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Evaluating DNA methylation episignatures as a first-tier diagnostic test in individuals with suspected genetic disorders

European Journal of Human Genetics volume 34, pages 296–299 (2026)Cite this article

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A Comment to this article was published on 26 October 2025

Abstract

DNA methylation (DNAm) episignature analysis is an emerging tool for diagnosing individuals with neurodevelopmental disorders, congenital anomalies, and growth disorders. We evaluated its clinical utility as a first-tier test in 62 individuals without prior molecular testing. DNAm arrays identified a diagnosis in 30.6% (19/62) of cases. The positivity rate was highest for Fragile X syndrome (100%, 5/5), followed by syndromic disorders (44%, 8/18) and imprinting disorders (25%, 6/24), including Silver-Russell, Beckwith-Wiedemann, and Prader-Willi syndromes. No diagnoses were made in 15 individuals with non-syndromic neurodevelopmental disorders. Alternative diagnoses were identified in 4.8% (3/62) of cases. These findings suggest that DNAm arrays can serve as an effective first-tier diagnostic tool, particularly for syndromic and imprinting disorders, with potential to improve diagnostic efficiency and reduce reliance on sequential genetic testing. While these findings support the use of DNAm arrays as an effective first-tier tool in selected populations, larger, unselected cohort studies are needed to validate its generalizability.

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Fig. 1: Facial phenotypes of individuals involved in the study.

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Data availability

Data that support the findings of this study are available on request from the corresponding author with reasonable patient privacy restrictions.

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Acknowledgements

We thank all the individuals and their families for their participation in the study. Tinatin Tkemaladze also wishes to express her gratitude to Sofia Douzgou Houge for facilitating the connection with Siddhant Banka, the lead author of the study.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: NIHR Manchester Biomedical Research Centre (NIHR203308) and the MRC Epigenomics of Rare Diseases Node (MR/Y008170/1) grants.

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Authors and Affiliations

  1. Department of Molecular and Medical Genetics, Tbilisi State Medical University, Tbilisi, Georgia

    Tinatin Tkemladze, Kakha Bregvadze, Eka Kvaratskhelia & Elene Abzianidze

  2. Division of Clinical Genetics, Givi Zhvania Pediatric University Clinic, Tbilisi State Medical University, Tbilisi, Georgia

    Tinatin Tkemladze

  3. Manchester Centre for Genomic Medicine, St Mary’s Hospital, Manchester University NHS Foundation Trust, Manchester, UK

    Christopher Campbell, Leigh Demain, Sarah Jenkinson, Sarah Hilton, David Gokhale & Siddharth Banka

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

    Michael Levy, Jennifer Kerkhof & Bekim Sadikovic

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

    Michael Levy, Jennifer Kerkhof & Bekim Sadikovic

  6. Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK

    Siddharth Banka

Authors
  1. Tinatin Tkemladze
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  2. Christopher Campbell
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  3. Kakha Bregvadze
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  4. Eka Kvaratskhelia
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  5. Elene Abzianidze
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  6. Leigh Demain
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  7. Sarah Jenkinson
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  8. Sarah Hilton
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  9. Michael Levy
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  10. Jennifer Kerkhof
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  11. David Gokhale
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  12. Bekim Sadikovic
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  13. Siddharth Banka
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Contributions

Conceptualization: T.T., S.B.; Data Curation: T.T., C.C., S.B.; Formal Analysis: T.T., K.B., C.C.; Investigation: T.T., C.C., L.D., S.B.; Methodology: B.S., S.B.; Project Administration: T.T., S.J., S.H., S.B.; Resources: T.T., S.B.; Software: C.C., B.S., M.L., J.K., D.G.; Writing-original draft: T.T., C.C., E.K., K.B., E.A., S.B.; Writing-review & editing: T.T., C.C., K.B., E.K., E.A., L.D., S.J., S.H., B.S., M.L., J.K., D.G., S.B.

Corresponding author

Correspondence to Tinatin Tkemladze.

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Competing interests

B.S. is a shareholder in EpiSign Inc.

Ethical approval

The study was approved by local Institutional Review Board. Written and oral consent from all individuals’ legal representatives was obtained. Consent was obtained to publish identifying photos.

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Tkemladze, T., Campbell, C., Bregvadze, K. et al. Evaluating DNA methylation episignatures as a first-tier diagnostic test in individuals with suspected genetic disorders. Eur J Hum Genet 34, 296–299 (2026). https://doi.org/10.1038/s41431-025-01939-1

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