Germ-line and somatic <i>EPHA2</i> coding variants in lens aging and cataract

<div><p>Rare germ-line mutations in the coding regions of the human EPHA2 gene (<i>EPHA2</i>) have been associated with inherited forms of pediatric cataract, whereas, frequent, non-coding, single nucleotide variants (SNVs) have been associated with age-related cataract. Here we sought to determine if germ-line <i>EPHA2</i> coding SNVs were associated with age-related cataract in a case-control DNA panel (> 50 years) and if somatic <i>EPHA2</i> coding SNVs were associated with lens aging and/or cataract in a post-mortem lens DNA panel (> 48 years). Micro-fluidic PCR amplification followed by targeted amplicon (exon) next-generation (deep) sequencing of <i>EPHA2</i> (17-exons) afforded high read-depth coverage (1000x) for > 82% of reads in the cataract case-control panel (161 cases, 64 controls) and > 70% of reads in the post-mortem lens panel (35 clear lens pairs, 22 cataract lens pairs). Novel and reference (known) missense SNVs in <i>EPHA2</i> that were predicted <i>in silico</i> to be functionally damaging were found in both cases and controls from the age-related cataract panel at variant allele frequencies (VAFs) consistent with germ-line transmission (VAF > 20%). Similarly, both novel and reference missense SNVs in <i>EPHA2</i> were found in the post-mortem lens panel at VAFs consistent with a somatic origin (VAF > 3%). The majority of SNVs found in the cataract case-control panel and post-mortem lens panel were transitions and many occurred at di-pyrimidine sites that are susceptible to ultraviolet (UV) radiation induced mutation. These data suggest that novel germ-line (blood) and somatic (lens) coding SNVs in <i>EPHA2</i> that are predicted to be functionally deleterious occur in adults over 50 years of age. However, both types of <i>EPHA2</i> coding variants were present at comparable levels in individuals with or without age-related cataract making simple genotype-phenotype correlations inconclusive.</p>