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

CNV DNA methylation Episignature Neurodevelopmental disorder PTHS Pitt-Hopkins syndrome TCF4 VUS

Journal

HGG advances
ISSN: 2666-2477
Titre abrégé: HGG Adv
Pays: United States
ID NLM: 101772885

Informations de publication

Date de publication:
02 Apr 2024
Historique:
received: 13 11 2023
revised: 26 03 2024
accepted: 26 03 2024
medline: 4 4 2024
pubmed: 4 4 2024
entrez: 4 4 2024
Statut: aheadofprint

Résumé

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 further 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 further 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 negative underscores the potential for multiple or nested episignatures and emphasizes the need for continued investigation to enhance specificity and coverage across PTHS-related variants.

Sections du résumé

BACKGROUND BACKGROUND
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 further functional insights into the molecular pathophysiology of this disorder.
METHODS METHODS
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 further assessed in relation to other neurodevelopmental disorders and its specificity was examined.
RESULTS RESULTS
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.
CONCLUSIONS CONCLUSIONS
This study defines a DNAm episignature for TCF4-related PTHS, enabling improved diagnostic accuracy and VUS reclassification. The finding that some cases scored negative underscores the potential for multiple or nested episignatures and emphasizes the need for continued investigation to enhance specificity and coverage across PTHS-related variants.

Identifiants

DOI: 10.1016/j.xhgg.2024.100289 PMID: 38571311
pubmed: 38571311
pii: S2666-2477(24)00028-9
doi: 10.1016/j.xhgg.2024.100289
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

100289

Informations de copyright

Copyright © 2024. Published by Elsevier Inc.

Auteurs

Liselot van der Laan (L)

Department of Human Genetics, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands; Amsterdam Reproduction & Development, Amsterdam, The Netherlands.

Peter Lauffer (P)

Department of Human Genetics, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands; Amsterdam Reproduction & Development, Amsterdam, The Netherlands.

Kathleen Rooney (K)

Verspeeten Clinical Genome Centre, London Health Science Centre, London, ON, Canada; Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada.

Ananília Silva (A)

Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada.

Sadegheh Haghshenas (S)

Verspeeten Clinical Genome Centre, London Health Science Centre, London, ON, Canada.

Raissa Relator (R)

Verspeeten Clinical Genome Centre, London Health Science Centre, London, ON, Canada.

Michael A Levy (MA)

Verspeeten Clinical Genome Centre, London Health Science Centre, London, ON, Canada.

Slavica Trajkova (S)

Department of Medical Sciences, University of Torino, Torino, Italy.

Sylvia A Huisman (SA)

Amsterdam UMC location University of Amsterdam, Emma Children's hospital, Department of Pediatrics, Amsterdam, The Netherlands; Zodiak, Prinsenstichting, Purmerend, The Netherlands.

Emilia K Bijlsma (EK)

Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.

Tjitske Kleefstra (T)

Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.

Bregje W van Bon (BW)

Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.

Özlem Baysal (Ö)

Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.

Christiane 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.

María Palomares-Bralo (M)

Institute of Medical and Molecular Genetics (INGEMM), La Paz University Hospital, Madrid, Spain.

Jan Fischer (J)

Institute for Clinical Genetics, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany.

Katalin Szakszon (K)

Institute of Paediatrics, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.

Laurence 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.

Amélie Piton (A)

Genetic diagnosis laboratories, Strasbourg Universitary Hospital, Strasbourg, 67000, France.

Simone Mesman (S)

Swammerdam Institute for Life Sciences, FNWI, University of Amsterdam, Amsterdam, The Netherlands.

Ron Hochstenbach (R)

Department of Human Genetics, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands; Amsterdam Reproduction & Development, Amsterdam, The Netherlands.

Mariet W Elting (MW)

Department of Human Genetics, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands; Amsterdam Reproduction & Development, Amsterdam, The Netherlands.

Johanna M van Hagen (JM)

Department of Human Genetics, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands; Amsterdam Reproduction & Development, Amsterdam, The Netherlands.

Astrid S Plomp (AS)

Department of Human Genetics, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands; Amsterdam Reproduction & Development, Amsterdam, The Netherlands.

Marcel M A M Mannens (MMAM)

Department of Human Genetics, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands; Amsterdam Reproduction & Development, Amsterdam, The Netherlands.

Mariëlle Alders (M)

Department of Human Genetics, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands; Amsterdam Reproduction & Development, Amsterdam, The Netherlands.

Mieke M van Haelst (MM)

Department of Human Genetics, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands; Amsterdam Reproduction & Development, Amsterdam, The Netherlands.

Giovanni B Ferrero (GB)

Department of Public Health and Pediatrics, University of Torino, Turin, Italy.

Alfredo Brusco (A)

Department of Medical Sciences, University of Torino, Turin, Italy.

Peter Henneman (P)

Department of Human Genetics, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands; Amsterdam Reproduction & Development, Amsterdam, The Netherlands.

David A Sweetser (DA)

Division of Medical Genetics and Metabolism and Center for Genomic Medicine, Massachusetts General for Children, Boston, Massachusetts.

Bekim 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.

Antonio Vitobello (A)

Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Amsterdam, The Netherlands.

Leonie A Menke (LA)

Amsterdam Reproduction & Development, Amsterdam, The Netherlands; Amsterdam UMC location University of Amsterdam, Emma Children's hospital, Department of Pediatrics, Amsterdam, The Netherlands. Electronic address: l.a.menke@amsterdamumc.nl.

Classifications MeSH