دورية أكاديمية
أعرض في EDS

Childhood-onset dystonia-causing KMT2B variants result in a distinctive genomic hypermethylation profile.

التفاصيل البيبلوغرافية
العنوان: Childhood-onset dystonia-causing KMT2B variants result in a distinctive genomic hypermethylation profile.
المؤلفون: Ciolfi A; Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146, Rome, Italy., Foroutan A; Department of Pathology and Laboratory Medicine, Western University, London, ON, N6A 3K7, Canada.; Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, Canada., Capuano A; Department of Neuroscience, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy., Pedace L; Department of Pediatric Onco-Hematology and Cell and Gene Therapy, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy., Travaglini L; Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146, Rome, Italy., Pizzi S; Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146, Rome, Italy., Andreani M; Department of Pediatric Onco-Hematology and Cell and Gene Therapy, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy., Miele E; Department of Pediatric Onco-Hematology and Cell and Gene Therapy, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy., Invernizzi F; Medical Genetics and Neurogenetics Unit, Fondazione IRCCS Istituto Neurologico C. Besta, Milano, Italy., Reale C; Medical Genetics and Neurogenetics Unit, Fondazione IRCCS Istituto Neurologico C. Besta, Milano, Italy., Panteghini C; Medical Genetics and Neurogenetics Unit, Fondazione IRCCS Istituto Neurologico C. Besta, Milano, Italy., Iascone M; Medical Genetics Laboratory, ASST Papa Giovanni XXIII, Bergamo, Italy., Niceta M; Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146, Rome, Italy., Gavrilova RH; Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA., Schultz-Rogers L; Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA., Agolini E; Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy., Bedeschi MF; Medical Genetic Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy., Prontera P; Maternal-Infantile Department, University Hospital of Perugia, Perugia, Italy., Garibaldi M; Department of Neuroscience, NESMOS, Sapienza University, Sant'Andrea Hospital, Rome, Italy., Galosi S; Department of Human Neuroscience, Child Neurology and Psychiatry, Sapienza University, Rome, Italy., Leuzzi V; Department of Human Neuroscience, Child Neurology and Psychiatry, Sapienza University, Rome, Italy., Soliveri P; Department of Neurology, Fondazione IRCCS Istituto Neurologico C. Besta, Milano, Italy., Olson RJ; Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA., Zorzi GS; Department of Child Neurology, Fondazione IRCCS Istituto Neurologico C. Besta, Milano, Italy., Garavaglia BM; Medical Genetics and Neurogenetics Unit, Fondazione IRCCS Istituto Neurologico C. Besta, Milano, Italy., Tartaglia M; Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146, Rome, Italy. marco.tartaglia@opbg.net., Sadikovic B; Department of Pathology and Laboratory Medicine, Western University, London, ON, N6A 3K7, Canada. bekim.sadikovic@lhsc.on.ca.; Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, Canada. bekim.sadikovic@lhsc.on.ca.; Molecular Diagnostics Division, London Health Sciences Centre, London, Canada. bekim.sadikovic@lhsc.on.ca.
المصدر: Clinical epigenetics [Clin Epigenetics] 2021 Aug 11; Vol. 13 (1), pp. 157. Date of Electronic Publication: 2021 Aug 11.
نوع المنشور: Comparative Study; Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: BiomedCentral Country of Publication: Germany NLM ID: 101516977 Publication Model: Electronic Cited Medium: Internet ISSN: 1868-7083 (Electronic) Linking ISSN: 18687075 NLM ISO Abbreviation: Clin Epigenetics Subsets: MEDLINE
أسماء مطبوعة: Publication: Oct./Nov. 2011- : London : BiomedCentral
Original Publication: Berlin : Springer-Verlag
مواضيع طبية MeSH: DNA Methylation/*genetics , Dystonic Disorders/*complications , Dystonic Disorders/*genetics , Dystonic Disorders/*physiopathology , Histone-Lysine N-Methyltransferase/*genetics , Histone-Lysine N-Methyltransferase/*metabolism, Adolescent ; Adult ; Age Factors ; Child ; Child, Preschool ; Cohort Studies ; Epigenesis, Genetic ; Female ; Genetic Variation ; Humans ; Infant ; Infant, Newborn ; Male ; Middle Aged ; Mutation ; Phenotype
مستخلص: 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.
(© 2021. The Author(s).)
References: Mov Disord. 2017 Jul;32(7):1087-1091. (PMID: 28520167)
Nat Genet. 2017 Feb;49(2):223-237. (PMID: 27992417)
Mol Cell. 2012 Nov 30;48(4):491-507. (PMID: 23200123)
Curr Neurol Neurosci Rep. 2017 Mar;17(3):26. (PMID: 28283962)
Philos Trans R Soc Lond B Biol Sci. 2014 Sep 26;369(1652):. (PMID: 25135975)
Nat Rev Dis Primers. 2018 Sep 20;4(1):25. (PMID: 30237473)
BMC Genomics. 2013 May 01;14:293. (PMID: 23631413)
BMC Bioinformatics. 2012 May 08;13:86. (PMID: 22568884)
Am J Hum Genet. 2016 Dec 1;99(6):1377-1387. (PMID: 27839873)
Development. 2014 Feb;141(3):526-37. (PMID: 24423662)
Bioinformatics. 2014 May 15;30(10):1363-9. (PMID: 24478339)
Nat Struct Mol Biol. 2009 May;16(5):564-71. (PMID: 19377480)
Nucleic Acids Res. 2019 Jul 2;47(W1):W199-W205. (PMID: 31114916)
Genome Biol. 2021 Jun 8;22(1):173. (PMID: 34103055)
Am J Hum Genet. 2020 Mar 5;106(3):356-370. (PMID: 32109418)
Epigenetics Chromatin. 2015 Jan 27;8:6. (PMID: 25972926)
Nature. 2020 May;581(7809):434-443. (PMID: 32461654)
Nucleic Acids Res. 1988 Feb 11;16(3):1215. (PMID: 3344216)
Hum Mutat. 2019 Aug;40(8):1030-1038. (PMID: 31116477)
Curr Neurol Neurosci Rep. 2019 Nov 25;19(11):92. (PMID: 31768667)
Nucleic Acids Res. 2015 Apr 20;43(7):e47. (PMID: 25605792)
Epigenomics. 2015;7(3):503-19. (PMID: 26077434)
Cell Rep. 2018 Oct 23;25(4):988-1001. (PMID: 30355503)
Cancer Res. 2018 Mar 1;78(5):1127-1139. (PMID: 29282222)
Clin Epigenetics. 2020 Jan 7;12(1):7. (PMID: 31910894)
Nature. 2015 Feb 19;518(7539):317-30. (PMID: 25693563)
Brain. 2020 Dec 5;143(11):3242-3261. (PMID: 33150406)
Genet Med. 2015 May;17(5):405-24. (PMID: 25741868)
Am J Hum Genet. 2021 Mar 4;108(3):502-516. (PMID: 33596411)
Genome Med. 2019 Dec 31;12(1):3. (PMID: 31892348)
Nat Genet. 2007 Mar;39(3):311-8. (PMID: 17277777)
Nat Genet. 2014 Mar;46(3):310-5. (PMID: 24487276)
Mov Disord. 2019 Oct;34(10):1516-1527. (PMID: 31216378)
Mol Cell. 2007 Aug 17;27(4):573-84. (PMID: 17707229)
Nat Genet. 2019 Jan;51(1):88-95. (PMID: 30531870)
Genet Med. 2021 Jun;23(6):1065-1074. (PMID: 33547396)
Am J Hum Genet. 2019 Apr 4;104(4):685-700. (PMID: 30929737)
PLoS One. 2011 Jan 18;6(1):e14524. (PMID: 21267076)
Bioinformatics. 2010 Mar 15;26(6):841-2. (PMID: 20110278)
Nat Biotechnol. 2009 Apr;27(4):361-8. (PMID: 19329998)
Nat Methods. 2018 Feb;15(2):123-126. (PMID: 29309061)
معلومات مُعتمدة: Vite Coraggiose Fondazione Bambino Gesù; CCR-2017-23669081 Italian Ministry of Health; RCR-2020-23670068_001 Italian Ministry of Health; Ricerca Corrente 2020 Italian Ministry of Health; Ricerca Corrente 2021 Italian Ministry of Health; FOE 2019 Italian Ministry of Research; EpiSign-CAN London Health Sciences Molecular Diagnostics Development Fund; EpiSign-CAN Genome Canada Genomic Applications Partnership Program Grant
فهرسة مساهمة: Keywords: DNA methylation; Dystonia 28; Episignature; KMT2B
المشرفين على المادة: EC 2.1.1.43 (Histone-Lysine N-Methyltransferase)
تواريخ الأحداث: Date Created: 20210812 Date Completed: 20220209 Latest Revision: 20220209
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC8359374
DOI: 10.1186/s13148-021-01145-y
PMID: 34380541
قاعدة البيانات: MEDLINE
الوصف
تدمد:1868-7083
DOI:10.1186/s13148-021-01145-y