Clinical features and genetic spectrum of NMNAT1-associated retinal degeneration

Objectives: To systematically analyse the NMNAT1 variant spectrum and frequency, the associated phenotypic characteristics, and potential genotype-phenotype correlations based on our data and literature review.

Methods: Biallelic potential pathogenic variants (PPV) in NMNAT1 were collected from our in-house exome sequencing data. Whole-genome sequencing was conducted subsequently for patients with only one heterozygous PPV detected in NMNAT1. The clinical data were reviewed and evaluated in detail. Furthermore, the literature was reviewed for reports of NMNAT1 variants and their associated phenotypes.

Results: Eleven NMNAT1 variants, including two novel variants, were detected in 8 families from our cohort. All of the 9 available patients showed generalized tapetoretinal dystrophy at an early age (88.9% in the first decade), and disciform macular atrophy was identified in six patients from five unrelated families. Among a total of 125 patients from 8 families of our cohort and 91 families reported by the available literature, 92.9% patients showed onset of disease in the first year after birth, and 89.0% patients showed visual acuity of 0.05 or lower. All of the 39 patients with fundus photos available presented disciform macular atrophy with generalized tapetoretinal dystrophy. Most (54/80, 67.5%) of causative NMNAT1 variants were missense. The most frequent variants in Caucasian and Asian population are p.E257K and p.R237C, respectively.

Conclusions: Early-onset age, disciform macular atrophy with generalized tapetoretinal dystrophy, and poor visual acuity are the typical features of NMNAT1-associated retinal degeneration. Different variant hot spots of NMNAT1 were observed in different populations.