Triplet repeat expansion-associated inherited corneal disease: from genetic mechanism to clinical consequences

Brief Lay background

Fuchs Endothelial Corneal Dystrophy (FECD) is an inherited eye condition where the cornea – the clear window at the front of the eye – loses its transparency.

A person with FECD will usually develop symptoms after the age of 40, which will then gradually worsen over time. As well as affecting their vision, the condition can also be very painful at advanced stages.

What problem/knowledge gap does it help address

Currently, a corneal transplant is the only effective treatment for patients with advanced FECD. But this surgery is expensive and there is a global shortage of donor tissue. New treatment approaches are urgently needed.

In the UK, around eight out of ten cases of FECD are caused by a type of mutation called a ‘triplet repeat expansion’ within the TCF4 gene – where three letters of the genetic code are abnormally repeated many times over. In other diseases caused by triplet repeats, the longer the length of the expanded sequence, the earlier the onset and severity of the disease – and each generation will inherit a longer triplet repeat expansion and experience more severe and debilitating symptoms.

Aim of the project

To investigate the relationship between triplet repeat expansions within the TCF4 gene and the age of onset and severity of FECD in patients – and explore its inheritance pattern within families.

Key procedures/objectives

1. Analyse genetic data from patients with FECD to examine the relationship between the length of the triplet repeat expansion within the TCF4 gene and the age they require a corneal transplant as a measure of disease severity.
2. Sequence DNA from corneal tissue and blood samples collected from FECD patients during transplant surgery – to compare the length of the triplet repeat expansion within the TCF4 gene in affected and healthy cells from the same person.
3. Study the length of the triplet repeat expansion in the siblings and adult children of FECD patients – to explore how many people who carry the triplet repeat expansion develop the condition and how it changes as it is passed from parent to child. 

Potential impact on people with sight loss

This research could ultimately lead to the development of new treatments – such as innovative gene therapies – which could help prevent or slow down sight loss in people who have a triplet repeat expansion within the TCF4 gene. 

A better knowledge of the impact of triplet repeat expansion mutations in affected cells could also lead to more accurate genetic counselling for FECD patients and their families – helping them to better plan for the future.