How Genetics Factor Into Corneal Disease

The most common question I encounter while working with patients is why did they develop a certain condition. The answer lies in the balance between two factors: genetic risk and environmental risk. Genetic and environmental risks influence one another to ultimately determine the development and progression of a disease. Simply put, the greater a patient’s genetic risk for a disease, the less exposure to environmental risk is needed to develop that disease. This article will examine how genetic testing can help improve outcomes in patients with keratoconus or those at risk for developing the condition.

FOCUS ON: KERATOCONUS

Because an increasing percentage of my time spent on patient care is involved with advanced anterior segment disease and specialty lenses, it is important for me to understand technologies that provide detailed information that is useful for both diagnosing and treating such diseases.

As we know, keratoconus is a progressive disease in which corneal thinning and ectasia occurs, causing irregular astigmatism early in the condition. As keratoconus progresses, the cornea continues to thin, and the ectasia progresses, creating additional levels of irregular astigmatism and higher-order aberrations that are particularly disruptive to visual quality. If keratoconus continues to progress without intervention, it can cause scarring, and in the most severe stages, hydrops can occur.

Treatment

Corneal cross-linking is a treatment option for patients with progressive keratoconus that works by stabilizing the cornea. However, having more clinical information about a patient’s keratoconus can help us manage this condition in a more effective way.

Detection

Early diagnosis of keratoconus typically involves suspicious keratometry readings, reduced BCVA, corneal steepening measured with topography, and corneal thinning measured with tomography. Diagnosis is sometimes clear, but can be unclear, and suspicious findings warrant close monitoring of the patient’s cornea.

Risk factors for developing keratoconus include family history, eye rubbing, allergy, asthma, and eczema.¹ Understanding a patient’s genetic risk can help us provide more targeted management options. Keratoconus is a polygenic disease, meaning it is based on several genetic risk factors. There is a genetic test available to assess an individual’s genetic risk of developing the condition. The test, AvaGen, the Genetic Eye Test (Avellino) involves taking buccal samples from the patient’s cheek and sending them to the lab for analysis. The lab then sends a report to the clinician through a HIPAA-compliant portal and provides a keratoconus risk assessment for the patient based on the analysis of 75 keratoconus–related genes. This gives the clinician and the patient insight into their risk of developing keratoconus.

WHEN TO PERFORM GENETIC TESTING

There are several scenarios that warrant taking a deeper look at a patient’s genetic risk for keratoconus. Early clinical findings that increase suspicion of keratoconus, but do not provide clear diagnosis, may warrant genetic analysis. An individual who has rapidly increasing levels of astigmatism or astigmatism that is oblique or against the rule increases suspicion. Reduced BCVA in a younger, otherwise healthy individual also increases suspicion and may warrant further analysis.

Advanced technologies provide us with greater insights into the health of the cornea, but at times may not provide a clear picture of a patient’s keratoconus diagnosis. For example, anterior corneal surface topography performed on a patient with early keratoconus may not demonstrate steepening that can initially manifest on the posterior surface. However, anterior segment OCT may reveal corneal thinning sooner than traditional corneal topography.

Because clinical presentation can be unclear at times, understanding genetic risk provides additional information on how to manage these patients. Another category of patients who would benefit from genetic testing is those with parents who have keratoconus to provide better guidance on closely monitoring these individuals.

Patients considering refractive surgery may also benefit from a clear understanding of genetic risk. Advanced corneal measurements have provided new ways to assess corneal integrity to rule out the presence of keratoconus prior to performing refractive surgery. Identifying genetic risk helps guide even better decisions for long-term visual outcomes.

Finally, patients undergoing orthokeratology (ortho-k) may benefit from genetic testing for keratoconus. Ortho-k is a procedure in which a lens with a reverse curve design flattens the central portion of the cornea, providing myopic correction for patients after the lenses are removed from the eye. Increasing use of ortho-k for myopia management provides an important opportunity for these patients. For those with suspicious corneal findings prior to initiating ortho-k, however, genetic testing would be warranted to rule out genetic risk, as would wanting to avoid additional pressure on the cornea in these individuals.

WHAT TO DO WITH GENETIC INFORMATION

It is critical to understand how to interpret and use genetic information. Because keratoconus is a polygenic condition, there are several genes that play a role in the risk of its development. With genetic testing, the clinician receives a report that shows whether the patient has a low, moderate, or high risk of developing keratoconus based on an analysis of 75 genes known to be associated with keratoconus. For individuals coming in for regular eye examinations with suspicious findings, but not a clear diagnosis of keratoconus, a moderate or high risk may provide reason for closer monitoring of their corneas to track potential keratoconic progression. Additionally, it could offer guidance on additional environmental modifications, such as controlling itching, which can be a contributory risk factor for progression of keratoconus.

High genetic risk of developing keratoconus my preclude refractive surgery or ortho-k in some patients, whereas low genetic risk provides clinical assurance to proceed with surgeries or treatments. Both of these procedures are meant to be performed on healthy corneas; performing them in patients with genetic risk may result in unwanted clinical outcomes.

CLINICAL EXAMPLE

A 9-year-old female patient came into the office for a comprehensive eye examination. Her parents had no initial concerns. The patient’s entering VA was 20/30 OD, 20/30 OS, and 20/25 OU. Refraction examination revealed -0.50 20/20 OD and -0.50 20/20 OS.

All other ocular health findings were normal. I discussed the patient’s myopia with her parents and described the typically progressive nature of the condition. With her age and low refractive status, the parents decided to proceed with ortho-k to help manage the myopia progression and perhaps halt it at an early age.

Topographies and anterior segment OCT were measured before beginning ortho-k treatment. The findings were unremarkable for frank keratoconus steepening, but did show a slightly asymmetric bowtie appearance that was more obvious in the right eye than the left eye (Figure 1). Anterior segment OCT findings were remarkable for thin corneas OU. Central corneal thickness was 443 mm OD and 449 mm OS (Figure 2). The patient’s keratoconus risk score was calculated using the table proposed by Qin et al.² The patient’s scores were 4 OD and 7 OS; scores above 3 indicate a high risk of keratoconus.

Based on the questionable findings, we ordered keratoconus genetic testing for this patient before initiating ortho-k treatment. The polygenetic analysis revealed a low genetic risk for developing keratoconus (Figure 3), which provided us the necessary information to proceed safely with ortho-k therapy.

USE GENETIC INFORMATION TO YOUR ADVANTAGE

Genetic information about a patient’s risk of developing keratoconus is a valuable clinical tool. Genetic testing provides opportunities for a well-informed clinical decision-making process when treating patients with keratoconus.

Editor’s note: The 9-year-old patient discussed in the clinical case example is the author’s child.