Identification and characterization of NMNAT1 gene mutations in an Iranian patient with Leber congenital amaurosis 9

Abstract

Key clinical message: The discovery of compound heterozygous NMNAT1 mutations (c.245T>C; p.Val82Ala and c.575A>G; p.Asp192Gly) provides a genetic explanation for Leber congenital amaurosis 9 in an Iranian patient. The proband's symptoms-including severe visual impairment, nystagmus, night blindness, and retinal degeneration-align with Leber congenital amaurosis 9 clinical features. This case underscores the value of exome-sequencing in diagnosing rare genetic disorders and highlights its role in guiding personalized genetic counseling and potential treatments.

Abstract: Leber congenital amaurosis is a severe early-onset inherited retinal dystrophy. This study delves into the genetic basis of Leber congenital amaurosis, pinpointing compound heterozygous mutations in the NMNAT1 gene as significant causative factors. While one mutation validates previous findings (c.245T>C; p.Val82Ala), the second (c.575A>G; p.Asp192Gly) proves novel, expanding the genetic landscape of Leber congenital amaurosis 9. Both mutations, inherited independently from nonconsanguineous parents, contribute to the intricate genetic basis of light on Leber congenital amaurosis 9 in this case. The identified mutations shed light on Leber congenital amaurosis genetics in the Iranian population, showcasing the efficacy of exome-sequencing for molecular diagnoses in hereditary retinal degeneration. These findings provide valuable insights for tailored genetic counseling and potential therapeutic interventions.

Keywords: Leber congenital amaurosis; NMNAT1 gene; exome‐sequencing; mutation.

FIGURE 1

The pedigree of the studied family. Male members are denoted by squares, while females are represented by circles. Affected individuals are marked with enclosed symbols, and the proband is distinguished by an arrow.

FIGURE 2

Results of Sanger sequencing are depicted, revealing compound heterozygous mutations in the proband. Specifically, the identified variants are c.245T>C; p.Val82Ala and c.575A > G; p.Asp192Gly of NMNAT1. The father exhibits the heterozygous c.575A>G; p.Asp192Gly mutation, while the mother carries the heterozygous c.245T>C; p.Val82Ala mutation.