CRB1-Related Leber Congenital Amaurosis: Reporting Novel Pathogenic Variants and a Brief Review on Mutations Spectrum

Abstract

Background: LLeber congenital amaurosis (LCA) is a rare inherited retinal disease causing severe visual impairment in infancy. It has been reported that 9-15% of LCA cases have mutations in CRB1 gene. The complex of CRB1 protein with other associated proteins affects the determination of cell polarity, orientation, and morphogenesis of photoreceptors. Here, we report three novel pathogenic variants in CRB1 gene and then briefly review the types, prevalence, and correlation of reported mutations in CRB1 gene.

Methods: Whole exome sequencing and targeted gene panel were employed. Then validation in the patient and segregation analysis in affected and unaffected members was performed.

Results: Our detected novel pathogenic variants (p.Glu703*, c.2128+1G>A and p.Ser758SerfsX33) in CRB1 gene were validated by Sanger sequencing. Segregation analysis confirmed the inheritance pattern of the pathogenic variants.

Conclusion: Our findings show that emerging the next-generation sequencing-based techniques is very efficient in identifying causative variants in disorders with locus heterogeneity.

Keywords: CRB1; Leber congenital amaurosis; Retinal dystrophies; Whole exome sequencing.

Fig. 1

Spectrum of mutations in functional domains of CRB1. Our novel pathogenic variants are illustrated with red color. The schematic representation of CRB1 domains was obtained from Phosphosite database (https://www.phosphosite.org/proteinAction?id= 11964200&showAllSites=true). EFG, EGF-like domain (Pfam: PF00008); hEGF, human growth factor-like EGF (Pfam: PF12661); Laminin_G_2, laminin G domain (Pfam: PF02210); TM, transmembrane

Fig. 2

Pedigrees of the investigated families. Probands were indicated by arrowheads

Fig. 3

Genotypes of the probands. (A) c.2107G>T in LC3288; (B) c.2276_2279dupCTTA in LC2708; (C) c.2128+1G>A in LC1815. Arrows show position of the variants