@article{c3f7cffcf34d4596879e5fe8eca6c724,
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as well as individuals with other neurodevelopmental disorders with episignatures and described 9 previously unpublished individuals with SIN3A haploinsufficiency.Methods: We studied the phenotypic characteristics and the genome-wide DNA methylation in the peripheral blood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.",
keywords = "DNA methylation, Epigenetics, SIN3A, WITKOS, Witteveen-Kolk syndrome",
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 = "Funding Information: We thank the families for their participation in this study. Funding for this study was provided, in part, by the government of Canada through Genome Canada and the Ontario Genomics Institute (OGI-188). This publication is further supported by the Project ProMiSe (project number NWA.1160.18.320) of the research program NWA-ORC, which is (partly) financed by the Dutch Research Council (NWO) and the Radboud University interfaculty collaboration initiative BRAINCHAIN to S.M.K. and T.K. and the Aspasia grant of the Dutch Research Council (015.014.036) and Netherlands Organization for Health Research and Development (91718310) to T.K. The collaborations in this study were facilitated by ERN ITHACA, one of the 24 European Reference Networks (ERNs) approved by the ERN Board of Member States and cofunded by the European Commission. Conceptualization: B.S. T.K. M.L.T. K.M.B.; Data Curation: R.R. J.C.-v.d.S. J.K. M.A.L. B.S. K.M.B. M.L.T. T.K.; Formal Analysis: J.C.-v.d.S. R.R. M.A.L. J.K. K.M.B. M.L.T. R.J.L. B.S. T.K.; Investigation: J.C.-v.d.S. R.R. J.K. R.S.F. H.W.M. A.C. E.R.F. N.L.C. M.J.L. D.B.E. R.C.R. S.A.S. A.R. D.R.M. S.K.D. B.M. S.D. A.J.M.D. L.D.K. S.M.K. R.P. P.R. T.K. B.S.; Methodology: J.C.-v.d.S. J.K. M.A.L. R.R. B.S.; Project Administration: J.C.-v.d.S. R.R. J.K. M.A.L. H.M. K.M.B. T.K. B.S.; Supervision: R.R. J.C.-v.d.S. K.M.B. T.K. B.S.; Validation: R.R. J.C.-v.d.S. J.K. M.A.L. B.S.; Visualization: J.C.-v.d.S. R.R.; Writing-original draft: J.C.-v.d.S. R.R. K.M.B.; Writing-review and editing: B.S. T.K. K.M.B. M.L.T. Informed consent for the use and publication of medical data and biological material was obtained from all individuals or their legal representatives by the involved clinician. Explicit consent for the publication of individual's photographs was obtained separately. Genetic testing and research were performed in accordance with protocols approved by the local institutional review boards. This study was approved by the Western University Research Ethics Board (REB 106302 and REB 116108). Funding Information: We thank the families for their participation in this study. Funding for this study was provided, in part, by the government of Canada through Genome Canada and the Ontario Genomics Institute (OGI-188). This publication is further supported by the Project ProMiSe (project number NWA.1160.18.320) of the research program NWA-ORC, which is (partly) financed by the Dutch Research Council (NWO) and the Radboud University interfaculty collaboration initiative BRAINCHAIN to S.M.K. and T.K. and the Aspasia grant of the Dutch Research Council (015.014.036) and Netherlands Organization for Health Research and Development (91718310) to T.K. The collaborations in this study were facilitated by ERN ITHACA, one of the 24 European Reference Networks (ERNs) approved by the ERN Board of Member States and cofunded by the European Commission. 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 = "Nature Publishing Group",
number = "1",
}