TY - JOUR
T1 - DNA methylation episignature and comparative epigenomic profiling for Pitt-Hopkins syndrome caused by TCF4 variants
AU - van der Laan, Liselot
AU - Lauffer, Peter
AU - Rooney, Kathleen
AU - Silva, Ananília
AU - Haghshenas, Sadegheh
AU - Relator, Raissa
AU - Levy, Michael A
AU - Trajkova, Slavica
AU - Huisman, Sylvia A
AU - Bijlsma, Emilia K
AU - Kleefstra, Tjitske
AU - van Bon, Bregje W
AU - Baysal, Özlem
AU - Zweier, Christiane
AU - Palomares-Bralo, María
AU - Fischer, Jan
AU - Szakszon, Katalin
AU - Faivre, Laurence
AU - Piton, Amélie
AU - Mesman, Simone
AU - Hochstenbach, Ron
AU - Elting, Mariet W
AU - van Hagen, Johanna M
AU - Plomp, Astrid S
AU - Mannens, Marcel M A M
AU - Alders, Mariëlle
AU - van Haelst, Mieke M
AU - Ferrero, Giovanni B
AU - Brusco, Alfredo
AU - Henneman, Peter
AU - Sweetser, David A
AU - Sadikovic, Bekim
AU - Vitobello, Antonio
AU - Menke, Leonie A
N1 - Publisher Copyright: © 2024 The Author(s)
PY - 2024/7/18
Y1 - 2024/7/18
N2 - 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.
AB - 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.
KW - CNV
KW - DNA methylation
KW - PTHS
KW - Pitt-Hopkins syndrome
KW - TCF4
KW - VUS
KW - episignature
KW - neurodevelopmental disorder
UR - http://www.scopus.com/inward/record.url?scp=85192008393&partnerID=8YFLogxK
U2 - 10.1016/j.xhgg.2024.100289
DO - 10.1016/j.xhgg.2024.100289
M3 - Article
C2 - 38571311
SN - 2666-2477
VL - 5
SP - 100289
JO - Human Genetics and Genomics Advances
JF - Human Genetics and Genomics Advances
IS - 3
M1 - 100289
ER -