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

Stehr, Antonia M.; Fischer, Jan; Mirza-Schreiber, Nazanin; Bernardi, Katerina; Porrmann, Joseph; Harrer, Philip; Kaiser, Frank; Jamra, Rami Abou; Winkelmann, Juliane ; Jech, Robert; Koy, Anne; Oexle, Konrad und Zech, Michael (2025): Variable expressivity of KMT2B variants at codon 2565 in patients with dystonia and developmental disorders. In: Parkinsonism & Related Disorders, Bd. 133, 107319

Abstract

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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1353-8020
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198