Mutations in the chromatin modifier gene KANSL1 cause the 17q21.31 microdeletion syndrome

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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.

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Figure 1: Clinical and genetic analysis of KANSL1.
Figure 2: Functional analysis of KANSL1.


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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

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.

Correspondence to Bert B A de Vries.

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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)

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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) doi:10.1038/ng.2262

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