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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11110%2F25%3A10497235" target="_blank" >RIV/00216208:11110/25:10497235 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00064165:_____/25:10497235

Výsledek na webu

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=7fafLJk9dp" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=7fafLJk9dp</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.parkreldis.2025.107319" target="_blank" >10.1016/j.parkreldis.2025.107319</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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 &gt; G, p.Arg2565Gly. In an additional patient, a de-novo c.7693C &gt; 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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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 &gt; G, p.Arg2565Gly. In an additional patient, a de-novo c.7693C &gt; 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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30103 - Neurosciences (including psychophysiology)

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Parkinsonism and Related Disorders

ISSN

1353-8020

e-ISSN

1873-5126

Svazek periodika

133

Číslo periodika v rámci svazku

April

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

6

Strana od-do

107319

Kód UT WoS článku

001427181000001

EID výsledku v databázi Scopus

2-s2.0-85217107094