Keratoconus (KC) is an eye disease that affects the thinning and irregularities of the corneal surface, developing in loss of vision. It occurs in approximately 1 in 2,000 individuals, typically beginning in puberty and progressing into early adulthood. Keratoconus is a complex and multifactorial disease resulting from the interplay of genetics and the environment. The exact role of genetics in keratoconus remains to be understood. The whole exome sequencing of the all protein-coding portion of the human genome by Next-generation sequencing (NGS) is a powerful and cost-effective method for the detection of disease variants underlying complex disease pathogenesis that is unprecedented in the field of keratoconus. This study particularly focuses on the genetic view of KC with both common polymorphisms as well as rare functional exonic variations. Since hypothesis-based approaches such as single candidate gene or targeted gene sequencing will only explore the selected genes. If the genetic factors underlying the disease are not situated in those genes, they cannot be picked up. This present study is the earliest effort to address early keratoconus patients through a hypothesis-free approach; whole-exome sequencing of all protein-coding regions of the genome. We propose a gene-centric approach for Indian patients with keratoconus. Understanding the genetics of KC likely provides some DNA-based diagnostic tool or novel therapeutic targets for disease prevention, early diagnosis to manage these cases before irreversible damage to the cornea, and management of the KC by delaying or arresting its progression; and improving the treatment of this severe vision-threatening eye problem.
   

    Keratoconus is a non-inflammatory, bilateral asymmetric and multifactorial ectatic disease of the cornea with a large impact on global health. It is characterized by stromal thinning, steepening and protrusion of the cornea that results in a conical shape leading to irregular astigmatism. The gradual stromal thinning, rupture of the anterior limiting membrane (basal membrane of the corneal epithelium), remodeling of the extracellular matrix and subsequent ectasia of the central & paracentral cornea are the most observed clinical & histopathological findings. These abnormal corneal configurations induce optical irregularity, contrast sensitivity, high order aberrations, decrease of visual acuity which leads to progressive myopia and astigmatism becoming more irregular. A family history of keratoconus, environmental stimuli, insults, oxidative stress, genetic predisposition, and allergy are risk factors for developing keratoconus. There are multiple associations of conventional risk factors such as frequent eye rubbing, presence of atopic diseases, exposure to UV light, comorbidities have been reported. Usually, the condition has been described as a noninflammatory disease; however, some recent studies reported it has been associated with ocular inflammation. KC is usually beginning in puberty age and manifested in the second or early third decades of early adulthood with equal distribution in males and females. The latest available estimate is 1in 2000 in the general population. The conventional and traditional conservative management of keratoconus begins with spectacle correction and contact lenses in early stages. With progression of the disease into more advanced and severe cases with corneal scarring may be needed corneal transplantation to restore useful vision to the eye. KC has been emerged as one of the leading eye health problems and rapidly increasing amongst Indians. Its burden has been to be estimated at nearly 2.3% in Indians (aged 30 years and above) in the rural region of Central India, but the exact prevalence is not known.

    Keratoconus is a progressive and complex disorder caused by both genetic and environmental factors. It’s a shared complex interplay between genetics and environment that is accompanied by corneal ectasia and progresses asymmetrically. The heredity of keratoconus has not yet been clearly established. The genetic architecture of KC is complex. So far various linkage, Genome-Wide-Association Study and candidate gene studies have identified a few genetic variations which show variable nature of their reproducibility among KC population across different geographical regions. The implicated common variations have been hypothesized to play a role on KC pathology with small effects and/or through genetic interaction between multiple genes. All the implicated strategies are mainly based on hypotheses or a single study and these are not replicated in a different region. Therefore, there is an extensive need to analyze the whole exome/genome to find out the causative genetic factor. Whole exome sequencing (a hypothesis-free approach) of all coding genes will help us to identify the potential role of rare functional variants in new susceptibility genes of KC disorder. The genetic component of KC in the Indian population is poorly understood therefore it is essential to characterize genetic risk factors in the Indian population.