NMNAT1 early-onset retinal dystrophy (EORD) caused by a novel 5‘UTR splice donor variant

BACKGROUND: NMNAT1 variants are a recognized cause of Leber congenital amaurosis (LCA), but NMNAT1-associated early-onset retinal dystrophy (EORD) phenotype remains rarely reported. Standard inherited retinal dystrophy (IRD) gene panel testing is limited in its ability to detect pathogenic non-coding variants, which are systematically excluded from conventional testing. MATERIALS AND METHODS: A 6-year-old female underwent comprehensive ophthalmic examination, followed by a 330 gene IRD panel, whole-genome sequencing (WGS) and parental segregation. RESULTS: The patient presented with nystagmus, esotropia, and reduced visual acuity. Multimodal imaging revealed atypical bilateral maculopathy while full-field ERG responses were borderline. The IRD panel was negative and subsequent WGS identified compound heterozygous NMNAT1 variant, a novel 5'UTR splice donor variant (c.-57 + 1 G > C) and a missense variant (c.480 G > C, p. Leu160Phe) confirmed to be in trans by parental segregation analysis. CONCLUSION: We report a novel NMNAT1 5'UTR splice donor variant in a case of NMNAT1-associated EORD, expanding the genotypic and phenotypic spectrum of NMNAT1 disease. Comprehensive genomic analysis is essential for diagnosing atypical IRD presentations.