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Identification of an episignature for the MEF2C-associated syndrome

European Journal of Human Genetics volume 34, pages 53–60 (2026)Cite this article

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Abstract

Neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (NEDHSIL), also known as MEF2C-related disorder or MEF2C haploinsufficiency syndrome (MCHS), is a condition caused by pathogenic variants in the Myocyte Enhancer Factor-2C (MEF2C) gene. This study aimed to identify a DNA methylation episignature specific to NEDHSIL and explore its similarities with other known episignatures. Genome-wide DNA levels were assessed in a cohort of patients with MEF2C mutations and controls, and differentially methylated CpG sites were identified. A bioinformatic analysis yielded a classifier that was trained against controls and other known episignature disorders within the EpiSign Knowledge Database. The classifier demonstrated high accuracy, sensitivity, and specificity in classifying NEDHSIL samples. Furthermore, functional annotation and comparative analysis revealed similarities between the NEDHSIL episignature and other genetic neurodevelopmental disorders. This study provides evidence for a DNA methylation episignature specific to NEDHSIL and highlights the potential utility of this epigenetic biomarker for diagnosing and understanding molecular pathophysiology of neurodevelopmental disorders associated with MEF2C mutations.

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Fig. 1: Episignature discovery plus validation cohort.
Fig. 2: Visualization of shared probes between NEDHSIL and episignature disorders.
Fig. 3: Correlation between NEDHSIL and other episignature disorders.

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Data availability

Datasets used in this study that are available publicly are previously described [23]. Anonymized data for each subject is described in the study. The individual genomic and epigenomic or any other personally identifiable data for other samples in the EpiSign Knowledge Database (EKD) are not available for deposition in publicly accessible databases due to institutional and ethics restrictions. Specifically, these include data and samples submitted from external institutions to London Health Sciences EKD that are subject to Institutional Material and Data Transfer agreements, data submitted to London Health Sciences for episignature assessment under Research Services Agreements, and research study cohorts under Institutional Research Ethics Approval (Western University REB 106302; and REB 116108). Some of the software packages used in this study are publicly available as described in the Materials and Methods. EpiSignTM is a commercial software and is not publicly available.

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Acknowledgements

We extend our gratitude to the participants and their families for their invaluable contribution.

Funding

Funding for this study is provided in part by the Government of Canada through Genome Canada and the Ontario Genomics Institute (OGI-188).

Author information

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada

    Ananília Silva, Haley McConkey & Bekim Sadikovic

  2. Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON, Canada

    Sadegheh Haghshenas, Michael A. Levy, Raissa Relator, Haley McConkey, Jennifer Kerkhof & Bekim Sadikovic

  3. Department of Human Genetics, Amsterdam Reproduction and Development Research Institute, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands

    Liselot van der Laan

  4. Greenwood Genetic Center, Greenwood, SC, 29646, USA

    Steve A. Skinner, Matthew L. Tedder & Jessica A. Cooley Coleman

  5. GAD INSERM UMR 1231, Fédération Hospitalo-Universitaire-TRANSLAD, University of Burgundy, Dijon, France

    Laurence Faivre & Antonio Vitobello

  6. Genetics Department, Reference Center for Developmental Disorders, University Hospital, Dijon, France

    Laurence Faivre

  7. UF de génétique médicale, Centre Hospitalier Métropole Savoie, BP 31135, 73011, Chambéry, France

    James Lespinasse

  8. Laboratoire de génomique médicale, Fédération Hospitalo-Universitaire-TRANSLAD, CHU Dijon Bourgogne, Dijon, France

    Antonio Vitobello

  9. Department of Clinical and Molecular Genetics, Hospital Universitari Vall d’Hebron, Barcelona, Spain

    Irene Valenzuela

  10. Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Melbourne, VIC, Australia

    Ingrid E. Scheffer & Sophie J. Russ-Hall

  11. Department of Pediatrics, University of Melbourne, Royal Children’s Hospital, Florey Institute, Murdoch Children’s Research Institute, Melbourne, VIC, Australia

    Ingrid E. Scheffer

  12. Division of Neurology, Department of Pediatrics, Montreal Children’s Hospital, 54473, McGill University Health Centre, Montreal, QC, Canada

    Kenneth A. Myers

Authors
  1. Ananília Silva
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  2. Sadegheh Haghshenas
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  3. Liselot van der Laan
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  4. Michael A. Levy
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  8. Steve A. Skinner
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  16. Matthew L. Tedder
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  17. Bekim Sadikovic
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  18. Jessica A. Cooley Coleman
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Contributions

Conceptualization: AS, BS; Data curation: AS JK; Formal analysis: AS, SH, MAL, RR; Funding acquisition: BS; Sample Collection: SAS, AV, IV, IES, KAM, MLT, JACC; Investigation: AS, MAL, JK, RR; Methodology: AS, MAL, RR; Project administration: HM, BS; Software: AS, MAL, RR; Supervision: BS; Validation: AS, SH, LVDL; Visualization: AS; Writing-original draft: AS; Writing-review and editing: AS, LVDL, SH, BS, JACC.

Corresponding author

Correspondence to Bekim Sadikovic.

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Competing interests

BS is a shareholder in EpiSign Inc involved in commercial applications of EpiSign™ technology.

Ethical approval

All samples and data records were anonymized to protect the identities of the individuals involved. The research protocol received ethical approval from the Research Ethics Board (REB 106302) at Western University and the Institutional Review Board (IRB) of Self Regional Healthcare. Informed consent was obtained from physicians for the utilization of clinical information pertaining to the described patients.

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Silva, A., Haghshenas, S., van der Laan, L. et al. Identification of an episignature for the MEF2C-associated syndrome. Eur J Hum Genet 34, 53–60 (2026). https://doi.org/10.1038/s41431-025-01983-x

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