A new study has identified a major genetic contributor to Fuchs’ Endothelial Corneal Dystrophy (FECD), a common cause of vision loss, also highlighting the significant roles of sex and ancestry.
FECD is a common, inherited eye condition that primarily affects the cornea, the clear front part of the eye. It is one of the leading causes of vision loss as people age and is the most common reason for corneal transplants in high-income countries. FECD affects the corneal endothelial cells (CECs), which form a layer responsible for controlling fluid balance in the cornea. When these cells are lost more quickly than usual in people with FECD, the cornea becomes swollen and cloudy, leading to blurred vision.
Research led by UCL Institute of Ophthalmology and supported by NIHR Moorfields Biomedical Research Centre, has investigated a genetic alteration in the TCF4 gene that increases the risk of developing FECD. The severity of the disease is linked to the number of copies of a repetitive DNA sequence called CTG18.1.
Studying the largest cohort to date of 894 FECD patients, it was found that more than 50 copies of the CTG repeat are more prevalent in people of European and South Asian descent. The study also confirmed that FECD is more common in women and the disparity is notably larger in patients who don’t have the CTG18.1 expansion. This indicates sex-specific factors could be at play.
Figures 1a & 1b. Slit-scanning in vivo confocal microscopy images of the corneal endothelium: A) Healthy control cornea: Image of a normal corneal endothelium, showing a uniform hexagonal cell pattern with consistent cell density and no visible guttae or abnormalities (white solid arrowhead). B) FECD: Increased confluency of guttata, illustrating a more extensive presence of these structures.
Professor Alice Davidson, UCL lead investigator of the study said: “We are thrilled to share these findings, which represent a significant step forward in our understanding of FECD. By uncovering the critical role of the CTG18.1 repeat expansion in the TCF4 gene, particularly its impact on disease risk and severity in the context of demographic factors, we are paving the way for more personalised approaches to treatment. Our study not only broadens our understanding of the genetic drivers of FECD across diverse populations but also underscores the importance of integrating genetic testing into clinical care.”
For future treatment and clinical trials, this study suggests the need to investigate further genetic insights to precisely address this condition. Gene therapies targeting CTG18.1 are in development, offering an alternative to the traditional reliance on cornea transplant surgery treatment pathway overshadowed by a global shortage of donor corneas and rising demand due to an ageing population.
The study has been published in JAMA Ophthalmology: For more information, contact: Helen Khan h.khan@ucl.ac.uk
