Research Review

Is Keratoconus Genetic?

Research Review

Is Keratoconus Genetic?

By Loretta B. Szczotka-Flynn, OD, PhD, MS, FAAO

As contact lens specialists, we are all familiar with keratoconus as a debilitating, ectatic, progressive corneal disease. Clinically, keratoconus is associated with increased regular and irregular corneal astigmatism, a thinned and displaced corneal apex, ring iron deposition in the corneal epithelium (Fleischer's ring), Vogt's striae in the posterior corneal stroma, and central corneal scarring, all of which decrease visual function. The cause of keratoconus is unknown, although metabolic/ chemical changes in the corneal tissue have been documented (Kenney et al, 2000; Yue et al, 1984; Yue et al, 1988). The disease has been associated with atopy (Rahi et al, 1977; Gasset et al, 1978; Harrison et al, 1989), connective tissue disorders (Ihalainen, 1986), eye rubbing (Ridley, 1961; Bawazeer, 2000), contact lens wear (Macsai et al, 1990), and familial inheritance patterns (Edwards et al, 2001; Rabinowitz, 1992 and 2003). Many of us have seen families with multiple affected family members. Figures 1a and 1b show topography maps of a parent and child in my practice who both suffer from keratoconus.

Figure 1a and b. Topography maps of a parent (left) and child (right) who have keratoconus.

Keratoconus Prevalence

Kennedy et al (1986) estimated the annual keratoconus incidence rate at two per 100,000, with a prevalence of 55 per 100,000. However, this is based on survey data from 1935 to 1982 at the Mayo Clinic in Olmsted County, Minnesota (Kennedy et al, 1986) at a time when corneal topography was not available. These estimates are improbably low given current diagnostic techniques. Other groups have reported the prevalence as high as 86 per 100,000 in Denmark (Nielsen et al, 2007) and incidence as high as 25 per 100,000 in populations that have traditions of consanguineous marriages (Georgiou et al, 2004); the higher incidence was suggestive of a genetic etiology.

Evidence of a Genetic Link

Several studies have suggested that keratoconus is genetic (Owens and Gamble, 2003; Wang et al, 2000), with reports from single families and twin studies also reported in earlier literature. In the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) Study, ~18 percent of subjects reported a family history of keratoconus (Szczotka- Flynn et al, 2008), and in New Zealand more than 23 percent of keratoconus patients reported a positive family history (Owens and Gamble, 2003). Wang, Rabinowitz and colleagues (2000) have reported that the prevalence of the disease in first-degree relatives of keratoconus patients is 3.34 percent. This represents an increase of 15 to 67 times over the general population prevalence of 0.23 to 0.05 percent. Keratoconus has also shown association with rare genetic syndromes (Al-Swailem et al, 2006; Shapiro and France, 1985; van Allen et al, 1999), further supporting the genetic hypothesis.

Genetic linkage analysis is based on the presumption that if a gene exists, then individuals in a family who were affected would preferentially inherit the affected portion of a chromosome from their parents. It generates a summary statistic describing the evidence of linkage called a LOD (logarithm of the backward odds) score. Usually a LOD score greater than 3.3 is significant for linkage. So far, the genetic linkage analysis studies in keratoconus have identified many potential keratoconus loci. Initially, the studies identified loci on chromosomes 20p, 16q (LOD 4.10) (Tyynismaa et al, 2002), 3pq (LOD 3.09) (Brancati et al, 2004), and 2p (LOD 3.26) (Hutchings et al, 2005), respectively. The "p" and "q" designations identify on which arm of the chromosome the mutation was found; the symbol "p" designates the short arm because "p" stands for "petit" or small in French. The letter "q" signifies the long arm merely because "q" follows "p" in the alphabet. Most of these studies were conducted in small family sets, and only a single known gene, Visual System Homobox Gene1 (VSX1), showed pathogenic mutations in a few families. In fact, several groups have now reported that keratoconus may be caused by a mutation in the VSX1 gene (Heon et al, 2002; Bisceglia et al, 2005; (Mok et al, 2008). However, at least eight other published papers or abstracts (Aldave et al, 2006; Tang et al, 2006; Ferrini et al, 2005; full list at suggest that mutations in VSX1 are rare in keratoconus patients and may not be pathogenic (Hosseini et al, 2008), thus this is not likely a candidate gene in the common form of the disorder.

At least five additional genome scans have since been performed with reported loci on 4q, 5q, 9p, 9q, 11p, 12p, 14q, 15q, 16q, and 18p. A novel locus for severe keratoconus and autosomal dominant polar cataract was mapped to 15q (Hughes et al, 2003). Also, a number of these regions may overlap with known loci for atopy (Blumenthal et al, 2006; Ferreira et al, 2005; Kurz et al, 2005) as keratoconus has a strong tendency to coexist with atopic disorders (Rahi et al, 1977; Gasset et al, 1978; Harrison et al, 1989).

Lessons From the Research

Therefore, there is a wealth of data suggesting that keratoconus pathogenesis is genetic. However, very few investigations have led to causative genes for keratoconus, other than rare mutations in a few families. These single reported mutations have been difficult to substantiate and replicate, and they are unlikely to be the cause of the common forms of the disorder. Therefore, at this time, it is reasonable to state that genetic causes underlie a patient's susceptibility to the disease, but as of yet, researchers have not found the one or more causative genes.

With promising preventive interventions for keratoconus around the corner such as collagen crosslinking, knowing who is susceptible to keratoconus would be a tremendous asset to those of us who council these patients on a daily basis. Genetic discovery could allow us to sooner detect who is likely to develop this corneal ectasia for earlier intervention. Additionally, considering the economic impact of lost work days from symptomatic keratoconus; the significantly decreased quality of life; and the costs, complications, and limited efficacy of corneal surgery, keratoconus patients and their eyecare providers greatly desire and could tremendously benefit from the development of effective screening and medical therapy that genetic discovery could provide.

So the next time patients ask, "How did I get keratoconus?" you may want to suggest that they may have been genetically predisposed, but some form of environmental stimulus such as eye rubbing probably modulated its severity. Until we can identify genetically predisposed patients, its best to prevent eye rubbing and provide the best lens fit and material possible. CLS

For references, please visit and click on document #178.

Dr. Szczotka-Flynn is an associate professor at the Case Western Reserve University Dept. of Ophthalmology & Visual Sciences and is director of the Contact Lens Service at University Hospitals Case Medical Center. She has received research funding from Ciba, Vistakon, Alcon, and CooperVision. You can reach her at