A novel pathogenic CRB1 variant presenting as Leber Congenital Amaurosis 8 and evaluation of gene editing feasibility

Introduction Leber Congenital Amaurosis (LCA) is an inherited retinal disease that presents in infancy with severely decreased vision, nystagmus, and extinguished electroretinography findings. LCA8 is linked to variants in the Crumbs homolog 1 (CRB1) gene.Case Description We report a novel CRB1 variant in a 14-year-old male presenting with nystagmus, worsening vision, and inability to fixate on toys in his infancy. Color fundus photography revealed nummular pigments in the macula and periphery. Imaging studies revealed thickened retina on standard domain optical coherence tomography and widespread atrophy of the retinal pigment epithelium on autofluorescence. Full-field electroretinography revealed extinguished scotopic and significantly reduced photopic responses. Genetic testing demonstrated a novel homozygous variant, c.3057 T > A; p.(Tyr1019Ter), in the CRB1 gene. This variant is not currently amenable to base editing, however, in silico analysis revealed several potential prime editing strategies for correction.Conclusion This case presentation is consistent with LCA8, suggesting pathogenicity of this novel variant and expanding our knowledge of disease-causing CRB1 variants.

Automated summary

This case study provides further evidence for the pathogenicity of the novel CRB1 variant in LCA8, expanding our understanding of disease-causing CRB1 variants.