A Cohort-Based Genetic Analysis of Keratoconus in Turkey Reveals a Substantial Proportion of Novel Variants and Suggests Possible Oligogenic Contributions to Keratoconus.

Background/

Objectives

Keratoconus is a corneal disorder that causes thinning and bulging of the cornea, resulting in astigmatism and other refractive errors. Mechanical effects and environmental factors are known to exacerbate the disease, and genetic predisposition plays a significant role in its development.

Methods

This study investigated the presence of genetic variants in 32 keratoconus patients. We used a next-generation sequencing-based method, and variant interpretation was performed according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Variants were prioritized based on multiple criteria, including population frequency data from the Genome Aggregation Database (gnomAD) (minor allele frequency < 1%), variant type and predicted functional effect, gene-disease association, inheritance pattern, phenotypic relevance, and in silico prediction tools.

Results

Thirteen variants were identified in 11 patients (34.3%). Two patients carried variants in two different genes, raising the possibility of oligogenic contributions. Ten variants (76.9%) were novel. The variants were detected in 12 genes, namely ADAMTS18, BEST1, CHST6, COL17A1, CYP1B1, KRT3, PAX6, SLC4A11, TACSTD2, UBIAD1, VSX1, and ZNF469. No association was observed between detected variants and patient age.

Conclusions

Our findings demonstrate a substantial proportion of novel variants and support the genetic heterogeneity of keratoconus, while also raising the possibility of oligogenic contributions in a subset of patients.