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.

Department of Human Neurosciences Sapienza University of Rome Rome Italy; Department of Pediatrics Faculty of Medicine and University Hospital Cologne University of Cologne Cologne Germany

Department of Neurology Charles University 1st Faculty of Medicine and General University Hospital Prague Prague Czech Republic

Department of Pediatrics Faculty of Medicine and University Hospital Cologne University of Cologne Cologne Germany; Center for Rare Diseases Faculty of Medicine and University Hospital Cologne University of Cologne Cologne Germany

Institute for Clinical Genetics University Hospital Carl Gustav Carus at TUD Dresden University of Technology Dresden Germany

Institute of Human Genetics Technical University of Munich School of Medicine and Health Munich Germany

Institute of Human Genetics Technical University of Munich School of Medicine and Health Munich Germany; Institute of Neurogenomics Helmholtz Zentrum München Munich Germany

Institute of Human Genetics Technical University of Munich School of Medicine and Health Munich Germany; Institute of Neurogenomics Helmholtz Zentrum München Munich Germany; Institute for Advanced Study Technical University of Munich Garching Germany

Institute of Human Genetics Technical University of Munich School of Medicine and Health Munich Germany; Institute of Neurogenomics Helmholtz Zentrum München Munich Germany; Munich Cluster for Systems Neurology Munich Germany; DZPG Deutsches Zentrum für Psychische Gesundheit Munich Germany

Institute of Human Genetics Technical University of Munich School of Medicine and Health Munich Germany; Neurogenetic Systems Analysis Group Institute of Neurogenomics Helmholtz Munich Neuherberg Germany

Institute of Human Genetics Technical University of Munich School of Medicine and Health Munich Germany; Neurogenetic Systems Analysis Group Institute of Neurogenomics Helmholtz Munich Neuherberg Germany; Institute of Neurogenomics Helmholtz Zentrum München Munich Germany

Institute of Human Genetics Universitätsklinikum Essen Essen Germany

Institute of Human Genetics University of Leipzig Medical Center Leipzig Germany

Parkinsonism Relat Disord. 2025 May;134:107795. doi: 10.1016/j.parkreldis.2025.107795. PubMed

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