DNA Methylation Signature for JARID2-Neurodevelopmental Syndrome

  • Int J Mol Sci. 2022 Jul 20;23(14):8001. doi: 10.3390/ijms23148001.
Eline A Verberne  1 ,  Liselot van der Laan  1 ,  Sadegheh Haghshenas  2 ,  Kathleen Rooney  2  3 ,  Michael A Levy  3 ,  Mariëlle Alders  1 ,  Saskia M Maas  1 ,  Sandra Jansen  1 ,  Agne Lieden  4  5 ,  Britt-Marie Anderlid  4  5 ,  Louise Rafael-Croes  6 ,  Philippe M Campeau  7 ,  Ayeshah Chaudhry  8  9 ,  David A Koolen  10 ,  Rolph Pfundt  10 ,  Anna C E Hurst  11 ,  Frederic Tran-Mau-Them  12  13 ,  Ange-Line Bruel  12  13 ,  Laetitia Lambert  14 ,  Bertrand Isidor  15 ,  Marcel M A M Mannens  1 ,  Bekim Sadikovic  2  3 ,  Peter Henneman  1 ,  Mieke M van Haelst  1
Affiliations
  • 1. Department of Human Genetics, Amsterdam Reproduction & Development Research Institute, Amsterdam University Medical Centers, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
  • 2. Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada.
  • 3. Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON N6A 5W9, Canada.
  • 4. Department of Clinical Genetics, Karolinska University Hospital, 17176 Stockholm, Sweden.
  • 5. Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176 Stockholm, Sweden.
  • 6. Department of Pediatrics, Dr. Horacio E. Oduber Hospital, Dr. Horacio E. Oduber Boulevard 1, Oranjestad, Aruba.
  • 7. Department of Pediatrics, University of Montreal, Montreal, QC H4A 3J1, Canada.
  • 8. Department of Laboratory Medicine and Genetics, Trillium Health Partners, Mississauga, ON L5B 1B8, Canada.
  • 9. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • 10. Department of Hum Genet, Radboud Institute for Molecular Life Sciences and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
  • 11. Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
  • 12. UF6254 Innovation en Diagnostic Genomique des Maladies Rares, 21070 Dijon, France.
  • 13. Équipe Génétique des Anomalies du Développement (GAD), CHU Dijon-Bourgogne, 21000 Dijon, France.
  • 14. Service de Génétique Clinique, CHRU Nancy, 54000 Nancy, France.
  • 15. Service de génétique médicale, CHU de Nantes, 44000 Nantes, France.
PMID: 35887345 DOI: 10.3390/ijms23148001
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.

Keywords
DNA methylation; JARID2; developmental disorder; epigenetics; episignature.