A recent study sheds light on tissue-specific instability in Fuchs Endothelial Corneal Dystrophy, the leading cause of corneal transplantation.
The study published in eBioMedicine utilized optical genome mapping (OGM) to explore CTG18.1 repeat expansions, the primary genetic risk factor for Fuchs Endothelial Corneal Dystrophy (FECD) across ethnic groups, which exclusively affects corneal endothelial cells (CECs). FECD is also the most common short tandem repeat (STR) expansion disease in humans.
The study analyzed genomic DNA samples from both affected corneal endothelial cells and unaffected peripheral blood leukocytes using OGM to size the CTG18.1 repeat expansions and investigate tissue-specific instability. Researchers recruited patients with clinical signs of FECD, removing diseased corneal endothelium during corneal transplantation surgery. Control samples came from corneal tissue discarded from donors.
After targeted genotyping and analysis, the study found that expanded CTG18.1 alleles, regardless of cell-type origin, exhibit dynamic behavior. However, specific clusters of CTG18.1 molecules were only detected in diseased CECs from expansion-positive cases. In contrast, repeats in leukocytes remained stable and shorter. The study reveals that CTG18.1 repeats may expand dynamically when the repeat size exceeds 63 CTG repeats, though future research is required to refine this threshold.
Additionally, OGM detected expanded CTG18.1 alleles in CECs but could not discriminate between samples with smaller alleles, suggesting a limitation when repeat sizes are below 166 CTG repeats. Moreover, progenitor allele size and age were also found to influence leukocyte-specific CTG18.1 instability levels.
The findings indicate CTG18.1 instability is a major component of FECD pathophysiology. The researchers conclude their findings demonstrate that FECD is likely a translationally relevant model system for a range of rare, and currently incurable, repeat-mediated human diseases that are also marked by somatic instability mechanisms.
A full list of author disclosures can be found in the published research.
