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To sign or not to sign: Is this still the question?

European Journal of Human Genetics (2025)Cite this article

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The Original Article was published on 03 October 2025

The Original Article was published on 29 July 2025

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The use of massive parallel sequencing into clinical practice has significantly improved the diagnostic yield in patients with rare diseases. However, a substantial proportion of these patients remain undiagnosed. This reflects the growing gap between our ability to accurately sequence the genome and our capacity to interpret genetic variation, as evidenced by the high prevalence of variants of uncertain significance (VUS) listed in diagnostic reports and public databases. Recently, genome-wide DNA methylation (DNAm) profiling analysis on peripheral blood has allowed to identify >100 unique array-based epigenomic profiles (i.e., DNAm signatures or episignatures) for an increasing number of rare diseases [1]. This emerging technology provides a powerful complementary tool for achieving definitive diagnoses in cases where genetic testing is uninformative. While previous work by various teams has demonstrated the value of this technology to interpret ambiguous genomic findings and definitely validated it as a diagnostic tool, further work is required to facilitate its broader integration in the clinical setting.

The two papers by Smits et al. [2] and Tkemladze et al. [3] offer further evidence of the fruitful use of DNAm signatures in diagnostic testing in specific contexts, particularly when dealing with VUS or patients with high clinical suspicion for a specific disorder in absence of any supportive molecular finding. Smits and co-workers [2] report on the clinical utility of episignature analysis in routine diagnostics providing data on a relatively large and unselected cohort of patients affected with neurodevelopmental disorders (NDDs). The overall message is of clinical interest as it offers real numbers on the use of this diagnostic tool. Specifically, they retrospectively analyzed 298 consecutive patients from a single clinical center who had been tested for the identification of disease-specific DNAm signatures by using a commercial platform (EpiSign, London, Canada). Among these, 55 had undergone targeted DNAm profiling analysis based on previous genetic findings (i.e., VUS testing), while 223, who were negative after routine molecular diagnostics, were agnostically assessed using a multiclass approach. They found a diagnostic yield for targeted analysis of 18% by VUS reclassification towards pathogenicity, and 9% for multiclass analysis by episignature matching. Notably, in 9/11 of episignature positive cases with suggestive clinical match, retrospective analyses allowed to identify the causative DNA variant in the indicated disease gene or independently confirmed an imprinting disorder. On the other hand, the authors report that alternative diagnoses (i.e., diagnoses not matching the original clinical suspicion and not supported by molecular evidence) were indicated by episignature analysis in 45% of positive cases, emphasizing the importance of current signature optimization to address diagnostic ambiguity.

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References

  1. Levy MA, McConkey H, Kerkhof J, Barat-Houari M, Bargiacchi S, Biamino E, et al. Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders. HGG Adv. 2021;3:100075.

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Funding

The work was supported by the Italian Ministry of Health (Current Research Funds, PNRR-MR1-2022-12376811, RF-2021-12374963).

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  1. Molecular Genetics and Functional Genomics, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy

    Marco Tartaglia & Andrea Ciolfi

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  1. Marco Tartaglia
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  2. Andrea Ciolfi
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AC and MT drafted and edited the manuscript.

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Correspondence to Marco Tartaglia.

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The authors declare no competing interests.

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Tartaglia, M., Ciolfi, A. To sign or not to sign: Is this still the question?. Eur J Hum Genet (2025). https://doi.org/10.1038/s41431-025-01969-9

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