Parkinsonism & related disorders · 2025
Variable expressivity of KMT2B variants at codon 2565 in patients with dystonia and developmental disorders.
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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, Zech Michael
Аннотация
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.
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.