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.

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