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

• Published in: Genetics in medicine Vol. 25; no. 1; pp. 63 - 75
• Main Authors: Coenen-van der Spek, Jet, Relator, Raissa, Kerkhof, Jennifer, McConkey, Haley, Levy, Michael A., Tedder, Matthew L., Louie, Raymond J., Fletcher, Robin S., Moore, Hannah W., Childers, Anna, Farrelly, Ellyn R., Champaigne, Neena L., Lyons, Michael J., Everman, David B., Rogers, R. Curtis, Skinner, Steven A., Renck, Alicia, Matalon, Dena R., Dills, Shelley K., Monteleone, Berrin, Demirdas, Serwet, Dingemans, Alexander J.M., Donker Kaat, Laura, Kolk, Sharon M., Pfundt, Rolph, Rump, Patrick, Sadikovic, Bekim, Kleefstra, Tjitske, Butler, Kameryn M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2023
• Subjects: DNA methylation; DNA Methylation - genetics; Epigenetics; Genome; Haploinsufficiency - genetics; Humans; Neurodevelopmental Disorders - genetics; SIN3A; WITKOS; Witteveen-Kolk syndrome; DNA methylation; Epigenetics; Witteveen-Kolk syndrome; WITKOS; SIN3A
• ISSN: 1098-3600; 1530-0366
• DOI: 10.1016/j.gim.2022.10.004

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as well as individuals with other neurodevelopmental disorders with episignatures and described 9 previously unpublished individuals with SIN3A haploinsufficiency. 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. 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. 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.