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001-es BibID:	BIBFORM121419
035-os BibID:	(cikkazonosító)85192008393
Első szerző:	van der Laan, Liselot
Cím:	[S] DNA methylation episignature and comparative epigenomic profiling for Pitt-Hopkins syndrome caused by TCF4 variants / 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, Zweier Christiane, 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.
Dátum:	2024
ISSN:	2666-2477
Megjegyzések:	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.
Tárgyszavak:	Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban folyóiratcikk CNV DNA methylation episignature neurodevelopmental disorder Pitt-Hopkins syndrome PTHS TCF4 VUS
Megjelenés:	Human Genetics and Genomics Advances. - 5 : 3 (2024), p. 1-10. -
További szerzők:	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 Zweier, Christiane Palomares-Bralo, María Fischer, Jan Szakszon Katalin (1977-) (csecsemő- és gyermekgyógyász, klinikai genetikus) Faivre, Laurence Piton, Amélie Mesman, Simone Hochstenbach, Ron Elting, Mariet W. van Hagen, Johanna M. Plomp, Astrid Mannens, Marcel M. Alders, Mariëlle van Haelst, Mieke M. Ferrero, Giovanni B. Brusco, Alfredo Henneman, Peter Sweetser, David A. Sadikovic, Bekim Vitobello, Antonio Menke, Leonie A.
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