Update on Kleefstra syndrome
Open accessAbstract
Kleefstra syndrome is characterized by the core phenotype of developmental delay/intellectual disability, (childhood) hypotonia and distinct facial features. The syndrome can be either caused by a microdeletion in chromosomal region 9q34.3 or by a mutation in the euchromatin histone methyltransferase 1 (EHMT1) gene. Since the early 1990s, 85 patients have been described, of which the majority had a 9q34.3 microdeletion (>85%). So far, no clear genotype-phenotype correlation could be observed by studying the clinical and molecular features of both 9q34.3 microdeletion patients and patients with an intragenic EHMT1 mutation. Thus, to further expand the genotypic and phenotypic knowledge about the syndrome, we here report 29 newly diagnosed patients, including 16 patients with a 9q34.3 microdeletion and 13 patients with an EHMT1 mutation, and review previous literature. The present findings are comparable to previous reports. In addition to our former findings and recommendations, we suggest cardiac screening during follow-up, because of the possible occurrence of cardiac arrhythmias. In addition, clinicians and caretakers should be aware of the regressive behavioral phenotype that might develop at adolescent/adult age and seems to have no clear neurological substrate, but is rather a so far unexplained neuropsychiatric feature.
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COL22A1 and COL11A1 exhibit increased expression in the bone tissue and hippocampus of mice with some of the symptoms of Kleefstra Syndrome.
“COL22A1 and COL11A1 exhibit increased expression in the bone tissue and hippocampus of mice with some of the symptoms of Kleefstra Syndrome (developmental delay, hypotonia, and craniofacial abnormalities), which is often accompanied by autistic symptoms and intellectual disability in humans [113, 114].”
From Self-domestication in Homo sapiens: Insights from comparative genomics (2017) · cites this paper as [114]
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Cites
Mutations in NOTCH1 cause aortic valve disease
Garg, V., Muth, A. N., Ransom, J. F., Schluterman, M. K., Barnes, R., King, I. N., Grossfeld, P. D., & Srivastava, D. (2005) · Nature · doi:10.1038/nature03940 · Cited by 1,509 · see citing works
A Complex with Chromatin Modifiers That Occupies E2F- and Myc-Responsive Genes in G 0 Cells
Ogawa, H., Ishiguro, K., Gaubatz, S., Livingston, D. M., & Nakatani, Y. (2002) · Science · doi:10.1126/science.1069861 · Cited by 769 · see citing works
Kleefstra, T., Brunner, H. G., Amiel, J., Oudakker, A. R., Nillesen, W. M., Magee, A. C., Geneviève, D., Cormier‐Daire, V., Esch, H. V., Fryns, J., et al. (2006) · The American Journal of Human Genetics · doi:10.1086/505693 · Cited by 395 · see citing works
Self-citationGenetic and Epigenetic Networks in Intellectual Disabilities
van Bokhoven, H. (2011) · Annual Review of Genetics · doi:10.1146/annurev-genet-110410-132512 · Cited by 382 · see citing works
Kleefstra, T., van Zelst-Stams, W. A., Nillesen, W. M., Cormier-Daire, V, Houge, G., Foulds, N., van Dooren, M., Willemsen, M. H., Pfundt, R., Turner, A., et al. (2009) · Journal of Medical Genetics · doi:10.1136/jmg.2008.062950 · Cited by 252 · see citing works
Self-citationEpigenetic Regulation of Learning and Memory by Drosophila EHMT/G9a
Kramer, J. M., Kochinke, K., Oortveld, M. A. W., Marks, H., Kramer, D., de Jong, E. K., Asztalos, Z., Westwood, J. T., Stunnenberg, H. G., Sokolowski, M. B., et al. (2011) · PLoS Biology · doi:10.1371/journal.pbio.1000569 · Cited by 204 · see citing works
Kleefstra, T., Smidt, M. P., Banning, M. J. G., Oudakker, A. R., Esch, H. V., de Brouwer, A. P. M., Nillesen, W., Sistermans, E. A., Hamel, B. C. J., de Bruijn, D., et al. (2005) · Journal of Medical Genetics · doi:10.1136/jmg.2004.028464 · Cited by 198 · see citing works
Self-citationKim, C., Jun, K., Lee, T., et al. (2001) · Molecular and Cellular Neuroscience · doi:10.1006/mcne.2001.1013 · Cited by 188 · see citing works
The chromosome 9q subtelomere deletion syndrome
Stewart, D. R., & Kleefstra, T. (2007) · American Journal of Medical Genetics Part C Seminars in Medical Genetics · doi:10.1002/ajmg.c.30148 · Cited by 94 · see citing works
Self-citationSubtelomeric deletions of chromosome 9q: A novel microdeletion syndrome
Stewart, D. R., Huang, A., Faravelli, F., Anderlid, B., Medne, L., Ciprero, K. L., Kaur, M., Rossi, E. G., Tenconi, R., Nordenskjöld, M., et al. (2004) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.30136 · Cited by 75 · see citing works
Yatsenko, S. A., Brundage, E. K., Roney, E. K., Cheung, S. W., Chinault, A. C., & Lupski, J. R. (2009) · Human Molecular Genetics · doi:10.1093/hmg/ddp114 · Cited by 73 · see citing works
Yatsenko, S. A., Cheung, S. W., Scott, D. A., et al. (2005) · Journal of Medical Genetics · doi:10.1136/jmg.2004.028258 · Cited by 71 · see citing works
Familial Kleefstra syndrome due to maternal somatic mosaicism for interstitial 9q34.3 microdeletions
Willemsen, M., Beunders, G., Callaghan, M., et al. (2010) · Clinical Genetics · doi:10.1111/j.1399-0004.2010.01607.x · Cited by 69 · see citing works
Self-citationCryptic terminal deletion of chromosome 9q34: a novel cause of syndromic obesity in childhood?
Cormier‐Daire, V., Molinari, F., Rio, M., Raoul, O., de Blois, M.-C., Romana, S. P., Vekemans, M. J. J., Münnich, A., & Colleaux, L. (2003) · Journal of Medical Genetics · doi:10.1136/jmg.40.4.300 · Cited by 68 · see citing works
Verhoeven, W. M. A., Egger, J. I. M., Vermeulen, K., van de Warrenburg, B. P. C., & Kleefstra, T. (2011) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.34186 · Cited by 56 · see citing works
Self-citationDawson, A., Putnam, S., Schultz, J., et al. (2002) · Clinical Genetics · doi:10.1111/j.1399-0004.2002.tb02255.x · Cited by 47 · see citing works
9q34.3 deletion syndrome in three unrelated children
Iwakoshi, M., Okamoto, N., Harada, N., Nakamura, T., Yamamori, S., Fujita, H., Niikawa, N., & Matsumoto, N. (2004) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.20602 · Cited by 47 · see citing works
A 1-Mb critical region in six patients with 9q34.3 terminal deletion syndrome
Harada, N., Visser, R., Dawson, A., Fukamachi, M., Iwakoshi, M., Okamoto, N., Kishino, T., Niikawa, N., & Matsumoto, N. (2004) · Journal of Human Genetics · doi:10.1007/s10038-004-0166-z · Cited by 40 · see citing works
Behavioral phenotype in the 9q subtelomeric deletion syndrome: A report about two adult patients
Verhoeven, W. M. A., Kleefstra, T., & Egger, J. I. M. (2009) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.31015 · Cited by 33 · see citing works
Self-citationThree patients with terminal deletions within the subtelomeric region of chromosome 9q
Neas, K. R., Smith, J. M., Chia, N., Huseyin, S., Heaps, L. S., Peters, G. B., Sholler, G. F., Tzioumi, D., Sillence, D. O., & Mowat, D. R. (2005) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.30496 · Cited by 30 · see citing works
A report of a child with a deletion (9)(q34.3): a recognisable phenotype?
Ayyash, H. F., Mueller, R., Maltby, E. L., et al. (1997) · Journal of Medical Genetics · doi:10.1136/jmg.34.7.610 · Cited by 27 · see citing works
Infant with multiple congenital anomalies and deletion (9)(q34.3)
Schimmenti, L. A., Berry, S. A., Tuchman, M., et al. (1994) · American Journal of Medical Genetics · doi:10.1002/ajmg.1320510211 · Cited by 27 · see citing works
Kleefstra, T., Koolen, D. A., Nillesen, W. M., de Leeuw, N., Hamel, B. C. J., Veltman, J. A., Sistermans, E. A., van Bokhoven, H., van Ravenswaay, C., & Vries, B. B. A. D. (2006) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.31123 · Cited by 24 · see citing works
Self-citationNillesen, W. M., Yntema, H. G., Moscarda, M., et al. (2011) · Human Mutation · doi:10.1002/humu.21523 · Cited by 18 · see citing works
Self-citationClinical and cytogenetic manifestations of subtelomeric aberrations: Report of six cases
Font-Montgomery, E. E., Weaver, D. D., Walsh, L. E., et al. (2004) · Birth Defects Research Part A Clinical and Molecular Teratology · doi:10.1002/bdra.20036 · Cited by 14 · see citing works
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Research works printed but not linked: 1
- Kleefstra T, Nillesen WM, Yntema HG: Kleefstra Syndrome; in Pagon RA, Bird TD, Dolan CR, Stephens K (eds): GeneReviews [Internet] (University of Washington, Seattle 1993- 2011). http://www.ncbi.nlm.nih.gov/books/ NBK47079/ (2010).
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Hyun, K., Jeon, J., Park, K., & Kim, J. (2017) · Experimental & Molecular Medicine · doi:10.1038/emm.2017.11 · Cited by 1,250 · see citing works
Genetic studies in intellectual disability and related disorders
Vissers, L. E. L. M., Gilissen, C., & Veltman, J. A. (2016) · Nature Reviews Genetics · doi:10.1038/nrg3999 · Cited by 761 · see citing works
An epigenetic framework for neurodevelopmental disorders: From pathogenesis to potential therapy
Millan, M. J. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.11.015 · Cited by 229 · see citing works
Self-domestication in Homo sapiens: Insights from comparative genomics
Theofanopoulou, C., Gastaldon, S., O’Rourke, T., Samuels, B. D., Messner, A., Martins, P. T., Delogu, F., Alamri, S., & Boeckx, C. (2017) · PLOS ONE · doi:10.1371/journal.pone.0185306 · Cited by 174 · see citing works
Neuronal network dysfunction in a model for Kleefstra syndrome mediated by enhanced NMDAR signaling
Frega, M., Linda, K., Keller, J. M., Gümüş-Akay, G., Mossink, B., van Rhijn, J.-R., Negwer, M., Klein Gunnewiek, T., Foreman, K., Kompier, N., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-12947-3 · Cited by 137 · see citing works
Self-citationBalemans, M. C. M., Ansar, M., Oudakker, A. R., van Caam, A. P. M., Bakker, B., Vitters, E. L., van der Kraan, P. M., de Bruijn, D. R. H., Janssen, S. M., Kuipers, A. J., et al. (2014) · Developmental Biology · doi:10.1016/j.ydbio.2013.12.016 · Cited by 72 · see citing works
Self-citationSchut, E. H. S., Alonso, A., Smits, S., Khamassi, M., Samanta, A., Negwer, M., Kasri, N. N., Navarro Lobato, I., & Genzel, L. (2020) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2020.107265 · Cited by 8 · see citing works
- Authors
- Willemsen, M. H., Vulto-van Silfhout, A. T., Nillesen, W. M., Wissink-Lindhout, W. M., van Bokhoven, H., Philip, N., Berry-Kravis, E. M., Kini, U., van Ravenswaaij-Arts, C. M. A., Delle Chiaie, B., Innes, A. M. M., Houge, G., Kosonen, T., Cremer, K., Fannemel, M., Stray-Pedersen, A., Reardon, W., Ignatius, J., Lachlan, K., Mircher, C., Helderman van den Enden, P. T. J. M., Mastebroek, M., Cohn-Hokke, P. E., Yntema, H. G., Drunat, S., & Kleefstra, T.
- Affiliations
- Radboud University Nijmegen (NL)
- Assistance Publique Hôpitaux de Marseille (FR)
- Churchill Hospital (GB)
- University of Calgary (CA)
- Haukeland University Hospital (NO)
- Hyvinkää Hospital (FI)
- Essen University Hospital (DE)
- Oslo University Hospital (NO)
- Children's Health Ireland at Crumlin (IE)
- University of Turku (FI)
- Princess Anne Hospital (GB)
- Fondation Jérôme-Lejeune (FR)
- Pluryn (NL)
- Assistance Publique – Hôpitaux de Paris (FR)
- ORCID
- Venue
- Molecular Syndromology
- Publisher
- S. Karger AG
- Published
- 2011
- Volume
- 2
- Issue
- 3-5
- Pages
- 202-212
- ISSN
- 1661-8769 (ISSN-L)
- 1661-8777
- PMC
- PMC3366700
- OpenAlex
- W2042460778
- Cited by
- 185
- References
- 25
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 18 · 2023: 15 · 2022: 10 · 2021: 15 · 2020: 13 · 2019: 8 · 2018: 13 · 2017: 12 · 2016: 17 · 2015: 19 · 2014: 14 · 2013: 8 · 2012: 4
- FWCI
- 5.18
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Molecular Syndromology (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- ePrints Soton (University of Southampton) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
- Radboud Repository (Radboud University) (submittedVersion)
- Funders
- ZonMw (907-00-365)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- Kleefstra syndrome, developmental delay, intellectual disability, hypotonia, facial dysmorphism, genotype-phenotype correlation, cardiac arrhythmias, cardiac screening, neuropsychiatric features
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