Multiomics Analysis Illuminates the Molecular Basis of Autosomal Dominant Optic Disc Drusen.

Abstract

Purpose : Autosomal Dominant Optic Disc Drusen (AD-ODD) is a hereditary eye disorder characterized by atypical calcified deposits in the optic nerve head. Despite its clinical importance and familial nature, the genetic and molecular foundations of AD-ODD are not fully elucidated. This study employs comprehensive multiomics analysis to unravel the intricate genetic and molecular landscape of AD-ODD, shedding light on the underlying pathogenic mechanisms and offering potential insights for therapeutic interventions in affected individuals.

Methods : We prospectively recruited a family with AD-ODD (6 affected members, ages 7-76 years) and performed clinical imaging. Whole-genome sequencing was used to detect rare genetic variants in the DNA isolated from saliva samples. Skin punch biopsies were performed on all the affected, one un-affected members of the family and 3 Healthy controls. Primary skin fibroblasts were cultured and used for transcriptomics, proteomics, and metabolomics.
Bioinformatics tools including Mass Hunter, STRING, DAVID and IPA were employed to identify key gene expression patterns, and molecular pathways.

Results : Fibroblast proteomics analysis of over 7500 proteins revealed that the top significantly decreased molecules impacted various aspects of mitochondrial function, lipid metabolism, and solute transport. The top increased molecules are involved in modification of the extracellular matrix and fibrosis, like those in age-related macular degeneration and other neurodegenerative diseases. Heatmap of top decreased 21 mitochondrial proteins revealed that the 2 most severely affected members of the family had the lowest levels of these proteins. Transcriptomic analysis revealed RNA expression signatures of AD-ODD patients were similar to disease pathways involved in Familial hypocalcemia and Cholelithiasis. Differential metabolomic analysis revealed a significantly altered metabolites of the N-acetylneuraminate biosynthesis, TCA Cycle and Pyruvate dehydrogenase Complex related pathways.

Conclusions : Using multiomic analysis of skin fibroblasts from patients with autosomal dominant optic disc drusen, we found that top molecular changes include defects in mitochondrial function, lipid metabolism, and solute transport. These results will serve as spring board for understanding pathogenesis of disease.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.