Biallelic Variants in EPHA2 Identified in Three Large Inbred Families with Early-Onset Cataract

Area of Science:

• Genetics
• Ophthalmology
• Molecular Biology

Background:

• Hereditary congenital cataract (HCC) presents significant clinical and genetic diversity.
• Understanding the genetic underpinnings of HCC is crucial for diagnosis and treatment.

Purpose of the Study:

• To investigate the genetic basis of hereditary congenital cataracts in three inbred families (LUCC03, LUCC16, LUCC24).
• To identify specific genetic variants in the EPHA2 gene associated with HCC in these families.

Main Methods:

• Ophthalmological examinations to characterize cataract phenotypes and inheritance patterns.
• Exome sequencing of probands to identify causative genetic variants.
• Computational structural modeling to predict the impact of identified variants on EPHA2 protein structure.

Main Results:

• Recessive inheritance of cataracts was observed in all three families.
• A novel homozygous c.2710delG;p.(Val904Cysfs*36) EPHA2 variant was identified in family LUCC03.
• A known homozygous c.2353G>A;p.(Ala785Thr) EPHA2 variant was found in families LUCC16 and LUCC24.
• Structural modeling indicated that both EPHA2 variants lead to protein misfolding.

Conclusions:

• The EPHA2 gene is implicated in hereditary congenital cataracts, with identified variants causing protein misfolding.
• These findings enhance the understanding of the molecular and phenotypic spectrum of EPHA2-related HCC.
• This research provides valuable insights for genetic counseling concerning EPHA2-related congenital cataracts.