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

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

. 2025 ; 133 (-) : 107319. [pub] 20250205

Jazyk angličtina Země Anglie, Velká Británie

Typ dokumentu časopisecké články, kazuistiky

Perzistentní odkaz   https://www.medvik.cz/link/bmc25009348

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.

Citace poskytuje Crossref.org

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$a Variable expressivity of KMT2B variants at codon 2565 in patients with dystonia and developmental disorders / $c AM. Stehr, J. Fischer, N. Mirza-Schreiber, K. Bernardi, J. Porrmann, P. Harrer, F. Kaiser, RA. Jamra, J. Winkelmann, R. Jech, A. Koy, K. Oexle, M. Zech
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$a 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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$a Fischer, Jan $u Institute for Clinical Genetics, University Hospital Carl Gustav Carus at TUD Dresden University of Technology, Dresden, Germany
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$a Mirza-Schreiber, Nazanin $u Institute of Human Genetics, Technical University of Munich, School of Medicine and Health, Munich, Germany; Neurogenetic Systems Analysis Group, Institute of Neurogenomics, Helmholtz Munich, Neuherberg, Germany
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$a Bernardi, Katerina $u Department of Human Neurosciences, Sapienza University of Rome, Rome, Italy; Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
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$a Porrmann, Joseph $u Institute for Clinical Genetics, University Hospital Carl Gustav Carus at TUD Dresden University of Technology, Dresden, Germany
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$a Harrer, Philip $u Institute of Human Genetics, Technical University of Munich, School of Medicine and Health, Munich, Germany; Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany
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$a Kaiser, Frank $u Institute of Human Genetics, Universitätsklinikum Essen, Essen, Germany
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$a Jamra, Rami Abou $u Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
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$a Winkelmann, Juliane $u Institute of Human Genetics, Technical University of Munich, School of Medicine and Health, Munich, Germany; Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; DZPG, Deutsches Zentrum für Psychische Gesundheit, Munich, Germany
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$a Jech, Robert $u Department of Neurology, Charles University, 1st Faculty of Medicine and General University Hospital in Prague, Prague, Czech Republic
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$a Koy, Anne $u Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Rare Diseases, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
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$a Oexle, Konrad $u Institute of Human Genetics, Technical University of Munich, School of Medicine and Health, Munich, Germany; Neurogenetic Systems Analysis Group, Institute of Neurogenomics, Helmholtz Munich, Neuherberg, Germany; Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany
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$a Zech, Michael $u 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. Electronic address: michael.zech@mri.tum.de
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