Insight into genes responsible for cornea plana, megalocornea, keratoconus and brittle cornea syndrome

Abstract Purpose Inherited diseases characterized by abnormal corneal morphology include cornea plana, megalocornea, keratoconus and brittle cornea syndrome. This study aims to investigate genes responsible for these diseases. Methods Variants in genes responsible for cornea plana, megalocornea, keratoconus and brittle cornea syndrome were analyzed and characterized by multistep bioinformatics approach based on three large data sets, including our in-house exome sequencing database from patients with inherited eye diseases, literature review, and gnomAD database. Additionally, the phenotypes of patients carrying these variants were collected. Results 125 variants in six genes, namely KERA (Keratocan; OMIM: 603288), CHRDL1 (Chordin-like 1; OMIM: 300350), VSX1 (Visual system homeobox 1; OMIM: 605020), TUBA3D (Tubulin, alpha-3d; OMIM: 617878), ZNF469 (Zinc finger protein 469; OMIM: 612078), and PRDM5 (PR domain-containing protein 5; OMIM: 614161), have been reported in 244 families by literature review, of which 78 with cornea plana, 38 with megalocornea, 67 with keratoconus, and 61 with brittle cornea syndrome. Three variants in KERA were identified in 2 families with cornea plana in our cohort. Moreover, all reported variants in VSX1 were reclassified as likely benign or benign based on several major evidence, including high allelic frequency in gnomAD, presence in unaffected individuals in in-house data set, and relatively tolerated by multiple computational prediction tools. Misinterpreted variants in VSX1 has been detected in up to 3.13% of the general population. Conclusions This study delineates the genetic and clinical landscape of cornea plana, megalocornea, keratoconus and brittle cornea syndrome for the first time. The pathogenicity of VSX1 variants could not be confirmed, making VSX1 an unlikely candidate gene for keratoconus. Correct classification of genes like VSX1 is critical in the era of genomic medicine.