Genetics of Keratoconus


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.

Keywords: keratoconus; cornea; mutations; GWAS; VSX1

Figure 1.

A graph depicting the incidence rates of keratoconus in different geographical locations (per 100 000).

Figure 2.

A pie chart showing the relative distribution of keratoconic patients of different age groups.



Arnal E, Peris‐Martinez C, Menezo JL, Johnsen‐Soriano S and Romero FJ (2011) Oxidative stress in keratoconus? Investigative Opthalmology and Visual Science 52: 8592–8597.

Bechara SJ, Waring GO III and Insler MS (1996) Keratoconus in two pairs of identical twins. Cornea 15: 90–93.

Bisceglia L, De Bonis P, Pizzicol C et al. (2009) Linkage analysis in keratoconus: replication of locus 5q21.2 and identification of other suggestive loci. Investigative Opthalmology and Visual Science 50: 1081–1086.

Burdon KP and Vincent AL (2013) Insights into keratoconus from a genetic perspective. Clinical and Experimental Optometry 96: 146–154.

Butcher WD (1976) Management of keratoconus. Australian Journal of Ophthalmology 4: 173–174.

Bykhovskaya Y, Li X, Epifantseva I et al. (2012) Variation in the lysyl oxidase (LOX) gene is associated with keratoconus in family‐based and case–control studies. Investigative Opthalmology and Visual Science 53: 4152–4157.

Caroline P, Andre M, Kinoshita B and Choo J (2008) Etiology, Diagnosis and Management of Keratoconus: New Thoughts and New Understandings. Pacific University College of Optometry. Retrieved 12–15.

Cassidy D, Beltz J, Jhanji V and Loughnan MS (2013) Recent advances in corneal transplantation for keratoconus. Clinical and Experimental Optometry 96: 165–172.

Chua BT, Volbracht C, Tan KO et al. (2003) Mitochondrial translocation of cofilin is an early step in apoptosis induction. Nature Cell Biology 5: 1083–1089.

Czugala M, Karolak JA, Nowak DM et al. (2012) Novel mutation and three other sequence variants segregating with phenotype at keratoconus 13q32 susceptibility locus. European Journal of Human Genetics 20: 389–397.

Dash DP, George S, O'Prey D et al. (2010) Mutational screening of VSX1 in keratoconus patients from the European population. Eye 24: 1085–1092.

Gordon‐Shaag A, Millodot M and Shneor E (2012) The epidemiology and etiology of keratoconus. International Journal of Keratoconus and Ectatic Corneal Diseases 1: 7–15.

Guan T, Liu C, Ma Z and Ding S (2012) The point mutation and polymorphism in keratoconus candidate gene TGFBI in Chinese population. Gene 503: 137–139.

Ha NT, Kanayasu K, Murakami A, Ishidoh K and Kanai A (2004) Microarray analysis identified differentially expressed genes in keratocytes from keratoconus patients. Current Eye Research 28: 373–379.

Horner JF (1869) Zur behandlung des keratoconus. Klinische Monatsblätter für Augenheilkunde 5: 25–46.

Hughes AE, Bradley DT, Campbell M et al. (2011) Mutation altering the miR‐184 seed region causes familial keratoconus with cataract. American Journal of Human Genetics 89: 628–633.

Karseras AG and Ruben M (1976) Aetiology of keratoconus. British Journal of Ophthalmology 60: 522.

Kennedy RH, Bourne WM and Dyer JA (1986) A 48‐year clinical and epidemiologic study of keratoconus. American Journal of Ophthalmology 101: 267–273.

Kim YJ, Kwak CI, Gu YY, Hwang IT and Chun J (2004) Annealing control primer system for identification of differentially expressed genes on agarose gels. BioTechniques 36: 424–430.

Lawless M, Coster DJ, Phillips AJ and Loane M (1989) Keratoconus: diagnosis and management. Australian and New Zealand Journal of Ophthalmology 17: 33–60.

Lechner J, Dash DP, Muszynska D et al., (2013) Mutational spectrum of the ZEB1 gene in corneal dystrophies supports a genotype–phenotype correlation. Investigative Opthalmology and Visual Science 54(5): 3215–3223.

Lee JE, Oum BS, Choi HY, Lee SU and Lee JS (2009) Evaluation of differentially expressed genes identified in keratoconus. Molecular Vision 15: 2480–2487.

Li X, Bykhovskaya Y, Canedo AL et al. (2013) Genetic association of COL5A1 variants in keratoconus patients suggests a complex connection between corneal thinning and keratoconus. Investigative Opthalmology and Visual Science 54(4): 2696–2704.

Li X, Bykhovskaya Y, Tang TG et al. (2012) An association between the calpastatin (CAST) gene and keratoconus. Cornea 32: 696–701.

Li X, Bykhovskaya Y, Haritunians T et al. (2012) A genome‐wide association study identifies a potential novel gene locus for keratoconus, one of the commonest causes for corneal transplantation in developed countries. Human Molecular Genetics 21: 421–429.

Liskova P, Palos M, Hardcastle AJ and Vincent AL (2013) Further genetic and clinical insights of posterior polymorphous corneal dystrophy 3. JAMA Ophthalmology 1–8. Doi: 10.1001/jamaophthalmol.2013.405.

Liu Z, Huang AJ and Pflugfelder SC (1999) Evaluation of corneal thickness and topography in normal eyes using the Orbscan corneal topography system. British Journal of Ophthalmology 83: 774–778.

McGhee CNJ (2013) Keratoconus: the arc of past, present and future. Clinical and Experimental Optometry 96: 137–139.

McGough A, Pope B, Chiu W and Weeds A (1997) Cofilin changes the twist of F‐actin: implications for actin filament dynamics and cellular function. Journal of Cell Biology 138: 771–781.

McMonnies CW and Boneham GC (2003) Keratoconus, allergy, itch, eye‐rubbing and hand‐dominance. Clinical and Experimental Optometry 86: 367–384.

Mohan RR, Kim WJ, Mohan RR, Chen L and Wilson SE (1998) Bone morphogenic proteins 2 and 4 and their receptors in the adult human cornea. Investigative Opthalmology and Visual Science 39: 2626–2636.

Nordan LT (1997) Keratoconus: diagnosis and treatment. International Ophthalmology Clinics 37: 51–63.

Nowak DM and Gajecka M (2011) The genetics of keratoconus. Middle East African Journal of Ophthalmology 18: 2–6.

Nowak DM, Karolak JA, Kubiak J et al. (2013) Substitution at IL1RN and deletion at SLC4A11 segregating with phenotype in familial Keratoconus. Investigative Opthalmology and Visual Science 54(3): 2207–2215.

Paliwal P, Singh A, Tandon R, Titiyal JS and Sharma A (2009) A novel VSX1 mutation identified in an individual with keratoconus in India. Molecular Vision 15: 2475– 2479.

Pearson RM (1989) Kalt, keratoconus and the contact lens. Optometry and Vision Science 66: 643–646.

Pouliquen Y (1987) Doyne lecture keratoconus. Eye (Lond) Lecture 1(Pt 1): 1–14.

Rabinowitz YS (1998) Keratoconus. Survey of Ophthalmology 42: 297–319.

Rabinowitz YS, Garbus J and McDonnell PJ (1990) Computer‐assisted corneal topography in family members of patients with keratoconus. Archives of Ophthalmology 108: 365–371.

dos Remedios CG, Chhabra D, Kekic M et al. (2003) Actin binding proteins: regulation of cytoskeletal microfilaments. Physiological Reviews 83: 433–473.

Smith TW (1977) Corneal topography. Documenta Opthalmologica 43: 249–276.

Stabuc‐Silih M, Ravnik‐Glavac M, Glavac D et al. (2009) Polymorphisms in COL4A3 and COL4A4 genes associated with keratoconus. Molecular Vision 15: 2848–2860.

Tang YG, Rabinowitz YS, Taylor KD et al. (2005) Genome wide linkage scan in a multigeneration Caucasian pedigree identifies a novel locus for keratoconus on chromosome 5q14.3‐q21.1. Genetics in Medicine 7: 397–405.

Thompson JS and Thompson MW (1986) Twins in medical genetics. In: Thompson JS, Thompson MW (eds), Genetics in Medicine. Philadelphia: WB Saunders.

Tuft SJ, Hassan H, George S et al. (2012) Keratoconus in 18 pairs of twins. Acta Ophthalmologica 90: 482–486.

Tyynismaa H, Sistonen P, Tuupanen S et al. (2002) A locus for autosomal dominant keratoconus: linkage to 16q22.3–q23.1 in Finnish families. Investigative Opthalmology and Visual Science 43: 3160–3164.

Udar N, Atilano SR, Brown DJ et al. (2006) SOD1: a candidate gene for keratoconus. Investigative Opthalmology and Visual Science 47: 3345–3351.

Vincent AL, Jordan C, Sheck L et al. (2013) Screening the visual system homeobox 1 gene in keratoconus and posterior polymorphous dystrophy cohorts identifies a novel variant. Molecular Vision 19: 852–860.

Wang Y, Rabinowitz YS, Rotter JI and Yang H (2000) Genetic epidemiological study of keratoconus: evidence for major gene determination. American Journal of Medical Genetics 93: 403–409.

Weed KH and McGhee CNJ (1998) Referral patterns, treatment management and visual outcome in keratoconus. Eye – Royal College of Ophthalmologists 12: 663–668.

Wheeler J, Hauser MA, Afshari NA, Allingham RA and Liu Y (2012) The genetics of keratoconus: a review. Reproductive System & Sexual Disorders Suppl 6: pii: 001.

You L, Kruse FE, Pohl J and Volcker HE (1999) Bone morphogenetic proteins and growth and differentiation factors in the human cornea. Investigative Opthalmology and Visual Science 40: 296–311.

Further Reading

Barbara A (2011) Textbook on Keratoconus: New Insights, 1st edn. Jaypee Brothers Medical Publishers (P) Ltd.

Pinero DP, Alio JL, Barraquer RI, Michael R and Jimenez R (2010) Corneal biomechanics, refraction, and corneal aberrometry in keratoconus: an integrated study. Investigative Opthalmology and Visual Science 51: 1948–1955.

Sinjab MM (2012) Keratoconus: When, Why and Why Not: A Step by Step Systematic Approach, 1st edn. Jaypee Brothers Medical Publishers (P) Ltd.

Steinert RF and Ashrafzadeh A (2008) Evaluation of LASIK flaps. In: Steinert RF and Huang D (eds) Anterior Segment Optical Coherence Tomography, chap. 3, p. 23–33. Thorofare, NJ. Slack.

Sugar J and Macsai MS (2012) What causes keratoconus? Cornea 31: 716–719.

Wachler BSB (2012) How We Conquered Keratoconus. Boxer Wachler Vision Institute.

You J, Hodge C, Wen L et al. (2013) Tear levels of SFRP1 are significantly reduced in keratoconus patients. Molecular Vision 19: 509–515.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Doss C, George Priya, Chaturvedi, Richa, and Hansoge, Lalith N(Nov 2013) Genetics of Keratoconus. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0025263]