Early detection is critical to the prevention of sight loss from glaucoma. Thanks to recent advances in polygenic genetic risk assessment, ophthalmologists may soon be able to focus on likely presymptomatic cases, creating individualized screening programs and planning future interventions.
“Ophthalmologists don’t actually treat glaucoma.” It’s a point Dr. Janey Wiggs makes often. Speaking at the 10th World Glaucoma Congress in Rome (WGC 2023) in June last year, the eminent ophthalmologist and ocular geneticist elaborated on this theme: Current therapies relieve excess intraocular pressure but do nothing to stop the biochemical mechanisms that disrupt flow through the trabecular meshwork.
Advances in genetics not the full story
From a patient’s point of view, the first unambiguous signs of glaucoma are visual defects due to nerve damage. Thus the emphasis on early detection through screening. Thanks to recent advances1 in polygenic risk assessment, however, ophthalmologists may soon be able to reach the presymptomatic in a more timely and effective manner.
Ocular geneticists like Dr. Wiggs have dedicated their careers to cracking the code behind glaucoma. She describes the “high impact” genes associated with the production of mutant forms of myocilin as the “lowest hanging fruit” in this quest.
Associated with early-onset glaucoma and open-angle glaucoma, mutant MYOC is passed down according to simple Mendelian inheritance patterns. Thus by testing children with a family history for early onset glaucoma, doctors can identify which will be disease-free, which will develop glaucoma and which will be carriers.
Breakthroughs like this have abounded in glaucoma since the genomics revolution revolving around the sequencing of the human genome. But even invaluable discoveries like this don’t tell the whole story.
From genomics to testing
Unfortunately, as Dr. Wiggs acknowledges, most forms of adult-onset glaucoma are of transgenic etiology and don’t follow such predictable inheritance patterns. Thanks to years worth of comparative studies, however, geneticists are now at the point of overcoming this obstacle.
By cross-referencing genomic studies with patient histories, geneticists have painstakingly identified a number of variants–often single nucleotide polymorphisms–that positively correlate with various forms of glaucoma. In January 2020, an Australian research team led by Dr. Jamie Craig announced the discovery that enough genetic loci have at last been identified for reliable polygenic prediction of glaucoma.2
Capitalizing on this discovery, in April 2023 SeonixBio (the Adelaide-based startup cofounded by Craig) debuted SightScore—the first polygenic risk assessment for glaucoma.
SightScore uses AI to compare a patient’s genetics against proprietary research findings and determine the future percentage risk of glaucoma, as well as information about the potential need for treatment and progression to more severe disease.
The predictive power of SightScore is in the numbers. The test analyzes thousands of loci across a patient’s genome. It not only identifies each polymorphism but also factors in the relative weight of each variant to generate a cumulative risk score.
In a recent interview with this magazine, Seonix’s CEO, Dr. Nick Haan, discussed the potential benefits of polygenic risk assessment for the treatment of glaucoma treatment.
“We have good treatments but don’t identify glaucoma as early as we could,” he said. “Half of glaucoma patients go undiagnosed.” He describes polygenic scoring as “another risk factor for a clinician to consider when making decisions about clinical interventions.”
Beneficiaries of polygenic risk score testing
According to Dr. Haan, three groups stand to benefit most from tests like SightScore. First, glaucoma suspects will be able to learn their likelihood of developing the disease. Their PRS score can also be used to predict the timing of onset and potential for disease progression.
Early to moderate-stage glaucoma patients will also gain a sense of potential disease progression. In addition, existing patients will also gain insight into which therapies are best suited to their condition as well as when or whether their current treatment regimen will need to be changed.
Finally, family members of glaucoma patients will be apprised of their own lifetime glaucoma risk and potential for serious disease. From this information, doctors can determine when or whether patients will need to begin screening.
The future of research, tailored therapies and more
With regulatory approval for commercial application still in the offing, Dr. Haan is, however, careful to limit prognostications as to SightScore’s eventual impact on overall clinical outcomes. Dr. Wiggs is more effusive.
Her presentations routinely cite the high correlation found by Dr. Craig’s team between top decile risk scores and overall incidence of glaucoma as well as disease severity and progression rate. Dr. Wiggs sees polygenic risk testing as not only the key development in the quest for presymptomatic diagnosis but also a tool for tailoring therapies throughout a patient’s disease arc.
Polygenic risk score testing promises a more efficient future for the early mitigation of glaucoma than the current gold standard of ongoing, indiscriminate screening. Before long a saliva sample will be sufficient to let the son or daughter of a parent with glaucoma know whether they need to keep an eye out for the same condition or remain blissfully estranged from the examination chair.
And just as the negative test confers peace of mind, the positive one will offer the gift of time. Genetic testing for colon and breast cancer has saved or prolonged many lives–in some cases even outright disease prevention.
While no prophylactic yet exists for glaucoma, genetic testing can inspire doctor-patient conversations on beneficial lifestyle changes to delay onset, slow progression and improve prognosis. Should disease prove inevitable, early action will go a long way toward limiting its severity and ensuring the best patient outcomes.
References
- Jain A, Zode G, Kasetti RB, et al. CRISPR-Cas9-based treatment of myocilin-associated glaucoma. Proc Natl Acad Sci U S A. 2017;114(42):11199-11204.
- Qassim A, Souzeau E, Siggs OM, et al. An Intraocular Pressure Polygenic Risk Score Stratifies Multiple Primary Open-Angle Glaucoma Parameters Including Treatment Intensity. Ophthalmology. 2020;127(7):901-907.