Awamleh, ZainChoufani, SanaaWu, WendyRots, DmitrijsDingemans, Alexander J. M.Nadif Kasri, NaelBoronat i Llop, Susanna, 1965-Ibáñez-Micó, SalvadorCuesta Herraiz, LauraFerrer, IreneMartínez Carrascal, AntonioPérez Jurado, Luis AlbertoAznar Laín, GemmaOrtigoza Escobar, Juan Daríode Vries, Bert B. A.Koolen, David A.Weksberg, Rosanna2024-04-162024-04-162024Awamleh Z, Choufani S, Wu W, Rots D, Dingemans AJM, Nadif Kasri N, et al. A new blood DNA methylation signature for Koolen-de Vries syndrome: Classification of missense KANSL1 variants and comparison to fibroblast cells. Eur J Hum Genet. 2024 Mar;32(3):324-32. DOI: 10.1038/s41431-024-01538-61018-4813http://hdl.handle.net/10230/59779Pathogenic variants in KANSL1 and 17q21.31 microdeletions are causative of Koolen-de Vries syndrome (KdVS), a neurodevelopmental syndrome with characteristic facial dysmorphia. Our previous work has shown that syndromic conditions caused by pathogenic variants in epigenetic regulatory genes have identifiable patterns of DNA methylation (DNAm) change: DNAm signatures or episignatures. Given the role of KANSL1 in histone acetylation, we tested whether variants underlying KdVS are associated with a DNAm signature. We profiled whole-blood DNAm for 13 individuals with KANSL1 variants, four individuals with 17q21.31 microdeletions, and 21 typically developing individuals, using Illumina's Infinium EPIC array. In this study, we identified a robust DNAm signature of 456 significant CpG sites in 8 individuals with KdVS, a pattern independently validated in an additional 7 individuals with KdVS. We also demonstrate the diagnostic utility of the signature and classify two KANSL1 VUS as well as four variants in individuals with atypical clinical presentation. Lastly, we investigated tissue-specific DNAm changes in fibroblast cells from individuals with KdVS. Collectively, our findings contribute to the understanding of the epigenetic landscape related to KdVS and aid in the diagnosis and classification of variants in this structurally complex genomic region.application/pdfeng© The Author(s) 2024, corrected publication 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41431-024-01538-6Diagnostic markersDNA methylationinfo:eu-repo/semantics/openAccess