A new blood DNA methylation signature for Koolen-de Vries syndrome: Classification of missense KANSL1 variants and comparison to fibroblast cells.

Autor: Awamleh Z; Genetics and Genome Biology Program, Research Institute, the Hospital for Sick Children, Toronto, ON, M5G 1×8, Canada., Choufani S; Genetics and Genome Biology Program, Research Institute, the Hospital for Sick Children, Toronto, ON, M5G 1×8, Canada., Wu W; Genetics and Genome Biology Program, Research Institute, the Hospital for Sick Children, Toronto, ON, M5G 1×8, Canada., Rots D; Department of Human Genetics, Radboud university medical center, Donders Institute for Brain, Cognition, and Behavior, Nijmegen, The Netherlands., Dingemans AJM; Department of Human Genetics, Radboud university medical center, Donders Institute for Brain, Cognition, and Behavior, Nijmegen, The Netherlands., Nadif Kasri N; Department of Human Genetics, Radboud university medical center, Donders Institute for Brain, Cognition, and Behavior, Nijmegen, The Netherlands., Boronat S; Department of Pediatrics, Hospital del Santa Creu y Sant Pau, Barcelona, Spain., Ibañez-Mico S; Department of Pediatric Neurology, Hospital Virgen de la Arrixaca, Murcia, Madrid, Spain., Cuesta Herraiz L; Department of Pediatric Neurology, Hospital de Manises, Valencia, Spain., Ferrer I; Department of Genetics, Consorcio Hospital General de Valencia, Valencia, Spain., Martínez Carrascal A; Department of Pediatrics, Hospital de Requena, Valencia, Spain., Pérez-Jurado LA; Genetics Unit, Universitat Pompeu Fabra, Hospital del Mar Research Institute (IMIM) and CIBERER, Barcelona, Spain., Aznar Lain G; Genetics Unit, Universitat Pompeu Fabra, Hospital del Mar Research Institute (IMIM) and CIBERER, Barcelona, Spain., Ortigoza-Escobar JD; Movement Disorders Unit, Institut de Recerca Sant Joan de Déu, CIBERER-ISCIII and European Reference Network for Rare Neurological Diseases (ERN-RND), Barcelona, Spain., de Vries BBA; Department of Human Genetics, Radboud university medical center, Donders Institute for Brain, Cognition, and Behavior, Nijmegen, The Netherlands., Koolen DA; Department of Human Genetics, Radboud university medical center, Donders Institute for Brain, Cognition, and Behavior, Nijmegen, The Netherlands. david.koolen@radboudumc.nl., Weksberg R; Genetics and Genome Biology Program, Research Institute, the Hospital for Sick Children, Toronto, ON, M5G 1×8, Canada. rweksb@sickkids.ca.; Division of Clinical and Metabolic Genetics, Department of Pediatrics, the Hospital for Sick Children, University of Toronto, Toronto, ON, M5G 1×8, Canada. rweksb@sickkids.ca.
Jazyk: angličtina
Zdroj: European journal of human genetics : EJHG [Eur J Hum Genet] 2024 Mar; Vol. 32 (3), pp. 324-332. Date of Electronic Publication: 2024 Jan 29.
DOI: 10.1038/s41431-024-01538-6
Abstrakt: Pathogenic 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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