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DNA methylation episignature for Witteveen-Kolk syndrome due to SIN3A haploinsufficiency.
Coenen-van der Spek, Jet; Relator, Raissa; Kerkhof, Jennifer; McConkey, Haley; Levy, Michael A; Tedder, Matthew L; Louie, Raymond J; Fletcher, Robin S; Moore, Hannah W; Childers, Anna; Farrelly, Ellyn R; Champaigne, Neena L; Lyons, Michael J; Everman, David B; Rogers, R Curtis; Skinner, Steven A; Renck, Alicia; Matalon, Dena R; Dills, Shelley K; Monteleone, Berrin; Demirdas, Serwet; Dingemans, Alexander J M; Donker Kaat, Laura; Kolk, Sharon M; Pfundt, Rolph; Rump, Patrick; Sadikovic, Bekim; Kleefstra, Tjitske; Butler, Kameryn M.
Afiliação
  • Coenen-van der Spek J; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
  • Relator R; Verspeeten Clinical Genome Centre, London Health Sciences Centre, London Health Sciences Foundation, London, Ontario, Canada.
  • Kerkhof J; Verspeeten Clinical Genome Centre, London Health Sciences Centre, London Health Sciences Foundation, London, Ontario, Canada.
  • McConkey H; Verspeeten Clinical Genome Centre, London Health Sciences Centre, London Health Sciences Foundation, London, Ontario, Canada; Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada.
  • Levy MA; Verspeeten Clinical Genome Centre, London Health Sciences Centre, London Health Sciences Foundation, London, Ontario, Canada.
  • Tedder ML; Greenwood Genetic Center, Greenwood, SC.
  • Louie RJ; Greenwood Genetic Center, Greenwood, SC.
  • Fletcher RS; Greenwood Genetic Center, Greenwood, SC.
  • Moore HW; Greenwood Genetic Center, Greenwood, SC.
  • Childers A; Greenwood Genetic Center, Greenwood, SC.
  • Farrelly ER; Lucile Packard Children's Hospital Stanford, Palo Alto, CA; Division of Medical Genetics, Department of Pediatrics, Stanford University, Palo Alto, CA.
  • Champaigne NL; Greenwood Genetic Center, Greenwood, SC.
  • Lyons MJ; Greenwood Genetic Center, Greenwood, SC.
  • Everman DB; Greenwood Genetic Center, Greenwood, SC.
  • Rogers RC; Greenwood Genetic Center, Greenwood, SC.
  • Skinner SA; Greenwood Genetic Center, Greenwood, SC.
  • Renck A; Division of Medical Genetics, Department of Pediatrics, Stanford University, Palo Alto, CA.
  • Matalon DR; Division of Medical Genetics, Department of Pediatrics, Stanford University, Palo Alto, CA.
  • Dills SK; Clinical Genetics, Levine Children's Specialty Center, Atrium Health, Charlotte, NC.
  • Monteleone B; Clinical Genetics, Levine Children's Specialty Center, Atrium Health, Charlotte, NC; Division of Medical Genetics, Department of Pediatrics, NYU Langone Health, NYU Long Island, New York, NY.
  • Demirdas S; Department of Clinical Genetics, Erasmus Medical Centre, Erasmus University, Rotterdam, The Netherlands.
  • Dingemans AJM; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
  • Donker Kaat L; Department of Clinical Genetics, Erasmus Medical Centre, Erasmus University, Rotterdam, The Netherlands.
  • Kolk SM; Department of Molecular Neurobiology, Donders Center for Neuroscience, Faculty of Science, Radboud University, Nijmegen, The Netherlands.
  • Pfundt R; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
  • Rump P; Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
  • Sadikovic B; Verspeeten Clinical Genome Centre, London Health Sciences Centre, London Health Sciences Foundation, London, Ontario, Canada; Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada. Electronic address: bekim.sadikovic@lhsc.on.ca.
  • Kleefstra T; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Centre of Excellence for Neuropsychiatry, Vincent van Gogh Institute for Psychiatry, Venray, The Netherlands. Electronic address: Tjitske.Kleefstra@radboudumc.nl.
  • Butler KM; Greenwood Genetic Center, Greenwood, SC. Electronic address: kbutler@ggc.org.
Genet Med ; 25(1): 63-75, 2023 01.
Article em En | MEDLINE | ID: mdl-36399132
ABSTRACT

PURPOSE:

Witteveen-Kolk syndrome (WITKOS) is a rare, autosomal dominant neurodevelopmental disorder caused by heterozygous loss-of-function alterations in the SIN3A gene. WITKOS has variable expressivity that commonly overlaps with other neurodevelopmental disorders. In this study, we characterized a distinct DNA methylation epigenetic signature (episignature) distinguishing WITKOS from unaffected individuals as well as individuals with other neurodevelopmental disorders with episignatures and described 9 previously unpublished individuals with SIN3A haploinsufficiency.

METHODS:

We studied the phenotypic characteristics and the genome-wide DNA methylation in the peripheral blood samples of 20 individuals with heterozygous alterations in SIN3A. A total of 14 samples were used for the identification of the episignature and building of a predictive diagnostic biomarker, whereas the diagnostic model was used to investigate the methylation pattern of the remaining 6 samples.

RESULTS:

A predominantly hypomethylated DNA methylation profile specific to WITKOS was identified, and the classifier model was able to diagnose a previously unresolved test case. The episignature was sensitive enough to detect individuals with varying degrees of phenotypic severity carrying SIN3A haploinsufficient variants.

CONCLUSION:

We identified a novel, robust episignature in WITKOS due to SIN3A haploinsufficiency. This episignature has the potential to aid identification and diagnosis of individuals with WITKOS.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Metilação de DNA / Transtornos do Neurodesenvolvimento Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Metilação de DNA / Transtornos do Neurodesenvolvimento Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article