Identification of candidate genes for keratoconus by trio-based whole-exome sequencing in 81 families from Northwest China.

Keratoconus (KC) is a progressive corneal ectatic disorder with genetic heterogeneity, yet the genetic variants underlying familial cases remain poorly characterized. We performed Trio-based whole-exome sequencing (Trio-WES) on 243 individuals from 81 KC families in Northwestern China and analyzed rare deleterious variants under three inheritance models. Following stringent quality control and filtering, we identified 706 rare deleterious candidate variants (576 compound heterozygous, 43 homozygous, and 87 de novo). The affected genes (n = 469) were enriched in pathways related to extracellular matrix (ECM) organization, cytoskeletal remodeling, cell adhesion, and PI3K-Akt signaling. Further assessment integrating family co-segregation, in silico prediction, American College of Medical Genetics and Genomics (ACMG) classification, cornea-related biological relevance, and database evidence identified 14 variants in 8 candidate genes (ATAD3A, COL6A3, FBXW9, VPS11, SELENBP1, DHX35, CDH23, and TTN) across 9 families. All variants were confirmed by Sanger sequencing and segregation analysis, and were additionally supported by cross-species conservation, protein structural localization, and validation in independent transcriptome datasets. These results expand the genetic landscape of familial KC in Northwestern China and provide a set of candidate genes for downstream functional studies and future clinical translation.