Abstract
Purpose :
Keratoconus (KC) is a multi-factorial disease with the involvement of genetic and environmental factors. The current study aims to explore the genetic heterogeneity and gene variant identification by high-throughput sequencing.
Methods :
Blood samples were collected from 9 KC families(24 KC subjects and 17 healthy first-degree relatives) at Narayana Nethralaya hospital post IEC approval and written informed consent, followed by Whole Exome Sequencing (WES). Variants in protein coding regions with loss of function were identified using SIFT and Polyphen-2. Allele frequency of variants were analysed using gnomAD.
Results :
WES revealed variations in the genes involved in regulation of inflammation, a major pathologic driver in KC patients. 485 variants in 57 genes were identified with diverse inheritance patterns. Within these, 28 variants were nonsynonymous with predicted deleterious effects. Further, the variants present in 2 or more families with allele frequency less than 1X10-5 were identified. Variations in novel genes involved in regulation of inflammatory signalling including ADAMTS18, ANKRD36B/C, CTBP2, FAM104B, KIR2DL1, etc were present in KC subjects. Network analysis revealed their interaction with 138 genes associated with major signalling pathways including inflammation, of which 131 genes showed differential expression in KC epithelium.
Conclusions :
Chronic inflammation in KC may be due to mutations in proteins that regulate inflammatory signalling pathways. Our data reveal novel genes including metalloproteinases with possible immunomodulatory roles which may be useful for genomic diagnostics as well as serve as therapeutic targets for KC. Together, our findings provide novel insights into plausible mechanisms underlying the pathogenesis of KC.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.