 (black arrow) was ligated to FZD4 exon 2.
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