Genetics of Keratoconus: A Comprehensive Review.

Keratoconus (KC) is a progressive, multifactorial corneal ectatic disorder characterized by localized stromal thinning and irregular astigmatism, with incidence and prevalence varying markedly among populations. These differences are influenced by environmental exposures, behavioral factors, and genetic predisposition. A positive family history is a well-established high-risk factor, and KC has also been documented in association with syndromic disorders such as Down syndrome, connective tissue disorders, and certain metabolic diseases. Over the past decades, numerous candidate genes have been investigated, encompassing those involved in extracellular matrix (ECM) assembly, collagen synthesis and cross-linking, oxidative stress defense, wound healing, and transcriptional regulation. Modern genomic approaches, including genome-wide association studies (GWAS), linkage analyses, and next-generation sequencing, have identified multiple loci and variants with potential pathogenic roles. Nonetheless, several genes have also been systematically tested and found to show no association in specific populations, highlighting the genetic variability of KC and the potential influence of population-specific factors. This dual landscape of positive and negative genetic findings underscores the complexity of KC pathogenesis and the necessity for ethnically diverse cohorts. In this review, we synthesize current evidence on genes implicated in KC, integrating confirmed pathogenic variants, associations, and negative findings across diverse populations, to provide a comprehensive overview of the genetic architecture of KC and to outline priorities for future research aimed at improving diagnosis, risk stratification, and therapeutic development.