DNA methylation episignature and comparative epigenomic profiling for Pitt-Hopkins syndrome caused by TCF4 variants.

Autor:	van der Laan L; Department of Human Genetics, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Reproduction & Development, Amsterdam, the Netherlands., Lauffer P; Department of Human Genetics, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Reproduction & Development, Amsterdam, the Netherlands., Rooney K; Verspeeten Clinical Genome Centre, London Health Science Centre, London, ON, Canada; Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada., Silva A; Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada., Haghshenas S; Verspeeten Clinical Genome Centre, London Health Science Centre, London, ON, Canada., Relator R; Verspeeten Clinical Genome Centre, London Health Science Centre, London, ON, Canada., Levy MA; Verspeeten Clinical Genome Centre, London Health Science Centre, London, ON, Canada., Trajkova S; Department of Medical Sciences, University of Torino, Torino, Italy., Huisman SA; Amsterdam UMC location University of Amsterdam, Emma Children's Hospital, Department of Pediatrics, Amsterdam, the Netherlands; Zodiak, Prinsenstichting, Purmerend, the Netherlands., Bijlsma EK; Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands., Kleefstra T; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands., van Bon BW; Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands., Baysal Ö; Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands., Zweier C; Department of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany; Department of Human Genetics, University of Bern, Inselspital Universitätsspital Bern, Bern, Switzerland., Palomares-Bralo M; Institute of Medical and Molecular Genetics (INGEMM), La Paz University Hospital, Madrid, Spain., Fischer J; Institute for Clinical Genetics, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany., Szakszon K; Institute of Paediatrics, Faculty of Medicine, University of Debrecen, Debrecen, Hungary., Faivre L; UFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR1231 GAD «Génétique des Anomalies du Développement», FHUTRANSLAD, Dijon, France; CHU Dijon Bourgogne, Centre de Génétique, Centre de Référence Maladies Rares «Anomalies du Développement et Syndromes Malformatifs», FHU-TRANSLDAD, Dijon, France., Piton A; Genetic Diagnosis Laboratories, Strasbourg University Hospital, Strasbourg 67000, France., Mesman S; Swammerdam Institute for Life Sciences, FNWI, University of Amsterdam, Amsterdam, the Netherlands., Hochstenbach R; Department of Human Genetics, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Reproduction & Development, Amsterdam, the Netherlands., Elting MW; Department of Human Genetics, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Reproduction & Development, Amsterdam, the Netherlands., van Hagen JM; Department of Human Genetics, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Reproduction & Development, Amsterdam, the Netherlands., Plomp AS; Department of Human Genetics, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Reproduction & Development, Amsterdam, the Netherlands., Mannens MMAM; Department of Human Genetics, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Reproduction & Development, Amsterdam, the Netherlands., Alders M; Department of Human Genetics, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Reproduction & Development, Amsterdam, the Netherlands., van Haelst MM; Department of Human Genetics, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Reproduction & Development, Amsterdam, the Netherlands., Ferrero GB; Department of Public Health and Pediatrics, University of Torino, Turin, Italy., Brusco A; Department of Medical Sciences, University of Torino, Turin, Italy., Henneman P; Department of Human Genetics, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Reproduction & Development, Amsterdam, the Netherlands., Sweetser DA; Division of Medical Genetics and Metabolism and Center for Genomic Medicine, Massachusetts General for Children, Boston, MA, USA., Sadikovic B; Department of Human Genetics, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Reproduction & Development, Amsterdam, the Netherlands; Verspeeten Clinical Genome Centre, London Health Science Centre, London, ON, Canada; Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada., Vitobello A; Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France., Menke LA; Amsterdam Reproduction & Development, Amsterdam, the Netherlands; Amsterdam UMC location University of Amsterdam, Emma Children's Hospital, Department of Pediatrics, Amsterdam, the Netherlands; Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Amsterdam, the Netherlands. Electronic address: l.a.menke@amsterdamumc.nl.
Jazyk:	angličtina
Zdroj:	HGG advances [HGG Adv] 2024 Jul 18; Vol. 5 (3), pp. 100289. Date of Electronic Publication: 2024 Apr 02.
DOI:	10.1016/j.xhgg.2024.100289
Abstrakt:	Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder caused by pathogenic variants in TCF4, leading to intellectual disability, specific morphological features, and autonomic nervous system dysfunction. Epigenetic dysregulation has been implicated in PTHS, prompting the investigation of a DNA methylation (DNAm) "episignature" specific to PTHS for diagnostic purposes and variant reclassification and functional insights into the molecular pathophysiology of this disorder. A cohort of 67 individuals with genetically confirmed PTHS and three individuals with intellectual disability and a variant of uncertain significance (VUS) in TCF4 were studied. The DNAm episignature was developed with an Infinium Methylation EPIC BeadChip array analysis using peripheral blood cells. Support vector machine (SVM) modeling and clustering methods were employed to generate a DNAm classifier for PTHS. Validation was extended to an additional cohort of 11 individuals with PTHS. The episignature was assessed in relation to other neurodevelopmental disorders and its specificity was examined. A specific DNAm episignature for PTHS was established. The classifier exhibited high sensitivity for TCF4 haploinsufficiency and missense variants in the basic-helix-loop-helix domain. Notably, seven individuals with TCF4 variants exhibited negative episignatures, suggesting complexities related to mosaicism, genetic factors, and environmental influences. The episignature displayed degrees of overlap with other related disorders and biological pathways. This study defines a DNAm episignature for TCF4-related PTHS, enabling improved diagnostic accuracy and VUS reclassification. The finding that some cases scored negatively underscores the potential for multiple or nested episignatures and emphasizes the need for continued investigation to enhance specificity and coverage across PTHS-related variants. Competing Interests: Declaration of interests B.S. is an employee and shareholder of EpiSign, Inc., a biotech firm involved in commercial application of EpiSign technology. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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