{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:37:30Z","timestamp":1790789850912,"version":"4.1.0"},"reference-count":108,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T00:00:00Z","timestamp":1767657600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Keratoconus (KC) is a progressive corneal ectasia and a leading cause of corneal transplantation in young adults. Once regarded as a biomechanical disorder, KC is now recognized as a complex disease driven by genetic predisposition, epigenetic modulation, and environmental triggers. Advances in genomics and transcriptomics have begun to elucidate the molecular mechanisms underlying corneal thinning and ectasia. Objectives: This review synthesizes two decades of evidence on the genetic and epigenetic architecture of keratoconus, highlights key molecular pathways implicated by these findings, and discusses translational implications for early diagnosis, risk prediction, and novel therapeutic strategies. Methods: A narrative review was conducted of peer-reviewed human, animal, and in vitro studies published from 2000 to 2025, with emphasis on genome-wide association studies (GWAS), sequencing data, methylation profiling, and non-coding RNA analyses. Findings were integrated with functional studies linking genetic variation to molecular and biomechanical phenotypes. Results: Genetic studies consistently implicate loci such as ZNF469, COL5A1, LOX, HGF, FOXO1, and WNT10A, alongside rare variants in Mendelian syndromes (e.g., brittle cornea syndrome, Ehlers\u2013Danlos spectrum). Epigenetic research demonstrates altered DNA methylation, dysregulated microRNAs (e.g., MIR184, miR-143, miR-182), and aberrant lncRNA networks influencing extracellular matrix remodeling, collagen cross-linking, oxidative stress, and inflammatory signaling. Gene\u2013environment interactions, particularly with eye rubbing and atopy, further shape disease expression. Translational progress includes polygenic risk scores, tear-based biomarkers, and early preclinical studies using RNA-based approaches (including siRNA and antisense oligonucleotides targeting matrix-degrading and profibrotic pathways) and proof-of-concept gene-editing strategies demonstrated in corneal cell and ex vivo models. Conclusions: Keratoconus arises from the convergence of inherited genomic risk, epigenetic dysregulation, and environmental stressors. Integrating multi-omic insights into clinical practice holds promise for earlier detection, precision risk stratification, and development of targeted therapies that move beyond biomechanical stabilization to disease modification.<\/jats:p>","DOI":"10.3390\/genes17010066","type":"journal-article","created":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T11:13:18Z","timestamp":1767697998000},"page":"66","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Genetic and Epigenetic Architecture of Keratoconus: Emerging Pathways and Clinical Implications"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-6807-9455","authenticated-orcid":false,"given":"Francesco","family":"Cappellani","sequence":"first","affiliation":[{"name":"Department of Medicine and Surgery, University of Enna \u201cKore\u201d, Piazza dell\u2019Universit\u00e0, 94100 Enna, Italy"},{"name":"Eye Center, G.B. Morgagni-DSV, 95100 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2969-8610","authenticated-orcid":false,"given":"Matteo","family":"Capobianco","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6710-2460","authenticated-orcid":false,"given":"Federico","family":"Visalli","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cosimo","family":"Mazzotta","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Enna \u201cKore\u201d, Piazza dell\u2019Universit\u00e0, 94100 Enna, Italy"},{"name":"Eye Center, G.B. Morgagni-DSV, 95100 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7938-876X","authenticated-orcid":false,"given":"Fabiana","family":"D\u2019Esposito","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Enna \u201cKore\u201d, Piazza dell\u2019Universit\u00e0, 94100 Enna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Tognetto","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Health Sciences, University of Trieste, 34127 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8424-0068","authenticated-orcid":false,"given":"Caterina","family":"Gagliano","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Enna \u201cKore\u201d, Piazza dell\u2019Universit\u00e0, 94100 Enna, Italy"},{"name":"Eye Center, G.B. Morgagni-DSV, 95100 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0999-5545","authenticated-orcid":false,"given":"Marco","family":"Zeppieri","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Health Sciences, University of Trieste, 34127 Trieste, Italy"},{"name":"Department of Ophthalmology, University Hospital of Udine, 33100 Udine, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"101559","DOI":"10.1016\/j.clae.2021.101559","article-title":"Keratoconus: An updated review","volume":"45","author":"Carracedo","year":"2022","journal-title":"Cont. 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