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These disorders have significant overlap in molecular pathways and phenotypes including intellectual disability, short stature, and obesity. Among the MDEMs is Kleefstra syndrome (KLFS), which is caused by haploinsufficiency of\n                    <jats:italic>EHMT1<\/jats:italic>\n                    . Preclinical studies have identified metabolic dysregulation and obesity in KLFS models, but proper clinical translation lacks. In this study, we aim to delineate growth, body composition, and endocrine\u2010metabolic characteristics in a total of 62 individuals with KLFS. Our results revealed a high prevalence of childhood\u2010onset overweight\/obesity (60%; 28\/47) with disproportionately high body fat percentage, which aligns perfectly with previous preclinical studies. Short stature was common (33%), likely due to advanced skeletal maturation. Endocrine\u2010metabolic investigations showed thyroid dysregulation (22%; 9\/41), elevated triglycerides, and decreased blood ammonia levels. Moreover, hand radiographs identified decreased bone mineralization (57%; 8\/14) and negative ulnar variance (71%; 10\/14). Our findings indicate a high (cardio)metabolic risk in KLFS. Therefore, we recommend monitoring of weight and endocrine\u2010metabolic profile. Supporting a healthy lifestyle and screening of bone mineralization is advised. Our comprehensive results support translational research and contribute to a better understanding of MDEM\u2010associated phenotypes.\n                  <\/jats:p>","DOI":"10.1002\/ajmg.a.63472","type":"journal-article","created":{"date-parts":[[2023,12,29]],"date-time":"2023-12-29T03:32:03Z","timestamp":1703820723000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Growth, body composition, and endocrine\u2010metabolic profiles of individuals with Kleefstra syndrome provide directions for clinical management and translational studies"],"prefix":"10.1002","volume":"194","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1138-8026","authenticated-orcid":false,"given":"Arianne","family":"Bouman","sequence":"first","affiliation":[{"name":"Department of Human Genetics Radboud University Medical Center  Nijmegen The Netherlands"},{"name":"Donders Institute for Brain, Cognition and Behaviour Radboud University Medical Center  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joyce M.","family":"Geelen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Developmental and Genetic Pediatrics, Amalia Children's Hospital Radboud University Medical Center  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joost","family":"Kummeling","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Radboud University Medical Center  Nijmegen The Netherlands"},{"name":"Donders Institute for Brain, Cognition and Behaviour Radboud University Medical Center  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annette","family":"Schenck","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Radboud University Medical Center  Nijmegen The Netherlands"},{"name":"Donders Institute for Brain, Cognition and Behaviour Radboud University Medical Center  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yvonne G.","family":"van der Zwan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Pediatric Endocrinology, Amalia Children's Hospital Radboud University Medical Center  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Willemijn M.","family":"Klein","sequence":"additional","affiliation":[{"name":"Department of Medical Imaging Radboud University Medical Center  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tjitske","family":"Kleefstra","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Radboud University Medical Center  Nijmegen The Netherlands"},{"name":"Donders Institute for Brain, Cognition and Behaviour Radboud University Medical Center  Nijmegen The Netherlands"},{"name":"Department of Clinical Genetics Erasmus MC  Rotterdam The Netherlands"},{"name":"Center of Excellence for Neuropsychiatry Vincent van Gogh Institute for Psychiatry  Venray The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,12,29]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0194697"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2013.12.016"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2012.03.016"},{"key":"e_1_2_12_5_1","unstructured":"BoneXpert. 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