Genetics in Keratoconus: where are we?

Yelena Bykhovskaya,Benjamin Margines,Yaron S Rabinowitz

doi:10.1186/s40662-016-0047-5

Abstract

Keratoconus (KC) is a non-inflammatory thinning and protrusion of the cornea in which the cornea assumes a conical shape. Complex etiology of this condition at present remains an enigma. Although environmental factors have been involved in KC pathogenesis, strong underlining genetic susceptibility has been proven. The lack of consistent findings among early genetic studies suggested a heterogeneity and complex nature of the genetic contribution to the development of KC. Recently, genome-wide linkage studies (GWLS) and genome-wide association studies (GWAS) were undertaken. Next-generation sequencing (NGS)-based genomic screens are also currently being carried out. Application of these recently developed comprehensive genetic tools led to a much greater success and increased reproducibility of genetic findings in KC. Involvement of the LOX gene identified through GWLS has been confirmed in multiple cohorts of KC patients around the world. KC susceptibility region located at the 2q21.3 chromosomal region near the RAB3GAP1 gene identified through GWAS was independently replicated. Rare variants in the ZNF469 gene (mutated in corneal dystrophy Brittle Cornea Syndrome) and in the TGFBI gene (mutated in multiple corneal epithelial–stromal TGFBI dystrophies) have been repeatedly identified in familial and sporadic KC patients of different ethnicities. Additional comprehensive strategies using quantitative endophenotypes have been successfully employed to bring further understanding to the genetics of KC. Additional genetic determinants including the COL5A1 gene have been identified in the GWAS of KC-related trait central corneal thickness. These recent discoveries confirmed the importance of the endophenotype approach for studying complex genetic diseases such as KC and showed that different connective tissue disorders may have the same genetic determinants.

Highlights

Keratoconus (KC) is a complex corneal condition characterized by progressive corneal thinning and steepening resulting in moderate to marked visual impairment [1]
Initial linkage findings using microsatellite markers were further confirmed by genotyping of high-density single nucleotide polymorphisms (SNPs) in and around the CAST gene in family and case-control panels of patients with KC followed by comprehensive linkage and association analysis [37, 39]
The published genome-wide association studies (GWAS) of central corneal thickness (CCT) to date focus primarily on common variants (i.e., MAF >5 %); when putative rare functional coding exome variants from the Illumina Human Exome array were evaluated, a novel rare WNT10A exonic variant, which increases the risk of KC by decreasing corneal thickness, was identified [113]

Summary

Background

Keratoconus (KC) is a complex corneal condition characterized by progressive corneal thinning and steepening resulting in moderate to marked visual impairment [1]. No evidence of association with VSX1 variants was identified in subsequent recent research studies with large patient cohorts and recently developed genotyping methods that allow for simultaneous interrogation of hundreds of thousands of independent SNPs providing information on common genomic variation [93,94,95,96,97,98,99]. The published GWAS of CCT to date focus primarily on common variants (i.e., MAF >5 %); when putative rare functional coding exome variants from the Illumina Human Exome array were evaluated, a novel rare WNT10A exonic variant (rs121908120), which increases the risk of KC by decreasing corneal thickness, was identified [113] This variant is located in a gene 437 kb away from the USP37 gene, previously associated with CCT, and completely accounts for the signal previously seen at USP37. No mutation(s) within the stem loop of MIR184 in isolated KC cases was detected in two independent screens, suggesting that mutations in MIR184 are more relevant to cases of KC associated with other ocular abnormalities [131, 132]

Findings

Discussion

Conclusion