{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T03:04:20Z","timestamp":1775617460343,"version":"3.50.1"},"reference-count":30,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2023,1,14]],"date-time":"2023-01-14T00:00:00Z","timestamp":1673654400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["EY015518"],"award-info":[{"award-number":["EY015518"]}]},{"name":"NIH","award":["EY025718"],"award-info":[{"award-number":["EY025718"]}]},{"name":"Children\u2019s Research Institute of Children\u2019s Wisconsin","award":["EY015518"],"award-info":[{"award-number":["EY015518"]}]},{"name":"Children\u2019s Research Institute of Children\u2019s Wisconsin","award":["EY025718"],"award-info":[{"award-number":["EY025718"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Histone lysine methyltransferase and demethylase enzymes play a central role in chromatin organization and gene expression through the dynamic regulation of histone lysine methylation. Consistent with this, genes encoding for histone lysine methyltransferases (KMTs) and demethylases (KDMs) are involved in complex human syndromes, termed congenital regulopathies. In this report, we present several lines of evidence for the involvement of these genes in developmental ocular phenotypes, suggesting that individuals with structural eye defects, especially when accompanied by craniofacial, neurodevelopmental and growth abnormalities, should be examined for possible variants in these genes. We identified nine heterozygous damaging genetic variants in KMT2D (5) and four other histone lysine methyltransferases\/demethylases (KMT2C, SETD1A\/KMT2F, KDM6A and KDM5C) in unrelated families affected with developmental eye disease, such as Peters anomaly, sclerocornea, Axenfeld-Rieger spectrum, microphthalmia and coloboma. Two families were clinically diagnosed with Axenfeld-Rieger syndrome and two were diagnosed with Peters plus-like syndrome; others received no specific diagnosis prior to genetic testing. All nine alleles were novel and five of them occurred de novo; five variants resulted in premature truncation, three were missense changes and one was an in-frame deletion\/insertion; and seven variants were categorized as pathogenic or likely pathogenic and two were variants of uncertain significance. This study expands the phenotypic spectra associated with KMT and KDM factors and highlights the importance of genetic testing for correct clinical diagnosis.<\/jats:p>","DOI":"10.3390\/genes14010216","type":"journal-article","created":{"date-parts":[[2023,1,16]],"date-time":"2023-01-16T03:10:34Z","timestamp":1673838634000},"page":"216","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Distinct Roles of Histone Lysine Demethylases and Methyltransferases in Developmental Eye Disease"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5098-6336","authenticated-orcid":false,"given":"Linda M.","family":"Reis","sequence":"first","affiliation":[{"name":"Department of Pediatrics and Children\u2019s Research Institute, Medical College of Wisconsin and Children\u2019s Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huban","family":"Atilla","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, School of Medicine, Ankara University, 0600 Ankara, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Kannu","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, University of Alberta, Edmonton, AB T6G 2R3, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adele","family":"Schneider","sequence":"additional","affiliation":[{"name":"Einstein Medical Center Philadelphia, Philadelphia, PA 19141, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3400-9287","authenticated-orcid":false,"given":"Samuel","family":"Thompson","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Children\u2019s Research Institute, Medical College of Wisconsin and Children\u2019s Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tanya","family":"Bardakjian","sequence":"additional","affiliation":[{"name":"Einstein Medical Center Philadelphia, Philadelphia, PA 19141, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0531-3586","authenticated-orcid":false,"given":"Elena V.","family":"Semina","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Children\u2019s Research Institute, Medical College of Wisconsin and Children\u2019s Wisconsin, Milwaukee, WI 53226, USA"},{"name":"Department of Ophthalmology and Visual Sciences, Medical College of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s13148-019-0802-2","article-title":"KMT2C\/D COMPASS complex-associated diseases [K(CD)COM-ADs]: An emerging class of congenital regulopathies","volume":"12","author":"Lavery","year":"2020","journal-title":"Clin. Epigenetics"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Boniel, S., Szymanska, K., Smigiel, R., and Szczaluba, K. (2021). Kabuki Syndrome-Clinical Review with Molecular Aspects. Genes, 12.","DOI":"10.3390\/genes12040468"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Barry, K.K., Tsaparlis, M., Hoffman, D., Hartman, D., Adam, M.P., Hung, C., and Bodamer, O.A. (2022). From Genotype to Phenotype-A Review of Kabuki Syndrome. Genes, 13.","DOI":"10.3390\/genes13101761"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"131","DOI":"10.3390\/pediatric14010019","article-title":"De Novo Mutation in KMT2C Manifesting as Kleefstra Syndrome 2: Case Report and Literature Review","volume":"14","author":"Siano","year":"2022","journal-title":"Pediatr. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2013","DOI":"10.1038\/s41380-020-0725-5","article-title":"Characterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome","volume":"26","author":"Kummeling","year":"2021","journal-title":"Mol. Psychiatry"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1086\/427563","article-title":"Mutations in the JARID1C gene, which is involved in transcriptional regulation and chromatin remodeling, cause X-linked mental retardation","volume":"76","author":"Jensen","year":"2005","journal-title":"Am. J. Hum. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1111\/cge.13755","article-title":"Further delineation of the female phenotype with KDM5C disease causing variants: 19 new individuals and review of the literature","volume":"98","author":"Carmignac","year":"2020","journal-title":"Clin. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e2026076118","DOI":"10.1073\/pnas.2026076118","article-title":"The genetic structure of the Turkish population reveals high levels of variation and admixture","volume":"118","author":"Kars","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1968","DOI":"10.1002\/humu.23880","article-title":"Iranome: A catalog of genomic variations in the Iranian population","volume":"40","author":"Fattahi","year":"2019","journal-title":"Hum. Mutat."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1038\/ejhg.2015.155","article-title":"Novel mutations in PAX6, OTX2 and NDP in anophthalmia, microphthalmia and coloboma","volume":"24","author":"Deml","year":"2016","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1007\/s00439-014-1481-x","article-title":"Whole exome sequence analysis of Peters anomaly","volume":"133","author":"Weh","year":"2014","journal-title":"Hum. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2000","DOI":"10.1002\/ajmg.a.35453","article-title":"Congenital corneal staphyloma as a complication of Kabuki syndrome","volume":"158A","author":"Tanaka","year":"2012","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"381","DOI":"10.7150\/ijbs.23517","article-title":"Expanding the Oro-Dental and Mutational Spectra of Kabuki Syndrome and Expression of KMT2D and KDM6A in Human Tooth Germs","volume":"14","author":"Porntaveetus","year":"2018","journal-title":"Int. J. Biol. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1186\/s13023-019-1219-x","article-title":"Kabuki syndrome: Novel pathogenic variants, new phenotypes and review of literature","volume":"14","author":"Shangguan","year":"2019","journal-title":"Orphanet. J. Rare Dis."},{"key":"ref_17","first-page":"696","article-title":"Clinical application of whole-exome sequencing across clinical indications","volume":"18","author":"Retterer","year":"2016","journal-title":"Genet. Med. Off. J. Am. Coll. Med. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2861","DOI":"10.1093\/hmg\/ddv046","article-title":"Mutations in the intellectual disability gene KDM5C reduce protein stability and demethylase activity","volume":"24","author":"Brookes","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Reis, L.M., Maheshwari, M., Capasso, J., Atilla, H., Dudakova, L., Thompson, S., Zitano, L., Lay-Son, G., Lowry, R.B., and Black, J. (2022). Axenfeld-Rieger syndrome: More than meets the eye. J. Med. Genet., Online ahead of print.","DOI":"10.1136\/jmg-2022-108646"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1111\/cge.12241","article-title":"Novel B3GALTL mutations in classic Peters plus syndrome and lack of mutations in a large cohort of patients with similar phenotypes","volume":"86","author":"Weh","year":"2014","journal-title":"Clin. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"R130","DOI":"10.1186\/gb-2009-10-11-r130","article-title":"BioGPS: An extensible and customizable portal for querying and organizing gene annotation resources","volume":"10","author":"Wu","year":"2009","journal-title":"Genome Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"104210","DOI":"10.1016\/j.ejmg.2021.104210","article-title":"Ophthalmic manifestations in Kabuki (make-up) syndrome: A single-center pediatric cohort and systematic review of the literature","volume":"64","author":"Prat","year":"2021","journal-title":"Eur. J. Med. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1038\/s41436-019-0743-3","article-title":"A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct from Kabuki syndrome","volume":"22","author":"Cuvertino","year":"2020","journal-title":"Genet. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1093\/hmg\/ddz284","article-title":"The histone methyltransferase KMT2D, mutated in Kabuki syndrome patients, is required for neural crest cell formation and migration","volume":"29","author":"Nehl","year":"2020","journal-title":"Hum. Mol. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"E9046","DOI":"10.1073\/pnas.1705011114","article-title":"UTX-guided neural crest function underlies craniofacial features of Kabuki syndrome","volume":"114","author":"Shpargel","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1186\/s13072-018-0241-x","article-title":"Physiological effects of KDM5C on neural crest migration and eye formation during vertebrate development","volume":"11","author":"Kim","year":"2018","journal-title":"Epigenetics Chromatin"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1007\/s00439-013-1263-x","article-title":"Haploinsufficiency of KDM6A is associated with severe psychomotor retardation, global growth restriction, seizures and cleft palate","volume":"132","author":"Lindgren","year":"2013","journal-title":"Hum. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1136\/bjo.2006.090639","article-title":"Down\u2019s syndrome and early cataract","volume":"90","author":"Haargaard","year":"2006","journal-title":"Br. J. Ophthalmol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1007\/s00439-018-1958-0","article-title":"RNA sequencing-based transcriptomic profiles of embryonic lens development for cataract gene discovery","volume":"137","author":"Anand","year":"2018","journal-title":"Hum. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1007\/s00439-020-02199-3","article-title":"The Human Gene Mutation Database (HGMD((R))): Optimizing its use in a clinical diagnostic or research setting","volume":"139","author":"Stenson","year":"2020","journal-title":"Hum. Genet."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/1\/216\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:05:58Z","timestamp":1760119558000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/1\/216"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,14]]},"references-count":30,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["genes14010216"],"URL":"https:\/\/doi.org\/10.3390\/genes14010216","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,14]]}}}