Defining the role of diagnostic genetic testing in glaucoma

Glaucoma genetics research is valuable for defining the molecular basis of the disease and targets for developing curative or even preventive therapies, and it also pro-vides a basis for diagnostic and screening tests.

In 2019, however, genetic testing for glaucoma diagnosis and screening is only ready for prime time in patients with early-onset disease, said Janey L. Wiggs, MD. Dr. Wiggs outlined the role of genetics in glaucoma at the 23rd annual Glaucoma Symposium, held during the 2019 Glaucoma 360 meeting.

“Nine genes are currently known to be responsible for early onset types of glaucoma,” said Dr. Wiggs, Paul Austin Chandler Professor of Ophthalmology, Harvard Medical School, Boston. “Genetic testing for patients with disease onset before age 40 can inform genetic counseling and risk assessment, and identify patients who in the future may benefit from gene-based therapies-some of which are already being devel-oped.”

Dr. Wiggs pointed out that a number of genes associated with adult onset forms of glaucoma have also been discovered. “Emerging polygenic risk scores using genetic variants associated with disease could allow for targeted surveillance and treatment in the future,” she added.

Discussing the role of genetic testing for glaucoma, Dr. Wiggs explained that it is use-ful to divide the disease into early-onset and adult-onset forms.

Early-onset glaucoma

The early-onset glaucomas (occurring before age 40), which include juvenile open-angle glaucoma, primary congenital glaucoma, and anterior segment dysgenesis syndromes, are rare and are caused by mutations that are also rare, but that have a large biological effects and therefore cause severe disease.

The early-onset types of glaucoma have a Mendelian inheritance pattern in families. Causative mutations are identified by genetic linkage studies and exome sequencing.

Dr. Wiggs said there are a number of important benefits of genetic testing for early-onset glaucoma. First, it can be used to target surveillance and therapy to people in the family who are carriers of the causative mutations.

“This eliminates unnecessary surveillance of family members who do not have mutations,” Dr. Wiggs said.

Because information from genetic testing allows determination of the mode of inheritance (autosomal dominant versus recessive), it can also be used to inform genetic counseling and risk assessment for family members.

Importantly, some of the genes that cause early-onset glaucoma are also responsible for systemic diseases. For example, in addition to its association with glaucoma and aniridia, some PAX6 mutations are also associated with Wilms tumor.

Clinical application

Testing for the nine genes known to cause early-onset glaucoma can be done using either a blood sample or saliva specimen. Using the nine gene panel, about 25% of patients with glaucoma onset before age 40 are found to have a mutation-a result that suggests that many genes capable of causing early-onset disease have not yet been found, said Dr. Wiggs.

“If the genetic testing does not find a mutation, we enroll the patient in our research studies to identify new genes so that hopefully we can increase the diagnostic yield to 80% or even 100%,” she said.

Dr. Wiggs described several cases to illustrate how diagnostic genetic testing is used in the care of patients with early-onset glaucoma. One case involved a 40-year-old pa-tient who presented complaining about problems with his vision.

His father had a history of blindness and on examination the patient was found to have elevated intraocular pressure (IOP) and visual field defects. Genetic testing was per-formed and identified a mutation in myocilin that is associated with early-onset glau-coma inherited as a dominant trait.

It was recommended that the man’s two children have genetic testing, and the results showed the mutation was carried by his 13-year-old son, but not by his daughter.

“The son’s IOP and visual field were still normal, but based on the genetic test result, we can develop a surveillance plan that would allow treatment initiation at the very earliest signs of disease,” Dr. Wiggs said. “Importantly, we were able to tell his daugh-ter that her risk of glaucoma was no greater than the risk in the general population.”

Dr. Wiggs also described two children with congenital glaucoma found to have differ-ent genetic mutations despite their similar phenotype. Genetic testing identified a FOXC1 mutation in one child and CYP1B1 mutations in the other infant.

“The genetic counseling for these patients’ families is very different,” she explained. “The FOXC1 mutation has a dominant pattern of inheritance that means everybody in the family has a 50% chance of inheritance of developing disease. The glaucoma caused by mutations in CYP1B1 is a recessive condition, and so two mutant copies of the gene are required for the disease to develop.”

Testing for adult-onset glaucoma

The DNA variants that have been associated with adult-onset glaucoma, which includes primary open-angle glaucoma, pseudoexfoliation glaucoma, and primary angle-closure glaucoma, are commonly found in the populations. By themselves, the mutations have only small effects, and the threshold for the development of clinical dis-ease is reached only when the mutations are present in aggregate or in combination with environmental factors.

“Many genes associated with adult-onset glaucoma have been discovered, and genet-ic risk scores using combinations of these genetic variants are likely to be clinically useful in glaucoma screening and diagnosis,” Dr. Wiggs said.

“Development of a genetic risk score for primary open-angle glaucoma could allow us to identify people who are at greatest risk for severe disease and allow us to tailor surveillance and monitoring for those individuals,” Dr. Wiggs said.