NDP – Familial Exudative Vitreoretinopathy

Familial exudative vitreoretinopathy (FEVR) is a hereditary retinal vascular disorder characterized by incomplete peripheral vascularization leading to exudation, neovascularization, and tractional retinal detachments. Norrin, encoded by NDP, is a secreted ligand that activates the Wnt/β-catenin pathway through FZD4 and LRP5 co-receptors, a critical signaling axis for retinal angiogenesis.

Inheritance is X-linked recessive, with multiple families demonstrating cosegregation of NDP variants and FEVR. In a Chinese pedigree, a novel missense variant c.310A>C (p.Lys104Gln) was identified in all four affected males and in three carrier females, but absent in unaffected relatives (PMID:27720678). Similarly, a four-generation family harbored c.370C>T (p.Leu124Phe) in NDP, segregating perfectly with disease in affected males (PMID:8252044). These segregation patterns across unrelated pedigrees support a definitive gene–disease relationship.

Across cohorts, NDP variants account for approximately 5–10% of FEVR probands. The spectrum includes missense changes (p.Lys104Gln, p.Leu124Phe), frameshift insertions (c.37dup (p.Leu13ProfsTer13)), and exon deletions. Skewed X-inactivation in heterozygous females explains variable expressivity in female carriers (PMID:38472449). Multiple novel and recurrent alleles have been described in diverse ethnic groups.

Functional assays corroborate loss-of-function as the mechanism of pathogenicity. The Leu13ProfsTer13 variant markedly reduces Norrin protein levels without affecting mRNA, impairs β-catenin reporter activity in luciferase assays, and disrupts secretion (PMID:38472449). Ndp knockout mice phenocopy the human retinal vasculopathy, confirming the critical role of Norrin signaling in vascular development.

No robust conflicting evidence has emerged; mosaic X-chromosome anomalies and modifier alleles may modulate penetrance but do not refute the causal link. NDP remains a less frequent but definitive cause of FEVR compared with FZD4 or LRP5.

In conclusion, NDP meets the highest ClinGen criteria for a definitive gene–disease association in X-linked FEVR, supported by segregation in multiple families, a clear LoF variant spectrum, and concordant functional data. Clinical genetic testing for NDP is essential for accurate diagnosis, family counseling, and therapeutic decision-making. Key Take-home: NDP variant analysis should be included in FEVR genetic panels to guide personalized management.

References

• Nature Genetics • 1993 • A mutation in the Norrie disease gene (NDP) associated with X-linked familial exudative vitreoretinopathy. PMID:8252044
• Journal of the Chinese Medical Association • 2016 • A novel missense mutation of NDP in a Chinese family with X-linked familial exudative vitreoretinopathy. PMID:27720678
• Molecular genetics and genomics • 2024 • Characterization of a novel heterozygous frameshift variant in NDP gene that causes familial exudative vitreoretinopathy in female patients. PMID:38472449

Evidence Based Scoring (AI generated)