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The full spectrum of clinical features and genotype\u2013phenotype correlations is currently not fully understood. We performed a retrospective chart review of patients with KLEFS evaluated at the Boston Children's Hospital Kleefstra Clinic. There were 65 individuals (40 females, 25 males, mean age 9.3\u2009years). 17% had large 9q34 deletions (\u2265\u20091\u2009Mb), 29% had small 9q34 deletions (&lt;\u20091\u2009Mb), and 54% had sequence variants. Global developmental delay (GDD) or intellectual disability (ID) was present in 77%. Behavioral disorders, such as autism spectrum disorder (38%), were common. Epilepsy affected 15%. Systemic health issues included structural cardiac defects (40%), hearing loss (32%), and constipation (31%). Novel features including subgroups with significant motor impairment (24%) and refractory epilepsy (9%), as well as small numbers with opsoclonus\u2010like eye movements (<jats:italic>n<\/jats:italic>\u2009=\u20092), thrombocytopenia (<jats:italic>n<\/jats:italic>\u2009=\u20092), progressive cerebral atrophy (<jats:italic>n<\/jats:italic>\u2009=\u20091), and adrenal carcinoma (<jats:italic>n<\/jats:italic>\u2009=\u20091). 9q34 deletion subgroups had higher rates of GDD\/ID (<jats:italic>p<\/jats:italic>\u2009=\u20090.037), significant motor impairment (<jats:italic>p<\/jats:italic>\u2009=\u20090.01), epilepsy (<jats:italic>p<\/jats:italic>\u2009=\u20090.004), and cortical visual impairment (<jats:italic>p<\/jats:italic>\u2009=\u20090.003) compared to the subgroup with sequence variants. This information may be used to improve clinical care as well as inform research and future therapeutic initiatives.<\/jats:p>","DOI":"10.1111\/cge.14697","type":"journal-article","created":{"date-parts":[[2025,1,3]],"date-time":"2025-01-03T01:13:24Z","timestamp":1735866804000},"page":"636-645","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Novel Phenotypes and Genotype\u2013Phenotype Correlations in a Large Clinical Cohort of Patients With Kleefstra Syndrome"],"prefix":"10.1111","volume":"107","author":[{"given":"Zo\u00eb J.","family":"Frazier","sequence":"first","affiliation":[{"name":"Rosamund Stone Zander Translational Neuroscience Center, Department of Neurology Boston Children's Hospital  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5455-4258","authenticated-orcid":false,"given":"Seyda","family":"Kilic","sequence":"additional","affiliation":[{"name":"School of Arts and Sciences Tufts University  Medford Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hailey","family":"Osika","sequence":"additional","affiliation":[{"name":"Rosamund Stone Zander Translational Neuroscience Center, Department of Neurology Boston Children's Hospital  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alisa","family":"Mo","sequence":"additional","affiliation":[{"name":"Department of Neurology Boston Children's Hospital  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meg","family":"Quinn","sequence":"additional","affiliation":[{"name":"Rosamund Stone Zander Translational Neuroscience Center, Department of Neurology Boston Children's Hospital  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Ballal","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology and Nutrition Boston Children's Hospital  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamar","family":"Katz","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences Boston Children's Hospital  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. Eliot","family":"Shearer","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology &amp; Communication Enhancement Boston Children's Hospital  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3875-871X","authenticated-orcid":false,"given":"Max A.","family":"Horlbeck","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics Boston Children's Hospital  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynn S.","family":"Pais","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics Boston Children's Hospital  Boston Massachusetts USA"},{"name":"Program in Medical and Population Genetics Broad Institute of MIT and Harvard  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kira A.","family":"Dies","sequence":"additional","affiliation":[{"name":"Rosamund Stone Zander Translational Neuroscience Center, Department of Neurology Boston Children's Hospital  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"O'Donnell\u2010Luria","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics Boston Children's Hospital  Boston Massachusetts USA"},{"name":"Program in Medical and Population Genetics Broad Institute of MIT and Harvard  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joe","family":"Kossowsky","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Critical Care and Pain Medicine Boston Children's Hospital  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan O.","family":"Lipton","sequence":"additional","affiliation":[{"name":"Rosamund Stone Zander Translational Neuroscience Center, Department of Neurology Boston Children's Hospital  Boston Massachusetts USA"},{"name":"Department of Neurology Boston Children's Hospital  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tjitske","family":"Kleefstra","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Erasmus University Rotterdam  Rotterdam the Netherlands"},{"name":"Center of Excellence for Neuropsychiatry Vincent van Gogh Institute for Psychiatry, Venray and Human Genetics, Radboud UMC  Nijmegen the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siddharth","family":"Srivastava","sequence":"additional","affiliation":[{"name":"Rosamund Stone Zander Translational Neuroscience Center, Department of Neurology Boston Children's Hospital  Boston Massachusetts USA"},{"name":"Department of Neurology Boston Children's Hospital  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,1,2]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2004.028464"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2016.06.003"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1086\/505693"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13229-018-0193-9"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2008.06.006"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.62448"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2012.267"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2008.062950"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2016.01.004"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.38280"},{"key":"e_1_2_8_12_1","volume-title":"GeneReviews\u00ae","author":"Kleefstra T.","year":"1993"},{"key":"e_1_2_8_13_1","first-page":"1","article-title":"Growth, Body Composition, and Endocrine\u2010Metabolic Profiles of Individuals With Kleefstra Syndrome Provide Directions for Clinical Management and Translational Studies","volume":"194","author":"Bouman A.","year":"2023","journal-title":"American Journal of Medical Genetics. 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