{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T13:26:57Z","timestamp":1775741217480,"version":"3.50.1"},"reference-count":25,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,4,29]],"date-time":"2025-04-29T00:00:00Z","timestamp":1745884800000},"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: Kleefstra syndrome 1(KLEFS1, OMIM#610253) is a rare neurodevelopmental disorder (NDD) instigated by heterozygous variants or microdeletions occurring in the 9q34.4 genomic region of the euchromatic histone methyltransferase-1 (EHMT1) gene and is inherited in an autosomal dominant (AD) manner. The clinical phenotype of KLEFS1 includes moderate to severe intellectual disability (ID), hypotonia, and distinctive facial features and additionally involves other organ systems (heart, renal, genitourinary, sensory) albeit with phenotypic heterogeneity between patients. The purpose of this study is to expand the genotypic spectrum of KLEFS1 and compare phenotypic features of the syndrome of already published cases. Methods: Exome sequencing (ES), chromosomal microarray analysis (CMA), as well as sanger sequencing, for confirmation of the de novo status of the frameshift variant, were used. Results: Here we describe two more cases, both males with a similar age and carriers of novel variants; one with a frameshift variant involving exon 13: p.Val692Glyfs*64 and the other with the smallest so far described, 11 Kb (exons 19-25), 9q34.4 microdeletion: 9q34.3 (140703393-140714454). Both presented with an NDD disorder with one showing more severe ID with significant social disabilities, while the other with the microdeletion had mild ID and following a normal education curriculum. Neither of them were obese nor had any other significant organ system disorder. Conclusions: The observed phenotypic variability due to genotypic differences in the two children contributes to the expanding spectrum of KLEFS1 disease phenotypes.<\/jats:p>","DOI":"10.3390\/genes16050521","type":"journal-article","created":{"date-parts":[[2025,5,1]],"date-time":"2025-05-01T03:50:43Z","timestamp":1746071443000},"page":"521","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A Novel Frameshift Variant and a Partial EHMT1 Microdeletion in Kleefstra Syndrome 1 Patients Resulting in Variable Phenotypic Severity and Literature Review"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6810-2922","authenticated-orcid":false,"given":"Maria","family":"Tzetis","sequence":"first","affiliation":[{"name":"Laboratory of Medical Genetics, Medical School, National and Kapodistrian University of Athens, Thivon & Levadias, 11527 Athens, Greece"},{"name":"Medical Genetics Laboratory, GeneTech Analytics Ltd., 41 Asklepiou, 41222 Larissa, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anastasios","family":"Mitrakos","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics, Medical School, National and Kapodistrian University of Athens, Thivon & Levadias, 11527 Athens, Greece"},{"name":"University Research Institute for the Study of Genetic and Malignant Disorders in Childhood, National and Kapodistrian University of Athens, Thivon and Levadias, 11527 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ioanna","family":"Papathanasiou","sequence":"additional","affiliation":[{"name":"Laboratory of Cytogenetics and Molecular Genetics, Faculty of Medicine, University of Thessaly, 3 Panepistimiou, Biopolis, 41500 Larissa, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vasiliki","family":"Koute","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Outpatient Clinic, Department of Pediatrics, University Hospital of Larissa, 41500 Larissa, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Konstantina","family":"Kosma","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics, Medical School, National and Kapodistrian University of Athens, Thivon & Levadias, 11527 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roser","family":"Pons","sequence":"additional","affiliation":[{"name":"First Department of Pediatrics, Medical School, \u201cAghia Sophia\u201d Children\u2019s Hospital, National and Kapodistrian University of Athens, Thivon and Papadiamantopoulou, 11527 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aspasia","family":"Michoula","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine, University of Thessaly, Biopolis, 41500 Larissa, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ioanna","family":"Grivea","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine, University of Thessaly, Biopolis, 41500 Larissa, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aspasia","family":"Tsezou","sequence":"additional","affiliation":[{"name":"Medical Genetics Laboratory, GeneTech Analytics Ltd., 41 Asklepiou, 41222 Larissa, Greece"},{"name":"Laboratory of Cytogenetics and Molecular Genetics, Faculty of Medicine, University of Thessaly, 3 Panepistimiou, Biopolis, 41500 Larissa, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1016\/j.ajhg.2024.06.008","article-title":"Comprehensive EHMT1 Variants Analysis Broadens Genotype-Phenotype Associations and Molecular Mechanisms in Kleefstra Syndrome","volume":"111","author":"Rots","year":"2024","journal-title":"Am. 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