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Stehr, A.M.* ; Fischer, J.* ; Mirza-Schreiber, N. ; Bernardi, K.* ; Porrmann, J.* ; Harrer, P. ; Kaiser, F.* ; Jamra, R.A.* ; Winkelmann, J. ; Jech, R.* ; Koy, A.* ; Oexle, K. ; Zech, M.

Variable expressivity of KMT2B variants at codon 2565 in patients with dystonia and developmental disorders.

Parkinsonism Relat. Disord. 133:107319 (2025)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
INTRODUCTION: Variable expressivity is an emerging characteristic of KMT2B-related dystonia. However, it remains poorly understood whether variants reoccurring at specific sites of lysine-specific methlytransferase-2B (KMT2B) can drive intra- and interfamilial clinical heterogeneity. Our goal was to ascertain independent families with variants affecting residue Arg2565 of KMT2B. METHODS: Whole-exome/genome sequencing, multi-site recruitment, genotype-phenotype correlations, and DNA methylation episignature analysis were performed. RESULTS: We report four individuals from two families harboring the variant c.7693C > G, p.Arg2565Gly. In an additional patient, a de-novo c.7693C > T, p.Arg2565Cys variant was identified. The observed phenotypic spectrum ranged from childhood-onset dystonia (N = 2) over unspecific intellectual disability syndromes (N = 2) to undiagnosed behavioral symptoms in adulthood (N = 1). Samples bearing p.Arg2565Gly had a KMT2B-typical episignature, although the effect on methylation was less pronounced than in carriers of loss-of-function KMT2B variants. CONCLUSIONS: We established the existence of a KMT2B missense-mutation hotspot associated with varying degrees of disease severity and expression, providing information for patient counseling and elucidation of pathomechanisms.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Developmental Disease ; Dystonia ; Episignature ; Kmt2b ; Recurrent Variation ; Variable Expressivity; Pathogenicity
ISSN (print) / ISBN 1353-8020
e-ISSN 1873-5126
Journal Parkinsonism & Related Disorders
Quellenangaben Volume: 133, Issue: , Pages: , Article Number: 107319 Supplement: ,
Publisher Elsevier
Publishing Place 125 London Wall, London, England
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
Grants Agency for Health Research of the Czech Republic
German Federal Ministry of Education and Research (BMBF, Bonn, Germany)
Else Kroner-Fresenius-Stiftung
Federal Ministry of Education and Research (BMBF)
Free State of Bavaria under the Excellence Strategy of the Federal Government
Lander
Technical University of Munich-Institute
German Research Foundation (DFG )
National Institute for Neurological Research, Czech Republic, Programme EXCELES
European Union - Next Generation EU
Charles University: Cooperatio Program in Neuroscience
EJP RD