Germ-line and somatic EPHA2 coding variants in lens aging and cataract.

Area of Science:

• Ophthalmology and Genetics
• Molecular Biology and Aging

Background:

• Germline mutations in EPHA2 are linked to inherited pediatric cataracts.
• Non-coding EPHA2 single nucleotide variants (SNVs) are associated with age-related cataracts.
• The role of coding EPHA2 SNVs in age-related cataract remains unclear.

Purpose of the Study:

• To investigate the association of germline EPHA2 coding SNVs with age-related cataract.
• To determine if somatic EPHA2 coding SNVs are linked to lens aging or cataract development.

Main Methods:

• Targeted next-generation sequencing of EPHA2 coding regions (17 exons) in adult DNA panels.
• Analysis of a case-control panel (161 cataract cases, 64 controls, >50 years).
• Analysis of a post-mortem lens panel (35 clear, 22 cataract lenses, >48 years).

Main Results:

• Novel and known functionally damaging EPHA2 missense SNVs were detected in both germline (blood) and somatic (lens) DNA.
• Variant allele frequencies were consistent with germline (>20%) and somatic (>3%) origins.
• EPHA2 variants were present at comparable levels in individuals with and without age-related cataract.

Conclusions:

• Germline and somatic coding SNVs in EPHA2, predicted to be deleterious, occur in adults over 50.
• These EPHA2 variants were found in both cataract and non-cataract groups.
• Simple genotype-phenotype correlations between EPHA2 coding SNVs and age-related cataract are inconclusive.