Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite MLL proteins being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases. Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance and characteristic brain magnetic resonance imaging findings. Over time, the majority of affected individuals developed prominent cervical, cranial and laryngeal dystonia. Marked clinical benefit, including the restoration of independent ambulation in some cases, was observed following deep brain stimulation (DBS). These findings highlight a clinically recognizable and potentially treatable form of genetic dystonia, demonstrating the crucial role of KMT2B in the physiological control of voluntary movement.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
NCBI Reference Sequence
We thank all our patients and their families for taking part in this study and encouraging international collaboration to seek out similar cases. Thanks are given to M. Ishida (GOS-ICH) for kindly providing the fetal cDNA, K. Tuschl (GOS-ICH) for kindly providing the human cDNA panel, L. Bassioni (Great Ormond Street Hospital, GOSH) for kindly selecting DaTSCAN images for the supplementary manuscript, M. Adams (National Hospital for Neurology and Neurosurgery, NHNN) for reviewing the imaging of the patients at NHNN and R. Meijer for helping with the sequencing analysis at the Department of Human Genetics (Nijmegen). We thank G. Moore (GOS-ICH) and P. Stanier (GOS-ICH) for proofreading the manuscript. Many thanks are given to A. Panahian-Jand (GOSH) for excellent administrative support. M.A.K. has a Wellcome Intermediate Clinical Fellowship (WT098524MA). E.M. and M.A.K. received funding from the Rosetrees Trust, the Great Ormond Street Hospital Children's Charity and the Gracious Heart Foundation. N.E.M. receives support from the UK Department of Health's NIHR Biomedical Research Centers funding streams. A. Papandreou has a joint Action Medical Research/British Paediatric Neurology Association Research Training Fellowship. J. Ng has an MRC Research Training Fellowship. A.N. has an Action Medical Research Training Fellowship. H.B.-P. has a DBS training travel grant from the Daniel Turnberg Trust Fund. H.H. is funded by the MRC and Wellcome Trust (Synaptopathies award). D.A. is supported by the Prusiner-Abramsky Award. H.P. has received grant support from the Dystonia Society (UK). K.J.P. has an Academy of Medical Sciences Clinical Starter Grant. B.P.-D. received funding from grants 20143130-La Marató de TV3 and PI15/00287-Ministerio Español de Economia y Competitividad. J.-P.L. has been supported by Guy's and St Thomas' Charity New Services and Innovation Grant G060708, the Dystonia Society (UK), grants 01/2011 and 07/2013 and an Action Medical Research, AMR-GN2097. This research was supported by the NIHR Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust, University College London and University of Cambridge and by funding from the NIHR for the BioResource for Rare Diseases (grant RG65966). This study makes use of data generated by the DECIPHER community. A full list of centers contributing to the generation of the data is available from http://decipher.sanger.ac.uk/ and via e-mail from firstname.lastname@example.org. Funding for the project was provided by the Wellcome Trust for UK10K (WT091310) and the DDD study. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant HICF-1009-003); see http://www.ddduk.org/access.html for full acknowledgment. This work was supported in part by the Intramural Research Program of the National Human Genome Research Institute and the Common Fund, NIH Office of the Director. This work was supported in part by the German Ministry of Research and Education (grants 01GS08160 and 01GS08167; German Mental Retardation Network) as part of the National Genome Research Network to A.R. and D.W., and by the Deutsche Forschungsgemeinschaft (AB393/2-2) to A.R. Brain expression data were provided by the UK Human Brain Expression Consortium (UKBEC), which comprises John A. Hardy, Mina Ryten, Michael Weale, Daniah Trabzuni, Adaikalavan Ramasamy, Colin Smith and Robert Walker, affiliated with the UCL Institute of Neurology (J.A.H., M.R. and D.T.), King's College London (M.R., M.W. and A.R.) and the University of Edinburgh (C.S. and R.W.).
Integrated supplementary information
Lower-limb dystonia and gait disturbance in patients with KMT2B variants.
Upper-limb dystonia in patients with KMT2B variants.
Progression to generalized dystonia in patients with KMT2B variants.
Cranial, cervical and laryngeal features in patients with KMT2B variants.
Motor overflow secondary to dystonia in patients with KMT2B variants.
Dystonic crisis in a patient with a KMT2B mutation.
Myoclonus dystonia in a patient with a KMT2B mutation
Response to deep brain stimulation in patient 9.
Response to deep brain stimulation in patient 17.
Response to deep brain stimulation in patient 21.
Response to deep brain stimulation in patient 22.
About this article
Genetic variants in the KDM6B gene are associated with neurodevelopmental delays and dysmorphic features
American Journal of Medical Genetics Part A (2019)