DNA methylation episignature and comparative epigenomic profiling for Pitt-Hopkins syndrome caused by TCF4 variants.
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BORIS DOI
Publisher DOI
PubMed ID
38571311
Description
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
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
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
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.
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
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
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
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.
Date of Publication
2024-07-18
Publication Type
article
Subject(s)
600 - Technology::610 - Medicine & health
Keyword(s)
CNV DNA methylation Episignature Neurodevelopmental disorder PTHS Pitt-Hopkins syndrome TCF4 VUS
Language(s)
en
Contributor(s)
van der Laan, Liselot | |
Lauffer, Peter | |
Rooney, Kathleen | |
Silva, Ananília | |
Haghshenas, Sadegheh | |
Relator, Raissa | |
Levy, Michael A | |
Trajkova, Slavica | |
Huisman, Sylvia A | |
Bijlsma, Emilia K | |
Kleefstra, Tjitske | |
van Bon, Bregje W | |
Baysal, Özlem | |
Palomares-Bralo, María | |
Fischer, Jan | |
Szakszon, Katalin | |
Faivre, Laurence | |
Piton, Amélie | |
Mesman, Simone | |
Hochstenbach, Ron | |
Elting, Mariet W | |
van Hagen, Johanna M | |
Plomp, Astrid S | |
Mannens, Marcel M A M | |
Alders, Mariëlle | |
van Haelst, Mieke M | |
Ferrero, Giovanni B | |
Brusco, Alfredo | |
Henneman, Peter | |
Sweetser, David A | |
Sadikovic, Bekim | |
Vitobello, Antonio | |
Menke, Leonie A |
Additional Credits
Universitätsklinik für Humangenetik
Series
HGG advances
Publisher
Elsevier
ISSN
2666-2477
Access(Rights)
open.access