1. DNA Methylation Signature for JARID2-Neurodevelopmental Syndrome
- Author
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Eline A. Verberne, Liselot van der Laan, Sadegheh Haghshenas, Kathleen Rooney, Michael A. Levy, Mariëlle Alders, Saskia M. Maas, Sandra Jansen, Agne Lieden, Britt-Marie Anderlid, Louise Rafael-Croes, Philippe M. Campeau, Ayeshah Chaudhry, David A. Koolen, Rolph Pfundt, Anna C. E. Hurst, Frederic Tran-Mau-Them, Ange-Line Bruel, Laetitia Lambert, Bertrand Isidor, Marcel M. A. M. Mannens, Bekim Sadikovic, Peter Henneman, Mieke M. van Haelst, Human genetics, Amsterdam Reproduction & Development (AR&D), Amsterdam Neuroscience - Complex Trait Genetics, Graduate School, Human Genetics, ACS - Pulmonary hypertension & thrombosis, ARD - Amsterdam Reproduction and Development, ANS - Cellular & Molecular Mechanisms, ANS - Complex Trait Genetics, and AGEM - Amsterdam Gastroenterology Endocrinology Metabolism
- Subjects
DNA methylation ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,epigenetics ,Organic Chemistry ,JARID2 ,developmental disorder ,episignature ,General Medicine ,Catalysis ,Computer Science Applications ,Inorganic Chemistry ,All institutes and research themes of the Radboud University Medical Center ,Physical and Theoretical Chemistry ,Molecular Biology ,Spectroscopy - Abstract
JARID2 (Jumonji, AT Rich Interactive Domain 2) pathogenic variants cause a neurodevelopmental syndrome, that is characterized by developmental delay, cognitive impairment, hypotonia, autistic features, behavior abnormalities and dysmorphic facial features. JARID2 encodes a transcriptional repressor protein that regulates the activity of various histone methyltransferase complexes. However, the molecular etiology is not fully understood, and JARID2-neurodevelopmental syndrome may vary in its typical clinical phenotype. In addition, the detection of variants of uncertain significance (VUSs) often results in a delay of final diagnosis which could hamper the appropriate care. In this study we aim to detect a specific and sensitive DNA methylation signature for JARID2-neurodevelopmental syndrome. Peripheral blood DNA methylation profiles from 56 control subjects, 8 patients with (likely) pathogenic JARID2 variants and 3 patients with JARID2 VUSs were analyzed. DNA methylation analysis indicated a clear and robust separation between patients with (likely) pathogenic variants and controls. A binary model capable of classifying patients with the JARID2-neurodevelopmental syndrome was constructed on the basis of the identified episignature. Patients carrying VUSs clustered with the control group. We identified a distinct DNA methylation signature associated with JARID2-neurodevelopmental syndrome, establishing its utility as a biomarker for this syndrome and expanding the EpiSign diagnostic test.
- Published
- 2022
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