Identification of a novel C-terminal extension mutation in EPHA2 in a family affected with congenital cataract.

Congenital cataracts occur in 3-4 per 10,000 live births and account for 5% to 20% of pediatric blindness worldwide. With more than 37 genes known to be associated with isolated congenital cataract, whole exome sequencing (WES) was recently introduced as an efficient method for screening all known factors. Whole exome analysis in two members of a four-generation pedigree affected with dominant congenital cataract and glaucoma was performed by WES; co-segregation analysis of identified variants in all pedigree members was completed by Sanger sequencing. Analysis of the WES data identified a novel pathogenic variant in EPHA2, c.2925dupC, p.(Ile976Hisfs*37), that demonstrated complete cosegregation with the phenotype in the pedigree. The mutation occurs in the final amino acid before the stop codon of the normal EPHA2 protein and is predicted to produce a mutant protein with an erroneous C-terminal extension of 35 amino acids. Nine other families have been previously reported with dominant congenital/juvenile cataracts and mutations in EPHA2. Two additional likely loss-of-function variants in genes known to cause dominant congenital cataract were considered and excluded based on control data and cosegregation analysis: a nonsense variant in CYRBB3, c.547G>T, p.(Glu183*), and a splicing variant in CRYBA2, c.446+1G>A. Identification of a novel pathogenic EPHA2 allele further implicates this gene in congenital cataract. This is only the second EPHA2 mutation that specifically affects the most C-terminal PSD95/Dlg/ZO1 (PDZ)-binding motif and the third pathogenic allele associated with an erroneous C-terminal extension beyond the normal stop codon.