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Genetic testing for inherited diseases

Dermot McGrath

Posted: Saturday, May 1, 2021

Genetic analysis is playing an increasingly valuable role in the diagnosis of a broad range of inherited corneal diseases, according to Joni A. Turunen MD, PhD, FEBO.
Speaking at the 11th EuCornea Virtual Congress, Dr Turunen said that considerable progress has been made in recent years in elucidating the molecular genetic basis of corneal dystrophies and paving the way for novel treatment strategies for these rare eye diseases.
“Genetic tests with high specificity and sensitivity are now commercially available to screen for genetic mutations in the genes responsible for the development of a number of corneal dystrophies,” he said.
Diagnosing inherited corneal disease is a complex process, as the disease may present with other ocular conditions such as developmental eye defects in megalocornea, microphthalmia, anterior segment dysgenesis or congenital cataracts. Systemic genetic syndromes such as Meretoja disease, familial amyloid polyneuropathy type IV and cryopyrin-associated periodic syndromes may also have ocular manifestations, noted Dr Turunen, an ophthalmologist at Helsinki University Hospital and group leader at Folkhälsan Research Center, Helsinki, Finland.
When considering genetic testing for corneal diseases, it is important to understand the kind of inherited diseases present in the specific population group, he said.
“Of course, this is getting more difficult nowadays because almost every country now has more mixed populations. We need to consider the family history of eye diseases and possible inheritance factors, to check for systemic diseases or symptoms and to carry out detailed clinical examinations and imaging,” he said.
Dr Turunen also stressed the importance of genetic counselling to advise patients and their families and to help them understand and adapt to the medical, psychological and familial implications of genetic contributions to disease.
“Genetic testing can be done in one variant at a time when we already know the variant in the family or doing whole-gene sequencing or using targeted gene panels, usually utilising exome sequencing,” he said.
The responsible genes for most corneal dystrophies have been identified in the recent update of the International Classification of Corneal Dystrophies (IC3D) and grouped into four distinct categories, explained Dr Turunen: epithelial and subepithelial dystrophies; epithelial stromal transforming growth factor beta-induced (TGFBI) dystrophies; stromal dystrophies; and endothelial dystrophies.
A lot of research has been conducted into TGFBI-associated corneal dystrophies, with more than 70 different TGFBI mutations described to date. These mutations cause a spectrum of different dystrophies, including granular corneal dystrophy type 1 and 2 (previously designated as Avellino corneal dystrophy), epithelial basement membrane dystrophy (EBMD), lattice corneal dystrophy, Reis-Bücklers corneal dystrophy and Thiel-Behnke corneal dystrophy.
“There is a great deal of clinical heterogeneity and the diagnosis is often unclear especially in younger individuals. Some of the mutations are very certain while others are only suspect. No doubt much of this is because mutations in the TGFBI gene are also responsible for at least five inheritable corneal dystrophies” he said.
The success rate of gene testing depends on quite a few variables, noted Dr Turunen.
“As an indication, a recent poster study from Blueprint Genetics reported that the causative variant for corneal dystrophies was successfully identified in 71% of patients,” he said.
Dr Turunen’s own research in this area has recently focused on two dystrophies: recurrent corneal erosion dystrophy (ERED) and keratoendotheliitis fugax hereditaria.
ERED is an autosomal dominant dystrophy characterised by recurrent corneal erosions presented in the first decades of life, leading to diffuse subepithelial opacities and fibrosis.
“It was reported recently that at least a subset of the patients harbour a mutation of a collagen type XVII alpha 1 chain gene (COL17A1). In our clinical research we have found five families from Finland with ERED carrying the same mutation in COL17A1. Our finding of the same variant in yet another population strengthens the evidence that this variant is a frequent cause of ERED,” he said.
Keratitis fugax hereditaria is another autosomal dominant corneal disease characterised by unilateral attacks of corneal inflammation starting at a median age of 11 years. Symptoms are redness, pain and photophobia, which typically flare up several times a year. Over time, these repeated attacks can cause corneal opacities and reduced vision.
Genetic analysis by Dr Turunen and co-workers identified a pathogenic variant c.61G>C in the NLRP3 gene, encoding cryopyrin, of 34 tested patients affected by keratis fugax hereditaria. “Given that the variant is present in both Finnish and Swedish populations at a frequency of about 0.02% and 0.01%, respectively, we have good reason to suspect that this disease also affects other populations of Scandinavian origin,” he said.
Joni A. Turunen: joni.turunen@helsinki.fi