Genetic Testing Vs Traditional Diagnostics for Keratoconus

We are still learning about the role of genetics in keratoconus. By and large, we know that keratoconus is a multifactorial disease associated with eye rubbing, atopic diseases, connective tissue disorders and Down syndrome.

Most patients have no known family history of the disease. The large Collaborative Longitudinal Evaluation of Keratoconus (CLEK) study, for example, showed that only 13.5% of those with keratoconus had a family history (Wagner et al.). However, there is significant evidence of a familial risk for keratoconus. Having a first-degree family member (parent, child or sibling) with keratoconus increases the risk for developing the disease by 15 to 67 times (Wang et al.).

There is still much to learn about how to interpret genetic testing for keratoconus.

In a paper presented at the 2022 American Society of Cataract and Refractive Surgery meeting, detailed clinical evaluations of 90 healthy participants whose siblings had keratoconus revealed that 30% of the healthy siblings - most of whom could see 20/20 uncorrected - had definitive keratoconus (11.5%) or suspicious topographies (18.8%) (Christy).

Where do genetic tests fit in practice?

Until recently, the role of genetics was mostly an academic puzzle without much relevance to clinical practice. With the availability of a genetic test for corneal diseases (AvaGen, Avellino), however, there is renewed interest in what this test means for patients and whether it should have any influence over our management of keratoconus.

AvaGen is an in-office cheek swab test that is administered by an eye care provider. For monogenic corneal dystrophies, such as granular dystrophy type 1 and 2, it provides a definitive yes or no result. Keratoconus, however, isn’t defined by a single genetic mutation. It is a polygenic condition, which means the test evaluates 75 genes and more than 2,000 gene variants that have already been associated with keratoconus (and there may be others). Results are provided in the form of a numeric score from 0 to 100 and identification of mild, moderate or severe risk.

The patient’s age and race have to be entered into the testing portal when submitting the test and get factored into the results.

At present, genetic testing can’t replace routine eye exams or topography/tomography for the diagnosis of keratoconus, but there are three scenarios in which it is quite useful in practice:

  1. Using genetic testing as a “tiebreaker” in borderline cases where the patient has some risk factors, such as irregular topography, a steep cornea or unstable refraction, but it is difficult to discern whether they truly have early keratoconus. A high risk score would lead an eye-care provider to see that patient again in 3 to 4 months rather than a year.
  2. Offering it to family members of keratoconus patients. While a low score in such cases is reassuring, I always emphasize to these patients that it is no guarantee and that they should continue to get annual eye exams.
  3. Genetic testing is often used as a screening tool for potential refractive surgery patients, to identify ectasia risk before they undergo elective surgery. Although we don’t yet have a definitive cut-off based on the test, it can help the clinician and patient decide to postpone surgery or opt for PRK or an implantable collamer lens rather than LASIK.

Interpreting results, assessing risk

There is still much to learn about how to interpret genetic testing for keratoconus. A very low score can be quite reassuring. A high score (85, for example) certainly points to the need for more frequent follow-up, closer diagnostic evaluation and potentially a referral to a corneal specialist.

Because keratoconus is a progressive disease, and the standard of care is to intervene early, knowing a genetic risk score can elevate the importance of frequent evaluation - ideally, with topography/tomography. A high score does not mean we should be recommending prophylactic cross-linking treatment; that requires diagnosis and documentation of progression.

Much less clear so far is what to do about scores in the middle range. Should people be more concerned about a score of 65, which is at the top of the moderate risk range, than a score of 35, near the bottom of that range? It is hard to say. In that middle range, one should definitely be looking for other signs that increase concern about keratoconus, such as high and/or increasing cylinder, myopic shift of at least 0.50 D, distorted mires on manual keratometry, unexplained problems with visual quality or an inability to correct to 20/20.

We can assume, at this present time, that genetic testing for keratoconus is still in its infancy. As more tests are done, the risk algorithm will continue to be adjusted. Ultimately, this will give us better normative values and even more accurate risk scores to guide patient care.


  • Christy JS. Corneal topographic changes in healthy siblings of patients with keratoconus. Presented at American Society of Cataract and Refractive Surgery Annual Meeting; April 22-26, 2022; Washington, D.C.
  • Wagner H, et al. Cont Lens Anterior Eye. 2007;doi:10.1016/j.clae.2007.03.001 30(4):223-32.
  • Wang Y, et al. Am J Med Genet. 2000;93(5):403-9.


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