DNA methylation episignature for Witteveen-Kolk syndrome due to SIN3A haploinsufficiency

Jet Coenen-van der Spek; Raissa Relator; Jennifer Kerkhof; Haley McConkey; Michael A. Levy; Matthew L. Tedder; Raymond J. Louie; Robin S. Fletcher; Hannah W. Moore; Anna Childers; Ellyn R. Farrelly; Neena L. Champaigne; Michael J. Lyons; David B. Everman; R. Curtis Rogers; Steven A. Skinner; Alicia Renck; Dena R. Matalon; Shelley K. Dills; Berrin Monteleone; Serwet Demirdas; Alexander J.M. Dingemans; Laura Donker Kaat; Sharon M. Kolk; Rolph Pfundt; Patrick Rump; Bekim Sadikovic; Tjitske Kleefstra; Kameryn M. Butler

doi:10.1016/j.gim.2022.10.004

DNA methylation episignature for Witteveen-Kolk syndrome due to SIN3A haploinsufficiency

Jet Coenen-van der Spek
, Raissa Relator
, Jennifer Kerkhof
, Haley McConkey
, Michael A. Levy
, Matthew L. Tedder
, Raymond J. Louie
, Robin S. Fletcher
, Hannah W. Moore
, Anna Childers
, Ellyn R. Farrelly
, Neena L. Champaigne
, Michael J. Lyons
, David B. Everman
, R. Curtis Rogers
, Steven A. Skinner
, Alicia Renck
, Dena R. Matalon
, Shelley K. Dills
, Berrin Monteleone

Serwet Demirdas, Alexander J.M. Dingemans, Laura Donker Kaat, Sharon M. Kolk, Rolph Pfundt, Patrick Rump, Bekim Sadikovic^*, Tjitske Kleefstra, Kameryn M. Butler

^*Corresponding author for this work

Clinical Genetics

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

11 Citations (Scopus)

Abstract

Purpose: Witteveen-Kolk syndrome (WITKOS) is a rare, autosomal dominant neurodevelopmental disorder caused by heterozygous loss-of-function alterations in the SIN3A gene. WITKOS has variable expressivity that commonly overlaps with other neurodevelopmental disorders. In this study, we characterized a distinct DNA methylation epigenetic signature (episignature) distinguishing WITKOS from unaffected individuals as well as individuals with other neurodevelopmental disorders with episignatures and described 9 previously unpublished individuals with SIN3A haploinsufficiency. Methods: We studied the phenotypic characteristics and the genome-wide DNA methylation in the peripheral blood samples of 20 individuals with heterozygous alterations in SIN3A. A total of 14 samples were used for the identification of the episignature and building of a predictive diagnostic biomarker, whereas the diagnostic model was used to investigate the methylation pattern of the remaining 6 samples. Results: A predominantly hypomethylated DNA methylation profile specific to WITKOS was identified, and the classifier model was able to diagnose a previously unresolved test case. The episignature was sensitive enough to detect individuals with varying degrees of phenotypic severity carrying SIN3A haploinsufficient variants. Conclusion: We identified a novel, robust episignature in WITKOS due to SIN3A haploinsufficiency. This episignature has the potential to aid identification and diagnosis of individuals with WITKOS.

Original language	English
Pages (from-to)	63-75
Number of pages	13
Journal	Genetics in Medicine
Volume	25
Issue number	1
Early online date	17 Nov 2022
DOIs	https://doi.org/10.1016/j.gim.2022.10.004
Publication status	Published - Jan 2023

Bibliographical note

Publisher Copyright:
© 2022 American College of Medical Genetics and Genomics

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Coenen-van der Spek, J., Relator, R., Kerkhof, J., McConkey, H., Levy, M. A., Tedder, M. L., Louie, R. J., Fletcher, R. S., Moore, H. W., Childers, A., Farrelly, E. R., Champaigne, N. L., Lyons, M. J., Everman, D. B., Rogers, R. C., Skinner, S. A., Renck, A., Matalon, D. R., Dills, S. K., ... Butler, K. M. (2023). DNA methylation episignature for Witteveen-Kolk syndrome due to SIN3A haploinsufficiency. Genetics in Medicine, 25(1), 63-75. https://doi.org/10.1016/j.gim.2022.10.004

@article{254b7c263f374630aaf7afd7f14b21e5,

title = "DNA methylation episignature for Witteveen-Kolk syndrome due to SIN3A haploinsufficiency",

abstract = "Purpose: Witteveen-Kolk syndrome (WITKOS) is a rare, autosomal dominant neurodevelopmental disorder caused by heterozygous loss-of-function alterations in the SIN3A gene. WITKOS has variable expressivity that commonly overlaps with other neurodevelopmental disorders. In this study, we characterized a distinct DNA methylation epigenetic signature (episignature) distinguishing WITKOS from unaffected individuals as well as individuals with other neurodevelopmental disorders with episignatures and described 9 previously unpublished individuals with SIN3A haploinsufficiency. Methods: We studied the phenotypic characteristics and the genome-wide DNA methylation in the peripheral blood samples of 20 individuals with heterozygous alterations in SIN3A. A total of 14 samples were used for the identification of the episignature and building of a predictive diagnostic biomarker, whereas the diagnostic model was used to investigate the methylation pattern of the remaining 6 samples. Results: A predominantly hypomethylated DNA methylation profile specific to WITKOS was identified, and the classifier model was able to diagnose a previously unresolved test case. The episignature was sensitive enough to detect individuals with varying degrees of phenotypic severity carrying SIN3A haploinsufficient variants. Conclusion: We identified a novel, robust episignature in WITKOS due to SIN3A haploinsufficiency. This episignature has the potential to aid identification and diagnosis of individuals with WITKOS.",

author = "\{Coenen-van der Spek\}, Jet and Raissa Relator and Jennifer Kerkhof and Haley McConkey and Levy, \{Michael A.\} and Tedder, \{Matthew L.\} and Louie, \{Raymond J.\} and Fletcher, \{Robin S.\} and Moore, \{Hannah W.\} and Anna Childers and Farrelly, \{Ellyn R.\} and Champaigne, \{Neena L.\} and Lyons, \{Michael J.\} and Everman, \{David B.\} and Rogers, \{R. Curtis\} and Skinner, \{Steven A.\} and Alicia Renck and Matalon, \{Dena R.\} and Dills, \{Shelley K.\} and Berrin Monteleone and Serwet Demirdas and Dingemans, \{Alexander J.M.\} and \{Donker Kaat\}, Laura and Kolk, \{Sharon M.\} and Rolph Pfundt and Patrick Rump and Bekim Sadikovic and Tjitske Kleefstra and Butler, \{Kameryn M.\}",

note = "Publisher Copyright: {\textcopyright} 2022 American College of Medical Genetics and Genomics",

year = "2023",

month = jan,

doi = "10.1016/j.gim.2022.10.004",

language = "English",

volume = "25",

pages = "63--75",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Elsevier",

number = "1",

}

Coenen-van der Spek, J, Relator, R, Kerkhof, J, McConkey, H, Levy, MA, Tedder, ML, Louie, RJ, Fletcher, RS, Moore, HW, Childers, A, Farrelly, ER, Champaigne, NL, Lyons, MJ, Everman, DB, Rogers, RC, Skinner, SA, Renck, A, Matalon, DR, Dills, SK, Monteleone, B, Demirdas, S, Dingemans, AJM, Donker Kaat, L, Kolk, SM, Pfundt, R, Rump, P, Sadikovic, B, Kleefstra, T & Butler, KM 2023, 'DNA methylation episignature for Witteveen-Kolk syndrome due to SIN3A haploinsufficiency', Genetics in Medicine, vol. 25, no. 1, pp. 63-75. https://doi.org/10.1016/j.gim.2022.10.004

TY - JOUR

T1 - DNA methylation episignature for Witteveen-Kolk syndrome due to SIN3A haploinsufficiency

AU - Coenen-van der Spek, Jet

AU - Relator, Raissa

AU - Kerkhof, Jennifer

AU - McConkey, Haley

AU - Levy, Michael A.

AU - Tedder, Matthew L.

AU - Louie, Raymond J.

AU - Fletcher, Robin S.

AU - Moore, Hannah W.

AU - Childers, Anna

AU - Farrelly, Ellyn R.

AU - Champaigne, Neena L.

AU - Lyons, Michael J.

AU - Everman, David B.

AU - Rogers, R. Curtis

AU - Skinner, Steven A.

AU - Renck, Alicia

AU - Matalon, Dena R.

AU - Dills, Shelley K.

AU - Monteleone, Berrin

AU - Demirdas, Serwet

AU - Dingemans, Alexander J.M.

AU - Donker Kaat, Laura

AU - Kolk, Sharon M.

AU - Pfundt, Rolph

AU - Rump, Patrick

AU - Sadikovic, Bekim

AU - Kleefstra, Tjitske

AU - Butler, Kameryn M.

PY - 2023/1

Y1 - 2023/1

N2 - Purpose: Witteveen-Kolk syndrome (WITKOS) is a rare, autosomal dominant neurodevelopmental disorder caused by heterozygous loss-of-function alterations in the SIN3A gene. WITKOS has variable expressivity that commonly overlaps with other neurodevelopmental disorders. In this study, we characterized a distinct DNA methylation epigenetic signature (episignature) distinguishing WITKOS from unaffected individuals as well as individuals with other neurodevelopmental disorders with episignatures and described 9 previously unpublished individuals with SIN3A haploinsufficiency. Methods: We studied the phenotypic characteristics and the genome-wide DNA methylation in the peripheral blood samples of 20 individuals with heterozygous alterations in SIN3A. A total of 14 samples were used for the identification of the episignature and building of a predictive diagnostic biomarker, whereas the diagnostic model was used to investigate the methylation pattern of the remaining 6 samples. Results: A predominantly hypomethylated DNA methylation profile specific to WITKOS was identified, and the classifier model was able to diagnose a previously unresolved test case. The episignature was sensitive enough to detect individuals with varying degrees of phenotypic severity carrying SIN3A haploinsufficient variants. Conclusion: We identified a novel, robust episignature in WITKOS due to SIN3A haploinsufficiency. This episignature has the potential to aid identification and diagnosis of individuals with WITKOS.

AB - Purpose: Witteveen-Kolk syndrome (WITKOS) is a rare, autosomal dominant neurodevelopmental disorder caused by heterozygous loss-of-function alterations in the SIN3A gene. WITKOS has variable expressivity that commonly overlaps with other neurodevelopmental disorders. In this study, we characterized a distinct DNA methylation epigenetic signature (episignature) distinguishing WITKOS from unaffected individuals as well as individuals with other neurodevelopmental disorders with episignatures and described 9 previously unpublished individuals with SIN3A haploinsufficiency. Methods: We studied the phenotypic characteristics and the genome-wide DNA methylation in the peripheral blood samples of 20 individuals with heterozygous alterations in SIN3A. A total of 14 samples were used for the identification of the episignature and building of a predictive diagnostic biomarker, whereas the diagnostic model was used to investigate the methylation pattern of the remaining 6 samples. Results: A predominantly hypomethylated DNA methylation profile specific to WITKOS was identified, and the classifier model was able to diagnose a previously unresolved test case. The episignature was sensitive enough to detect individuals with varying degrees of phenotypic severity carrying SIN3A haploinsufficient variants. Conclusion: We identified a novel, robust episignature in WITKOS due to SIN3A haploinsufficiency. This episignature has the potential to aid identification and diagnosis of individuals with WITKOS.

UR - https://www.scopus.com/pages/publications/85142485706

U2 - 10.1016/j.gim.2022.10.004

DO - 10.1016/j.gim.2022.10.004

M3 - Article

C2 - 36399132

AN - SCOPUS:85142485706

SN - 1098-3600

VL - 25

SP - 63

EP - 75

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 1

ER -

DNA methylation episignature for Witteveen-Kolk syndrome due to SIN3A haploinsufficiency

Abstract

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