Millions of people have put aside their eyeglasses or contact lenses thanks to a procedure called LASIK. But for carriers of a rare condition called granular corneal dystrophy (GCD), LASIK can damage the cornea, even causing blindness. The Avellino DNA Dual Test for LASIK Safety, from Avellino Laboratory, can identify individuals genetically predisposed to this complication, offering a great example of an “actionable” genetic test.
Ophthalmologists can provide the cheek swab test to patients considering LASIK, and results are available within 2 days. Company founder and CEO Gene Lee pursued development of the test after learning about the genetic connection in early 2008. It’s now standard-of-care in Korea and Japan, and became available in the US in April. Insurance typically doesn’t cover it (yet), but the test is often incorporated into a work-up for LASIK, and out-of-pocket costs about $100.
“We started doing it last year and we’ve found it to give increased peace of mind and confidence in the procedure. If someone has this condition and it is clinically apparent and visible, the test would just confirm the visual findings. But a number of patients have subclinical findings or none, and this genetic test is the only way to identify the condition,” Richard Rothman, MD, an ophthalmologist who practices in Las Vegas told me. And patients who have the mutation can tell their relatives to be tested before choosing LASIK.
THE GENETICS OF GRANULAR CORNEAL DYSTROPHY
GCD results from mutations in the transforming growth factor beta induced (TGFΒI) gene, which encodes the protein keratoepithelin. The affected part of the cornea, the stroma, consists of extracellular matrix (the goo between cells) and stacks of collagen fibrils, with some other proteins such as fibronectin and integrins, and scant keratocytes that produce the keratoepithelin that keeps the cornea clear. Combine carrying a mutation with stress – such as radiation, hypoxia, chemotherapy, peroxide, or perhaps a laser procedure — and keratoepithelin misfolds into a gunky, amyloid-like mess.
The two types of GCD are due to mutations in different parts of the gene. The type 1 or classic presentation results from a mutation in exon 12, giving a “bread crumb” like appearance to the cornea. Type 2 is known as “Avellino” because the first identified cases, in 1988, lived in the town by that name in Italy. This type resembles a “snowflake icicle” due to a mutation in exon 4 (the exons are the parts of genes that encode protein). Other studies identified patients in Japan and Korea, and then pretty much everywhere.
For individuals who have two mutations (homozygotes), proteins deposit in the corneas during infancy, causing blindness by the teens. The condition is much milder, with later onset, in people with one mutation (heterozygotes). But if vision isn’t very impaired, or begins late in life, then visual loss rather than improvement months to years after LASIK comes as quite a shock. People can carry the mutation and not know it. And that’s where the test comes in.
A DISORDER OF PROTEIN MISFOLDING
LASIK (laser-assisted in situ keratomileusis) creates a thin flap in the cornea that is hinged back to reveal the middle layer, where an excimer laser is applied to alter the topography to better focus light rays on the retina. Normally, the intervention activates transforming growth factor beta to repair the wound. But in people with one mutation, the surgery makes keratoepithelin misfold and aggregate at the flap. This action accelerates the corneal dystrophy and may cause another complication in which torn collagen fibers bind various proteins, producing a “sands of Sahara“ effect. Ouch.
GCD is rare. Avellino Laboratory has identified 390 people with one or two mutations among 420,000 being worked up for possible LASIK. More than 30 mutations are known, and they also account for the related condition lattice corneal dystrophy. The nomenclature is still traditionally clinical, based on appearance, but subtyping now reflects genetic distinctions. For families aware of the pattern of inheritance because homozygotes are blind, full gene sequencing is available from several labs.
LET’S NOT FORGET SINGLE GENE TESTS
Every morning, I look through digests of news releases about genetic research from a wonderful service from the American Association for the Advancement of Science called EurekAlert. A few weeks ago, the news release about the LASIK genetic test caught my eye because of its simplicity, its utility, and the fact that it looks for mutations in ONE gene. That’s unusual these days.
More often, the studies in the news release roster, and therefore those that make the news, deal with big data. They track thousands upon thousands of sites in genomes that vary among individuals, boiling down to a dozen or so that can serve as usually weak risk factors (genome-wide association studies or GWAS); follow epigenetics (sites of methylation) and changes in gene expression; or sequence exomes and genomes. All good of course, but usually not immediately of any help to patients. And many news releases mix up the techniques or write so vaguely that it’s difficult to know what exactly the findings are without reading the technical papers.
Around the time of the LASIK news release was another on a GWAS finding a dozen risk sites for Parkinson’s disease, a report in the Journal of Urology tracking methylation profiles of three genes that predict which prostate cancer biopsies are false negatives, and reports on finding common gene variants behind autism and schizophrenia. Inheriting a mix of variants can set the stage for each condition. An additional, triggering mutation or exposure to an environmental factor might then turn risk into reality.
These are all quite different genetic scenarios than a single gene mutation that makes itself known after surgery injures the eye.
I realize that large-scale investigations take massive and talented teamwork, and that the projects are vital to understanding pathology, which fuels new treatments. But I’m starting to feel an information overload that makes me appreciate the single-gene tests that a patient can benefit from right now. Many have been available for years, but we don’t hear about them as often as the megadata. They’re not news.
Perhaps the best example of a an actionable single-gene test is the one for factor V Leiden, a mutation in a clotting factor gene. Knowing it’s there means you can avoid dangerous clots by taking blood thinners, wearing special support socks, and avoiding long plane rides or crouching for long periods, as reporter David Bloom did in 2003 when reporting from Iraq in a tank with his legs folded underneath him for hours. He died of a pulmonary embolism following deep vein thrombosis.