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

Liselot van der Laan; Peter Lauffer; Kathleen Rooney; Ananília Silva; Sadegheh Haghshenas; Raissa Relator; Michael A Levy; Slavica Trajkova; Sylvia A Huisman; Emilia K Bijlsma; Tjitske Kleefstra; Bregje W van Bon; Özlem Baysal; Christiane Zweier; María Palomares-Bralo; Jan Fischer; Katalin Szakszon; Laurence Faivre; Amélie Piton; Simone Mesman; Ron Hochstenbach; Mariet W Elting; Johanna M van Hagen; Astrid S Plomp; Marcel M A M Mannens; Mariëlle Alders; Mieke M van Haelst; Giovanni B Ferrero; Alfredo Brusco; Peter Henneman; David A Sweetser; Bekim Sadikovic; Antonio Vitobello; Leonie A Menke

doi:10.1016/j.xhgg.2024.100289

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

Liselot van der Laan, Peter Lauffer, Kathleen Rooney, Ananília Silva, Sadegheh Haghshenas, Raissa Relator, Michael A Levy, Slavica Trajkova, Sylvia A Huisman, Emilia K Bijlsma, Tjitske Kleefstra, Bregje W van Bon, Özlem Baysal, Christiane Zweier, María Palomares-Bralo, Jan Fischer, Katalin Szakszon, Laurence Faivre, Amélie Piton, Simone MesmanRon Hochstenbach, Mariet W Elting, Johanna M van Hagen, Astrid S Plomp, Marcel M A M Mannens, Mariëlle Alders, Mieke M van Haelst, Giovanni B Ferrero, Alfredo Brusco, Peter Henneman, David A Sweetser, Bekim Sadikovic, Antonio Vitobello, Leonie A Menke

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

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.

Original language	English
Pages (from-to)	100289
Journal	Human Genetics and Genomics Advances
DOIs	https://doi.org/10.1016/j.xhgg.2024.100289
Publication status	E-pub ahead of print - 2 Apr 2024

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10.1016/j.xhgg.2024.100289

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van der Laan, L., Lauffer, P., Rooney, K., Silva, A., Haghshenas, S., Relator, R., Levy, M. A., Trajkova, S., Huisman, S. A., Bijlsma, E. K., Kleefstra, T., van Bon, B. W., Baysal, Ö., Zweier, C., Palomares-Bralo, M., Fischer, J., Szakszon, K., Faivre, L., Piton, A., ... Menke, L. A. (2024). DNA methylation episignature and comparative epigenomic profiling for Pitt-Hopkins syndrome caused by TCF4 variants. Human Genetics and Genomics Advances, 100289. Advance online publication. https://doi.org/10.1016/j.xhgg.2024.100289

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title = "DNA methylation episignature and comparative epigenomic profiling for Pitt-Hopkins syndrome caused by TCF4 variants",

abstract = "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.",

author = "{van der Laan}, Liselot and Peter Lauffer and Kathleen Rooney and Anan{\'i}lia Silva and Sadegheh Haghshenas and Raissa Relator and Levy, {Michael A} and Slavica Trajkova and Huisman, {Sylvia A} and Bijlsma, {Emilia K} and Tjitske Kleefstra and {van Bon}, {Bregje W} and {\"O}zlem Baysal and Christiane Zweier and Mar{\'i}a Palomares-Bralo and Jan Fischer and Katalin Szakszon and Laurence Faivre and Am{\'e}lie Piton and Simone Mesman and Ron Hochstenbach and Elting, {Mariet W} and {van Hagen}, {Johanna M} and Plomp, {Astrid S} and Mannens, {Marcel M A M} and Mari{\"e}lle Alders and {van Haelst}, {Mieke M} and Ferrero, {Giovanni B} and Alfredo Brusco and Peter Henneman and Sweetser, {David A} and Bekim Sadikovic and Antonio Vitobello and Menke, {Leonie A}",

note = "Copyright {\textcopyright} 2024. Published by Elsevier Inc.",

year = "2024",

month = apr,

day = "2",

doi = "10.1016/j.xhgg.2024.100289",

language = "English",

pages = "100289",

journal = "Human Genetics and Genomics Advances",

issn = "2666-2477",

publisher = "Cell Press",

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van der Laan, L , Lauffer, P, Rooney, K, Silva, A, Haghshenas, S, Relator, R, Levy, MA, Trajkova, S, Huisman, SA, Bijlsma, EK, Kleefstra, T, van Bon, BW, Baysal, Ö, Zweier, C, Palomares-Bralo, M, Fischer, J, Szakszon, K, Faivre, L, Piton, A, Mesman, S, Hochstenbach, R, Elting, MW, van Hagen, JM, Plomp, AS , Mannens, MMAM , Alders, M, van Haelst, MM, Ferrero, GB, Brusco, A, Henneman, P, Sweetser, DA, Sadikovic, B, Vitobello, A & Menke, LA 2024, 'DNA methylation episignature and comparative epigenomic profiling for Pitt-Hopkins syndrome caused by TCF4 variants', Human Genetics and Genomics Advances, pp. 100289. https://doi.org/10.1016/j.xhgg.2024.100289

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

PY - 2024/4/2

Y1 - 2024/4/2

N2 - 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.

AB - 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.

U2 - 10.1016/j.xhgg.2024.100289

DO - 10.1016/j.xhgg.2024.100289

M3 - Article

C2 - 38571311

SN - 2666-2477

SP - 100289

JO - Human Genetics and Genomics Advances

JF - Human Genetics and Genomics Advances

ER -