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Ocular Surface Insights into Genetic Testing

Click to view article: Ocular Surface Insight, Summer 2021 issue:

By Dr. Seema Nanda - Clinical Director: Nanda Dry Eye & Vision Institute

The Background

Patients come in for their annual eye exam with complaints of the usual blurred vision with excessive computer usage. They constantly rub their eyes and use copious amounts of artificial tears to lubricate their poorly wetting corneas. Refractions are performed and patients can barely discern the 20/20 line. Slit lamp findings reveal mild punctate keratopathy, so the doctor assumes the blur is due to their dry eyes. Accordingly, new contact lenses are dispensed and they leave.

The preceding typical scenario is performed in doctors’ offices everyday around the globe. The patients’ refractive error illustrated a mild increase in their astigmatism, which was not a cause of any significant concern. The topographical measurements also demonstrated unremarkable findings. Unfortunately, years can pass before a confirmation of keratoconus may become present. But, now with the advent of genetic testing, a more definitive way to predict the likelihood of developing corneal problems is finally available.

Before this breakthrough, four main procedures have been used to detect keratoconus conclusively. First, in-office protocols customarily entailed retinoscopy to detect the classic ‘scissors-reflex’ seen with keratoconus; however, many practitioners today use auto-refractors which bypasses this common finding.1 Second, a marked increase in astigmatism at an oblique axis can be regarded as another red flag; still, if this rise is subtle from year-to-year, then this finding also may be overlooked. Third, keratometry readings are similarly good indicators of progression, especially if steeper corneal curvatures are noted. Nevertheless, if the cone is not central nor in one’s visual axis, this finding too can be missed, which will lead to a delay in diagnosis. Fourth, the use of corneal tomography or topography can capture the early stage of form-fruste keratoconus, but can be cost-prohibitive in a clinical setting. Since all these methods have their limitations, the latest technique of genetic testing has come into the limelight. It can detect corneal anomalies from dystrophies to degenerations, especially in those individuals who have a family history of keratoconus, with a simple swab of one’s cheek.

The Benefits

A major benefit of genetic testing is early detection, which can allow for better management of patients who may have keratoconus. For example, if a young adult wants to have LASIK surgery, and the clinician performs all the necessary tests to determine if patient would be a good candidate, the doctor could still miss early signs of the condition. With genetic testing, if that LASIK candidate is diagnosed with keratoconus, an alternative option with a Refractive Lens Exchange (RLE) or Implantable Collamer Lens (ICL) could be inserted to mitigate the condition. Another more advantageous use would be to detect the condition and then discuss preventative therapies with cross-linking in those patients with higher probability of development of the disease. Risk assessment is another benefit of genetic testing and is one approach to gauge patient management of their potential disease progression. In those patients with low risk, that is, minimal clinical evidence of keratoconus, but with a family history of the condition and/or comorbidities, evaluation would be prudent every six to twelve months. On the other hand, patients with a greater likelihood for progression should be monitored more regularly at four to six-month intervals. For example, individuals who are younger, with symptoms of atopy and/or allergic conjunctivitis, are more prone to rubbing their eyes, which has shown an increased incidence of keratoconus. Also, people who have notably larger amounts of astigmatism, that is both asymmetrical and oblique, but with no significant corneal findings, are also at greater risk for developing keratoconus. Testing of immediate family members, especially younger siblings, should also be considered and preventive measures with cross-linking should be discussed. A third benefit of genetic testing is the ability to test for other genetic markers. Although, the majority of patients encountered in clinics may have keratoconus, with a higher prevalence rate in men (60.6%) than women (39.4%), other corneal conditions can also be identified as well.3,6 Approximately one in 1,100 people may have corneal dystrophies and present with symptoms of vision loss, eye pain, dry eye, and sensitivity to light or glare.3,4,5

These dystrophies are variable and may develop early in childhood or as later years, in their fifties or sixties.3,8 Currently, there are 70 different genetic mutations (TGFBIs) that have been found to cause corneal dystrophy.7 A custom panel is utilized that can examine more than 1,000 variants across 75 genes for keratoconus and more than 70 TGFBI mutations which include: Granular Type 1 and 2, Lattice Type 1, Reis-Bucklers and Theill-Behnke Corneal Dystrophy.

The Method

The doctor obtains a buccal, or cheek, swab from the patient and sends it to the Avellino lab for evaluation. For keratoconus, a detailed report, uploaded to a HIPPA-compliant portal, will show the Risk Score categorized as “LOW”, “MEDIUM”, or “HIGH.” The report will also include a variant analysis and interpretation. For the corneal dystrophy, “YES” or “NO” diagnoses with relevant additional variant analysis and interpretation will be included. Genetic counselors also would be available to provide support and answer questions for the eyecare professionals and their patients. Incredibly, these genetic tests are already available in the US, Europe, Japan, Korea, and China. Currently, with greater advances in technology, genetic testing can be offered in practices worldwide that will help clinicians potentially preserve vision with an early diagnosis. An innovative test for corneal disorders that uses DNA-sequencing to assess risk in developing keratoconus and definitively diagnosing five major corneal dystrophies, can be revealed quickly with a few strokes of a swab.

Click to view article: Ocular Surface Insight, Summer 2021 issue:

References: 1. Al-Mahrouqi H, Oraba SB, Al-Habsi S, et al. Retinoscopy as a Screening Tool for Keratoconus. Cornea. 2019;38(4):442-445. 2. Alio J, ed. Keratoconus: Recent Advances in Diagnosis and Treatment. Cham, Switzerland: Springer; 2017. Singh AD, ed. Essentials in Ophthalmology. 3. Godefrooij DA, de Wit GA, Uiterwaal CS, Imhof SM, Wisse RP. Age-speci c Incidence and Prevalence of Keratoconus: A Nationwide Registration Study. Am J Ophthalmol 2017; 175: 169-172 4. Bourges JL. Corneal dystrophies. J Fr Ophtalmol. 2017;40(6):e177-e192. 5. National Institutes of Health website, TGFBI gene. Accessed August 18, 2019. 1 6. Mayo Clinic. Fuchs’ dystrophy. Accessed August 23, 2019. 1 7. Chao-Shern C, DeDionisio LA, Jang JH, et al. Evaluation of TGFBI corneal dystrophy and molecular diagnostic testing. Eye (Lond). 2019;33:874-881.1 8. Musch DC, Niziol LM, Stein JD, Kamyar RM, Sugar A. Prevalence of corneal dystrophies in the United States: estimates from claims data. Invest Ophthalmol Vis Sci. 2011;52(9):6959-6963

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