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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)
Verlagsversion Forschungsdaten DOI PMC
Open Access Hybrid
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Developmental Disease ; Dystonia ; Episignature ; Kmt2b ; Recurrent Variation ; Variable Expressivity; Pathogenicity
Sprache englisch
Veröffentlichungsjahr 2025
HGF-Berichtsjahr 2025
ISSN (print) / ISBN 1353-8020
e-ISSN 1873-5126
Zeitschrift Parkinsonism & Related Disorders
Quellenangaben Band: 133, Heft: , Seiten: , Artikelnummer: 107319 Supplement: ,
Verlag Elsevier
Verlagsort 125 London Wall, London, England
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Neurogenomics (ING)
POF Topic(s) 30205 - Bioengineering and Digital Health
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-503200-001
Förderungen 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
DOI 10.1016/j.parkreldis.2025.107319
WOS ID 001427181000001
Scopus ID 85217107094
PubMed ID 39933316
Erfassungsdatum 2025-04-08
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