Genetic Aspects of Keratoconus: A Literature Review Exploring Potential Genetic Contributions and Possible Genetic Relationships with Comorbidities

Abstract

Introduction

Keratoconus (KC) is a complex, genetically heterogeneous, multifactorial degenerative disorder that is accompanied by corneal ectasia which usually progresses asymmetrically. With an incidence of approximately 1 per 2000 and 2 cases per 100,000 population presenting annually, KC follows an autosomal recessive or dominant pattern of inheritance and is, apparently, associated with genes that interact with environmental, genetic, and/or other factors. This is an important consideration in refractive surgery in the case of familial KC, given the association of KC with other genetic disorders and the imbalance between dizygotic twins. The present review attempts to identify the genetic loci contributing to the different KC clinical presentations and relate them to the common genetically determined comorbidities associated with KC.

Methods

The PubMed, MEDLINE, Google Scholar, and GeneCards databases were screened for KC-related articles published in English between January 2006 and November 2017. Keyword combinations of “keratoconus,” “risk factor(s),” “genetics,” “genes,” “genetic association(s),” and “cornea” were used. In total, 217 articles were retrieved and analyzed, with greater weight placed on the more recent literature. Further bibliographic research based on the 217 articles revealed another 124 relevant articles that were included in this review. Using the reviewed literature, an attempt was made to correlate genes and genetic risk factors with KC characteristics and genetically related comorbidities associated with KC based on genome-wide association studies, family-based linkage analysis, and candidate-gene approaches.

Results

An association matrix between known KC-related genes and KC symptoms and/or clinical signs together with an association matrix between identified KC genes and genetically related KC comorbidities/syndromes were constructed.

Conclusion

Twenty-four genes were identified as potential contributors to KC and 49 KC-related comorbidities/syndromes were found. More than 85% of the known KC-related genes are involved in glaucoma, Down syndrome, connective tissue disorders, endothelial dystrophy, posterior polymorphous corneal dystrophy, and cataract.