Norrie disease with asymmetric retinal severity associated with novel NDP variants

Norrie disease (ND) is a severe X-linked retinal disorder caused by variants in the NDP gene and is typically characterized by bilateral total retinal detachment (RD) and blindness in infancy. We report three patients from two unrelated families with NDP-associated retinopathy carrying two NDP variants not previously reported in association with ND: c.365A>G, p.(Tyr122Cys), and c.134T>C, p.(Val45Ala).

Clinical evaluations included fundus examination, fluorescein angiography, ultrasonography, auditory brainstem response testing, and genetic analysis.

Case 1 [p.(Tyr122Cys)] demonstrated asymmetric retinal findings, with retinal dysplasia and avascular retina in one eye and total RD in the fellow eye; retinal photocoagulation was performed in the less severely affected eye. Case 2 [p.(Val45Ala)] showed bilateral total RD and blindness. Case 3, the younger brother of Case 2 with the same variant, exhibited severe fibroproliferative changes in one eye and a falciform retinal fold with peripheral avascular retina in the fellow eye; retinal photocoagulation was performed in the milder eye. The p.(Tyr122Cys) and p.(Val45Ala) variants were each classified as likely pathogenic according to ACMG/AMP criteria.

These cases demonstrate considerable phenotypic variability within the spectrum of NDP-associated retinopathy and highlight the phenotypic overlap between ND and familial exudative vitreoretinopathy, expanding our understanding of genotype -phenotype correlations in NDP-associated retinal disease.