Genetics of Keratoconus

Abstract

Keratoconus is a mysterious disease of cornea with diverse genetic complexity. Past 160 years of molecular genetics revolution has witnessed the identification of candidate genes with multiple loci through genome‐wide association studies (GWAS). This article provides key insight into the genetics of keratoconus along with diagnosis, treatment and management. Key Concepts: Keratoconus is a noninflammatory corneal progressive ectasia that is bilateral and asymmetric, characterised by steepening and deformation of the cornea, thinning of the apical cornea and corneal scarring. Patients with moderate keratoconus are observed with Fleischer ring around the cone base due to an accumulation of iron deposits. Also Vogt striae, which are fine vertical lines due to compression of Descemet membrane, can be seen. In keratoconus, the cornea's normal defence system is lost and leads to accumulation of free radicals in the tissue, which can cause structural damage. Monozygotic twins have higher concordance of keratoconus than dizygotic twins, which is shown by their phenotypic similarity. This type of evaluation can be made in situations where a clinical sign does not show a genetic pattern. As far as the age groups that get afflicted with the disease are concerned, the keratoconus‐affected individuals between 30–40 years of age are higher than the other groups. Approximately 17 genomic loci have been described from 12 studies based on linkage analysis. This propounds at large the genetic disparities in keratoconus. Further, these studies make possible to consider the mutational effects in different genes that are responsible for the disease. Visual System Homeobox 1 ( VSX1 ) is the most widely reported gene for keratoconus. This gene codes for a transcription factor that helps in ocular development and development of cornea. Mutations in the locus of this gene are reported to be pathogenic and are positive in keratoconus patients. Early signs for diagnosing include irregularity of reflex observed by retinoscopy, distortion of the corneal reflection observed by keratometry and conical contour revealed by the fit of a corneal lens. Nowadays, surgical procedures to selectively replace either the anterior or the posterior layer are used. Keratoplasty is employed to remove the damaged cornea. The distorted cornea is replaced entirely or partially by graft. Entire removal of the keratoconic cornea is called penetrating keratoplasty, whereas if a part of the cornea is removed, it is called lamellar keratoplasty.