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Background <p>&#xa0;Familial exudative vitreoretinopathy (FEVR) represents a clinically and genetically diverse ophthalmic disorder marked by incomplete development of retinal blood vessels. The <i>NDP</i> gene predominantly underlies X-linked FEVR.</p> Methods <p>Copy number variation sequencing, chromosomal microarray, whole exome sequencing and Sanger sequencing were performed to identify and validate the candidate variant. The functional effect of the candidate variant was further investigated in HEK293 and HeLa cells with pcMINI and pcMINI-N vectors by means of minigene splicing assay in vitro. A summary of known pathogenic variants in the 5′-untranslated regions (5′ UTR) of the <i>NDP</i> gene and their clinical characteristics was formulated.</p> Results <p>&#xa0;Whole exome sequencing identified a novel hemizygous 5′ UTR variant (NM_000266.4: c.-167_-166delinsAAGG) in the <i>NDP</i> gene. Sanger sequencing confirmed cosegregation of this variant with FEVR in the affected family members. Minigene splicing assays demonstrated that this variant resulted in partial deletions in exon 2. Pathogenic variations in the 5′ UTR were categorized into three types: 1. indels in dipyrimidine repeats (exon 1); 2. variants in splice sites (intron 1); and 3. variants in exon 2 (5′ UTR). Among patients with variations in dipyrimidine repeats (5 out of 8), most were diagnosed with retinopathy of prematurity (ROP). Patients with splice-site variants in intron 1 (4 out of 6) were predominantly diagnosed with Norrie disease (ND), while all patients (7 out of 7) with variations in exon 2 (5′ UTR region) were diagnosed with FEVR.</p> Conclusions <p>&#xa0;A likely pathogenic variant was identified in 5′UTR of the <i>NDP</i> gene, and validation confirmed its impact on <i>NDP</i> splicing. The present analysis results also indicate a correlation between the location of the variations in 5′UTR and disease, providing assistance in disease prognosis.</p>

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5′ UTR variant in the NDP gene leads to incorrect splicing and familial exudative vitreoretinopathy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月31日

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  • Siping Liu,
  • Ke Xiong,
  • Xin Jiang,
  • Lijun Tang,
  • Leyi Chen,
  • Yihong Li,
  • Bei Jia

摘要

Background

 Familial exudative vitreoretinopathy (FEVR) represents a clinically and genetically diverse ophthalmic disorder marked by incomplete development of retinal blood vessels. The NDP gene predominantly underlies X-linked FEVR.

Methods

Copy number variation sequencing, chromosomal microarray, whole exome sequencing and Sanger sequencing were performed to identify and validate the candidate variant. The functional effect of the candidate variant was further investigated in HEK293 and HeLa cells with pcMINI and pcMINI-N vectors by means of minigene splicing assay in vitro. A summary of known pathogenic variants in the 5′-untranslated regions (5′ UTR) of the NDP gene and their clinical characteristics was formulated.

Results

 Whole exome sequencing identified a novel hemizygous 5′ UTR variant (NM_000266.4: c.-167_-166delinsAAGG) in the NDP gene. Sanger sequencing confirmed cosegregation of this variant with FEVR in the affected family members. Minigene splicing assays demonstrated that this variant resulted in partial deletions in exon 2. Pathogenic variations in the 5′ UTR were categorized into three types: 1. indels in dipyrimidine repeats (exon 1); 2. variants in splice sites (intron 1); and 3. variants in exon 2 (5′ UTR). Among patients with variations in dipyrimidine repeats (5 out of 8), most were diagnosed with retinopathy of prematurity (ROP). Patients with splice-site variants in intron 1 (4 out of 6) were predominantly diagnosed with Norrie disease (ND), while all patients (7 out of 7) with variations in exon 2 (5′ UTR region) were diagnosed with FEVR.

Conclusions

 A likely pathogenic variant was identified in 5′UTR of the NDP gene, and validation confirmed its impact on NDP splicing. The present analysis results also indicate a correlation between the location of the variations in 5′UTR and disease, providing assistance in disease prognosis.