TY - JOUR
T1 - Childhood-onset dystonia-causing KMT2B variants result in a distinctive genomic hypermethylation profile
AU - Ciolfi, Andrea
AU - Foroutan, Aidin
AU - Capuano, Alessandro
AU - Pedace, Lucia
AU - Travaglini, Lorena
AU - Pizzi, Simone
AU - Andreani, Marco
AU - Miele, Evelina
AU - Invernizzi, Federica
AU - Reale, Chiara
AU - Panteghini, Celeste
AU - Iascone, Maria
AU - Niceta, Marcello
AU - Gavrilova, Ralitza H.
AU - Schultz-Rogers, Laura
AU - Agolini, Emanuele
AU - Bedeschi, Maria Francesca
AU - Prontera, Paolo
AU - Garibaldi, Matteo
AU - Galosi, Serena
AU - Leuzzi, Vincenzo
AU - Soliveri, Paola
AU - Olson, Rory J.
AU - Zorzi, Giovanna S.
AU - Garavaglia, Barbara M.
AU - Tartaglia, Marco
AU - Sadikovic, Bekim
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - Background: Dystonia is a clinically and genetically heterogeneous movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements and/or postures. Heterozygous variants in lysine methyltransferase 2B (KMT2B), encoding a histone H3 methyltransferase, have been associated with a childhood-onset, progressive and complex form of dystonia (dystonia 28, DYT28). Since 2016, more than one hundred rare KMT2B variants have been reported, including frameshift, nonsense, splice site, missense and other in-frame changes, many having an uncertain clinical impact. Results: We characterize the genome-wide peripheral blood DNA methylation profiles of a cohort of 18 patients with pathogenic and unclassified KMT2B variants. We resolve the “episignature” associated with KMT2B haploinsufficiency, proving that this approach is robust in diagnosing clinically unsolved cases, properly classifying them with respect to other partially overlapping dystonic phenotypes, other rare neurodevelopmental disorders and healthy controls. Notably, defective KMT2B function in DYT28 causes a non-random DNA hypermethylation across the genome, selectively involving promoters and other regulatory regions positively controlling gene expression. Conclusions: We demonstrate a distinctive DNA hypermethylation pattern associated with DYT28, provide an epigenetic signature for this disorder enabling accurate diagnosis and reclassification of ambiguous genetic findings and suggest potential therapeutic approaches.
AB - Background: Dystonia is a clinically and genetically heterogeneous movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements and/or postures. Heterozygous variants in lysine methyltransferase 2B (KMT2B), encoding a histone H3 methyltransferase, have been associated with a childhood-onset, progressive and complex form of dystonia (dystonia 28, DYT28). Since 2016, more than one hundred rare KMT2B variants have been reported, including frameshift, nonsense, splice site, missense and other in-frame changes, many having an uncertain clinical impact. Results: We characterize the genome-wide peripheral blood DNA methylation profiles of a cohort of 18 patients with pathogenic and unclassified KMT2B variants. We resolve the “episignature” associated with KMT2B haploinsufficiency, proving that this approach is robust in diagnosing clinically unsolved cases, properly classifying them with respect to other partially overlapping dystonic phenotypes, other rare neurodevelopmental disorders and healthy controls. Notably, defective KMT2B function in DYT28 causes a non-random DNA hypermethylation across the genome, selectively involving promoters and other regulatory regions positively controlling gene expression. Conclusions: We demonstrate a distinctive DNA hypermethylation pattern associated with DYT28, provide an epigenetic signature for this disorder enabling accurate diagnosis and reclassification of ambiguous genetic findings and suggest potential therapeutic approaches.
KW - DNA methylation
KW - Dystonia 28
KW - Episignature
KW - KMT2B
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U2 - 10.1186/s13148-021-01145-y
DO - 10.1186/s13148-021-01145-y
M3 - Article
C2 - 34380541
AN - SCOPUS:85112295053
SN - 1868-7075
VL - 13
JO - Clinical Epigenetics
JF - Clinical Epigenetics
IS - 1
M1 - 157
ER -