Genetic test determines risk for keratoconus and corneal dystrophies

When evaluating patients for LASIK or irregular astigmatism, oftentimes their diagnostic images and an environmental risk assessment don’t give a clear picture on how to proceed. But when I use Avellino’s AvaGen test, the first genetic eye test that helps to determine the risk of keratoconus and the presence of corneal dystrophies, I get an important piece of data to help solve the puzzle.

AvaGen gives me extra confidence in clinical decision making regarding follow-up, next steps, and/or clearance for potential corneal refractive surgery. I became an early adopter of the laboratory developed test when it became available in 2019.

ACCURACY COUNTS

The analytical metrics for AvaGen show a sensitivity of 100%; specificity of 100%; accuracy of 100%; and a precision of 92.7%.¹

Keratoconus is a progressive vision disorder affecting approximately 885,000 people (1 in 375), but the actual prevalence of keratoconus varies significantly based on different studies.^2-4 It is often underdiagnosed or misdiagnosed in its early stages, when it can be better managed and treated to protect and preserve vision.

Incorrect diagnosis can occur because keratoconus has general symptoms associated with other eye conditions, such as:

• Blurring of vision and/or loss of vision
• Decreased tolerance to contact lenses
• Increased sensitivity to light and glare
• Difficulty driving at night
• A halo around lights and ghosting (especially at night)
• Eye strain
• Eye irritation, redness, swelling, and/or excessive eye rubbing

In addition to being unable to clearly identify subtle findings via topography alone, misdiagnosis of keratoconus can occur as a result of a “two-hit hypothesis.” For example, identical twins with keratoconus risk may have different outcomes. One may progress to clinical keratoconus because of atopy and eye rubbing or LASIK, while the other twin may stay subclinical without progression due to a different set of factors.

Corneal dystrophies are a rarer group of genetic diseases, which can cause vision loss, pain, and discomfort for the nearly 280,000 Americans with this condition.⁵ Other diagnostic tools are often unable to provide a definitive diagnosis, as AvaGen does.

RISK FACTORS

Keratoconus is a polygenic disease, and TGFBI-related corneal stromal dystrophies are monogenic. AvaGen provides a validated keratoconus genetic risk score, which is adjusted to a patient’s ethnicity and genetic risk, which allows me to truly provide precision medicine.

According to a study published in the American Journal of Ophthalmology,³ several populations at the greatest risk for these conditions are those with Middle Eastern descent (1 in every 21 people) and individuals whose origins are traced to the Netherlands (1 out of every 375 people). Asian and Indian populations also have higher risks for keratoconus.^6,7

Over time, AvaGen data may also help to further pinpoint how ethnicity influences keratoconus and corneal dystrophies, allowing for better patient management. In addition to genetics, other risk factors for keratoconus include comorbid systemic diseases, including atopy, asthma, ocular allergies, floppy eyelids, sleep apnea, atopic dermatitis, connective tissue disorders (Down syndrome and Marfan syndrome); prior refractive surgery; family history; and frequent eye rubbing.

WHAT’S INVOLVED?

AvaGen is a simple, yet powerful test. It only requires a cheek swab test, which is then sent to Avellino’s high-complexity CLIA-certified laboratory for analysis. Ordering physicians receive results in days in an intuitive and actionable report via a HIPAA-secured patient portal.

A genetic counselor provides an optional complimentary consult to the ordering physician and patient, which can last up to 30 minutes.

HOW IT HELPS

AvaGen examines 75 keratoconus-related genes and more than 2,000 gene variants to develop an actionable keratoconus genetic risk score.⁷

For corneal dystrophies, AvaGen determines if a patient has any of the 70 TGFBI gene variants associated with the condition, and provides a conclusive diagnosis of stromal corneal dystrophy subtypes, such as Epithelial Basement Membrane, Granular, Lattice, and Avellino disease distinctions, Reis-Bucklers, Schnyder, and Theill-Behnke.

There are many benefits to diagnosing keratoconus earlier. Because it’s a progressive disease, the sooner I diagnose it the better chance I have to stabilize and preserve vision with FDA-approved interstrand cross-linking (ICL) treatment. A patient who begins this treatment after already showing signs of keratoconus may have a more negative outcome compared with someone who starts treatment many years earlier. If left untreated, poor vision can only be corrected with corneal transplantation.

Furthermore, understanding a patient’s genetic risk for keratoconus helps me to determine if a patient is a candidate for LASIK, corneal refractive surgery (PRK), or ICL surgeries, with or without cross-linking. If LASIK, PRK, or small incision lenticule extraction (SMILE) is performed on a patient with keratoconus, secondary ectasia can occur.

AvaGen has helped me to both rule in cross-linking treatment for patients I would have waited on, and rule out corneal laser vision correction (LVC) and instead offer ICL surgery. It also helps me to establish an earlier baseline of a patient’s risk for disease. I can increase monitoring, education, or management strategies.

The AvaGen test can also serve as a warning to keratoconus patients, who can then notify close family members, such as siblings or children, and recommend that they get genetically tested so keratoconus can be caught and stabilized at the subclinical or early stage.

IDENTIFYING CANDIDATES

Until now, genetic data has been missing from the equation. I order AvaGen whenever I have any red flag concerns in refractive surgical evaluations, such as high astigmatism (>2 D), steep corneal curvature (>45 D), patients whose astigmatism or myopia accelerates rapidly, against-the-rule or irregular astigmatism, a truncated central bowtie of astigmatism in younger patients of any amount, a thin cornea (<520 microns), or a patient’s family members have keratoconus.

The main disadvantage to patients is their out-of-pocket cost of $300, because health insurers don’t cover it. However, that amount isn’t significant enough to not recommend it; and 80% of patients I recommend it to get it. Patient feedback has been positive. I think people are getting used to genetic testing as part of their health care, and they understand that this information is useful.

CONCLUSION

Today, advanced ocular measures are available with many different devices. Although these instruments can help ophthalmologists have greater confidence in clinical decision-making, most physician offices only have a placido topographer and perhaps a tomography machine because most instruments are quite expensive. Furthermore, devices for biomechanics of the cornea (e.g., Courvis ST, Pentacam) and corneal epithelial mapping (e.g., corneal OCT) are too complex for many clinicians to use in their everyday practices.

As a corneal specialist, I only have a Pentacam, a few placido topography devices, and a corneal hysteresis device. AvaGen provides valuable information without adding any significant capital expenses to my practice or occupying office space.

As I gain experience with AvaGen, I may require patients to take the test prior to seeing me, so that I have all of their scores related to topography, tomography, and corneal hysteresis. This will enable me to assess patients as thoroughly as possible, and to make the process more efficient.

I am thrilled that genetic testing has entered the eyecare industry. We have needed this type of advanced technology for some time now. AvaGen is the first of many genetic-based tests that I hope will be available for eyecare professionals. ■

References

1. Data on file at Avellino Lab.
2. Gordon-Shaag A, et al. Biomed Res Int. 2015:795738.
3. Godefrooij DA, et al. Am J Ophthalmol. 2017;175:169-172.
4. Torres Netto EA, et al. Br J Ophthalmol. 2018;102:1436-1441.
5. Musch DC, et al. 2011. Available at https://bit.ly/2YxXTeJ . Last accessed Aug. 11, 2021.
6. Wheeler J, et al. The genetics of keratoconus: a review. Reprod Sys Sexual Disord. 2012;June 3 (Suppl 6):001.
7. Hashemi H, et al. Cornea. 2020;39(2):263-270.