ABSTRACT We show that haploinsufficiency of _KANSL1_ is sufficient to cause the 17q21.31 microdeletion syndrome, a multisystem disorder characterized by intellectual disability, hypotonia

and distinctive facial features. The KANSL1 protein is an evolutionarily conserved regulator of the chromatin modifier KAT8, which influences gene expression through histone H4 lysine 16

(H4K16) acetylation. RNA sequencing studies in cell lines derived from affected individuals and the presence of learning deficits in _Drosophila melanogaster_ mutants suggest a role for

_KANSL1_ in neuronal processes. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your

our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS A NOVEL _DE NOVO_ HETEROZYGOUS _DYRK1A_ MUTATION CAUSES COMPLETE LOSS OF DYRK1A FUNCTION AND DEVELOPMENTAL DELAY

Article Open access 17 June 2020 KAT6B OVEREXPRESSION RESCUES EMBRYONIC LETHALITY IN HOMOZYGOUS NULL KAT6A MICE RESTORING VITALITY AND NORMAL LIFESPAN Article Open access 25 February 2025

CORNELIA DE LANGE SYNDROME-ASSOCIATED MUTATIONS CAUSE A DNA DAMAGE SIGNALLING AND REPAIR DEFECT Article Open access 25 May 2021 REFERENCES * Koolen, D.A. et al. _Nat. Genet._ 38, 999–1001

(2006). Article  CAS  Google Scholar  * Sharp, A.J. et al. _Nat. Genet._ 38, 1038–1042 (2006). Article  CAS  Google Scholar  * Shaw-Smith, C. et al. _Nat. Genet._ 38, 1032–1037 (2006).

Article  CAS  Google Scholar  * Koolen, D.A. et al. _J. Med. Genet._ 45, 710–720 (2008). Article  CAS  Google Scholar  * Tan, T.Y. et al. _J. Med. Genet._ 46, 480–489 (2009). Article  CAS 

Google Scholar  * Hutton, M. et al. _Nature_ 393, 702–705 (1998). Article  CAS  Google Scholar  * Dubourg, C. et al. _Eur. J. Med. Genet._ 54, 144–151 (2011). Article  Google Scholar  *

Cooper, G.M. et al. _Nat. Genet._ 43, 838–846 (2011). Article  CAS  Google Scholar  * Mendjan, S. et al. _Mol. Cell_ 21, 811–823 (2006). Article  CAS  Google Scholar  * Li, X. et al. _Mol.

Cell_ 36, 290–301 (2009). Article  CAS  Google Scholar  * Dou, Y. et al. _Cell_ 121, 873–885 (2005). Article  CAS  Google Scholar  * Ng, S.B. et al. _Nat. Genet._ 42, 790–793 (2010). Article

  CAS  Google Scholar  * Raja, S.J. et al. _Mol. Cell_ 38, 827–841 (2010). Article  CAS  Google Scholar  * Lone, M. et al. _J. Cell Sci._ 123, 2369–2374 (2010). Article  CAS  Google Scholar

  Download references ACKNOWLEDGEMENTS We thank the subjects and their parents for participation in this study and H. van Bokhoven for his comments on the manuscript. We thank M. Schepens,

K. van de Donk and personnel from the Microarray Facility and Sequencing Facility Nijmegen for technical assistance. We thank K. Keleman (Institute of Molecular Pathology) and S. Sweeney

(University of York) for _Drosophila_ stocks. This study was financially supported by the Dutch Brain Foundation (KS 2012(1)-119 to D.A.K.), the Netherlands Organization for Health Research

and Development (ZonMW; grants 917-66-363 and 911-08-025 to J.A.V., 916-86-016 to L.E.L.M.V., 917-96-346 to A.S. and 917-86-319 to B.B.A.d.V.), the European Union–funded TECHGENE project

(Health-F5-2009-223143 to J.A.V. and H.S.), the AnEUploidy project (LSHG-CT-2006-37627 to H.G.B., J.A.V and B.B.A.d.V.) and the GENCODYS project (HEALTH-F4-2010-241995 to A.S. and

B.B.A.d.V.). We obtained informed consent for participation in the study and to publish clinical photographs for individuals 1–4. The Medical Review Ethics Committee of the Radboud

University Nijmegen Medical Center approved the study. AUTHOR INFORMATION Author notes * David A Koolen, Jamie M Kramer and Kornelia Neveling: These authors contributed equally to this work.

* Annette Schenck, Helger G Yntema and Bert B A de Vries: These authors jointly directed this work. AUTHORS AND AFFILIATIONS * Department of Human Genetics, Radboud University Nijmegen

Medical Center, Nijmegen, The Netherlands David A Koolen, Jamie M Kramer, Kornelia Neveling, Willy M Nillesen, Christian Gilissen, Eugene T P Verwiel, Sarah Martens, Ernie M H F Bongers, 

Petra de Vries, Hans Scheffer, Lisenka E L M Vissers, Arjan P M de Brouwer, Han G Brunner, Joris A Veltman, Annette Schenck, Helger G Yntema & Bert B A de Vries * Nijmegen Center for

Molecular Life Sciences, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands David A Koolen, Jamie M Kramer, Kornelia Neveling, Willy M Nillesen, Christian Gilissen, Eugene

T P Verwiel, Sarah Martens, Ernie M H F Bongers, Petra de Vries, Hans Scheffer, Lisenka E L M Vissers, Arjan P M de Brouwer, Han G Brunner, Joris A Veltman, Annette Schenck, Helger G Yntema

 & Bert B A de Vries * Institute for Genetic and Metabolic Disease, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands David A Koolen, Kornelia Neveling, Willy M

Nillesen, Christian Gilissen, Eugene T P Verwiel, Sarah Martens, Ernie M H F Bongers, Petra de Vries, Hans Scheffer, Lisenka E L M Vissers, Arjan P M de Brouwer, Han G Brunner, Joris A

Veltman, Helger G Yntema & Bert B A de Vries * Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands Jamie M Kramer, 

Arjan P M de Brouwer, Annette Schenck & Bert B A de Vries * South West Thames Regional Genetics Service, St George's University of London, London, UK Heather L Moore-Barton & 

Frances V Elmslie * Service de Génétique, Centre Hospitalier Régional et Universitaire (CHRU) Hôpital Bretonneau, Tours, France Annick Toutain * Département de Génétique, Hôpital

Necker–Enfants Malades, Paris, France Jeanne Amiel & Valérie Malan * Institut National de la Santé et de la Recherche Médicale (INSERM) U781, Université Paris Descartes–Sorbonne Paris

Cité, Institut Imagine, Paris, France Jeanne Amiel & Valérie Malan * Section of Clinical Genetics and Metabolism, The Children's Hospital Colorado, University of Colorado Denver,

Aurora, Colorado, USA Anne Chun-Hui Tsai * Department of Molecular and Human Genetics, Medical Genetics Laboratories, Baylor College of Medicine, Houston, Texas, USA Sau Wai Cheung *

Department of Epidemiology, Biostatistics and Health Technology Assessment, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands Ton Feuth Authors * David A Koolen View

author publications You can also search for this author inPubMed Google Scholar * Jamie M Kramer View author publications You can also search for this author inPubMed Google Scholar *

Kornelia Neveling View author publications You can also search for this author inPubMed Google Scholar * Willy M Nillesen View author publications You can also search for this author

inPubMed Google Scholar * Heather L Moore-Barton View author publications You can also search for this author inPubMed Google Scholar * Frances V Elmslie View author publications You can

also search for this author inPubMed Google Scholar * Annick Toutain View author publications You can also search for this author inPubMed Google Scholar * Jeanne Amiel View author

publications You can also search for this author inPubMed Google Scholar * Valérie Malan View author publications You can also search for this author inPubMed Google Scholar * Anne Chun-Hui

Tsai View author publications You can also search for this author inPubMed Google Scholar * Sau Wai Cheung View author publications You can also search for this author inPubMed Google

Scholar * Christian Gilissen View author publications You can also search for this author inPubMed Google Scholar * Eugene T P Verwiel View author publications You can also search for this

author inPubMed Google Scholar * Sarah Martens View author publications You can also search for this author inPubMed Google Scholar * Ton Feuth View author publications You can also search

for this author inPubMed Google Scholar * Ernie M H F Bongers View author publications You can also search for this author inPubMed Google Scholar * Petra de Vries View author publications

You can also search for this author inPubMed Google Scholar * Hans Scheffer View author publications You can also search for this author inPubMed Google Scholar * Lisenka E L M Vissers View

author publications You can also search for this author inPubMed Google Scholar * Arjan P M de Brouwer View author publications You can also search for this author inPubMed Google Scholar *

Han G Brunner View author publications You can also search for this author inPubMed Google Scholar * Joris A Veltman View author publications You can also search for this author inPubMed 

Google Scholar * Annette Schenck View author publications You can also search for this author inPubMed Google Scholar * Helger G Yntema View author publications You can also search for this

author inPubMed Google Scholar * Bert B A de Vries View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS D.A.K. and B.B.A.d.V. designed the

study. K.N. performed expression profiling. W.M.N. designed and performed the genetics experiments. J.M.K. performed the experiments in _Drosophila_. C.G. and E.T.P.V. performed the

bioinformatics experiments. S.M., P.d.V., L.E.L.M.V. and A.P.M.d.B. contributed to the expression profiling and genetics experiments. D.A.K., H.L.M.-B., F.V.E., A.T., J.A., V.M., A.C.-H.T.,

S.W.C., E.M.H.F.B., H.G.B. and B.B.A.d.V. recruited and evaluated the study subjects. T.F. performed statistical analysis. H.G.Y. supervised W.M.N. and S.M., J.A.V. and H.S. supervised K.N.,

C.G. and E.T.P.V., A.S. supervised J.M.K., and B.B.A.d.V. supervised D.A.K. D.A.K., J.M.K., K.N. and B.B.A.d.V. wrote the manuscript. CORRESPONDING AUTHOR Correspondence to Bert B A de

Vries. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. SUPPLEMENTARY INFORMATION SUPPLEMENTARY TEXT AND FIGURES Supplementary Methods,

Supplementary Note, Supplementary Figure 1 and Supplementary Tables 1–4 and 8 (PDF 388 kb) SUPPLEMENTARY TABLE 5 Differentially expressed genes in 17q21.31 microdeletion samples compared to

controls. (XLSX 61 kb) SUPPLEMENTARY TABLE 6 Differentially expressed genes in individual 4 compared to controls (XLSX 626 kb) SUPPLEMENTARY TABLE 7 143 genes differentially expressed in

both types of mutations (XLSX 35 kb) RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Koolen, D., Kramer, J., Neveling, K. _et al._ Mutations in the

chromatin modifier gene _KANSL1_ cause the 17q21.31 microdeletion syndrome. _Nat Genet_ 44, 639–641 (2012). https://doi.org/10.1038/ng.2262 Download citation * Received: 29 November 2011 *

Accepted: 06 April 2012 * Published: 29 April 2012 * Issue Date: June 2012 * DOI: https://doi.org/10.1038/ng.2262 SHARE THIS ARTICLE Anyone you share the following link with will be able to

read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing

initiative