Trio-based exome sequencing broaden the genetic spectrum in keratoconus

Keratoconus (KC) is a complex corneal disorder with genetic factors involving in its pathogenesis. The genetic etiology of KC has not been fully elucidated. In this study, we aimed to expand the genetic spectrum in KC by trio-based exome sequencing. Trio-based exome sequencing was conducted in 20 patients with KC and their unaffected parents to broaden the genetic spectrum of the disease. With a series of filtering criteria, de novo, recessive homozygous, and compound heterozygous variants in candidate genes were identified, and the candidate genes were classified for further analysis. Finally, we identified 60 variants in 32 candidate genes through trio-based exome sequencing. Among the candidate genes, 10 genes (ARHGEF10, ARHGEF17, ASPM, FLNA, NDRG1, NEB, PLS3, STARD8, SYNE1, TTN) were classified as cytoskeleton-related genes, 4 genes (COL28A1, SDK1, STAB1, TENM2) were classified as cell adhesion-related genes, and 18 genes (APLP2, BCORL1, CCNB3, FOXN1, FUT8, GALNT10, HEPH, HHIP, HMGB3, HS6ST2, JADE3, KIAA0040, MCF2L, MYOF, QRICH2, RPS6KA6, SMARCA1, TNRC6A) were classified into other genes group. Additionally, the candidate rare deleterious variants in TTN were highly repeated in 25% trios. In conclusion, the study provided new insights into the genetic spectrum of KC which might underlie the genetic etiology for the disease. The findings would improve our understanding of pathogenesis in KC and provide critical clues to future functional validation.