Abstract
Smith-Magenis syndrome (SMS) and Potocki-Lupski syndrome (PTLS) are reciprocal genomic disorders caused by deletions and duplications of the 17p11.2 chromosomal region, respectively. This study aimed to identify and validate DNA methylation episignatures specific to SMS and PTLS, and to investigate their reciprocal relationship and shared molecular features with other neurodevelopmental disorders. Genome-wide DNA methylation was analyzed in individuals with an SMS (n = 26) or PTLS (n = 27) phenotype associated with copy number variation, and SMS patients with RAI1 sequence variants using the Infinium EPIC array. Differentially methylated CpG sites were identified and used to develop support vector machine (SVM)-based classifiers, which demonstrated high sensitivity and specificity for both syndromes. The analysis revealed a mirror-like episignature, with SMS showing predominant hypomethylation and PTLS displaying hypermethylation at shared loci. Functional correlation with other neurodevelopmental disorders highlighted significant overlap with known episignatures, including those associated with MEF2C-related disorders. Notably, individuals with RAI1 sequence variants did not exhibit the same DNA methylation patterns, suggesting that the epigenetic alterations are primarily driven by copy number changes. These findings establish SMS and PTLS as distinct yet interconnected epigenetic entities, offering valuable diagnostic biomarkers and insights into the molecular pathophysiology of 17p11.2-associated neurodevelopmental disorders.
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Data availability
The deposition of individual epigenomic or any other personally identifiable data that has not previously been made publicly available for samples in the EpiSign Knowledge Database (EKD) is prohibited from deposition in publicly accessible databases due to institutional and ethical 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). EpiSign is a commercial software and is not publicly available.
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Acknowledgements
We wish to thank all the individuals, family members and staff from all the units that participated in the study.
Funding
Funding for this study is provided in part by the Government of Canada through Genome Canada and the Ontario Genomics Institute (OGI-188) and Italian Ministry of Health (PNRR-MR1-2022-12376811 and RF-2021-12374963, to MT). Liselot van der Laan was awarded with the AR&D Travel grant from the Amsterdam UMC, which provided financial support for this work. This work was generated in part within the European Reference Network for Rare Malformation Syndromes, Intellectual and Other Neurodevelopmental Disorders (ERN ITHACA).
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Conceptualization; LVDL, KS, KK, and BS.; Data Curation; KR, LVDL, KK, MAL, and RR.; Formal analysis; KR, LVDL, KK, MAL, and RR.; Investigation; LVDL, KR, MA, AB, ALA, NBP, AMCG, BRD, GC, CD, DE, VG, BG, DG, and GBF. MK, MN, AN, VO, SO, WGP, AMP, TR, NRP, QS, ST, MT, MAT, AT, UK, IV, JMVH, AMVDKK, PH, MMAMM, and MMVH.; Methodology; LVDL, KR, KK, and BS.; Project administration; BS.; Supervision; BS and MMVH.; Validation; KR, LVDL, BS, and MMVH.; Visualization; LVDL, KK, and KR.; Writing-original draft; LVDL, KK, and KR.; Writing-review and editing; LVLD, KK, BS, and MMVH.
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B.S. is a shareholder in EpiSign Inc.
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Written informed consent was obtained from all individuals or family members prior to inclusion in this study including for the use of DNA and clinical information. The study was conducted in accordance with the regulations of the Western University Research Ethics Board (REB116108, and REB106302).
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van der Laan, L., Karimi, K., Rooney, K. et al. DNA methylation episignature for Smith-Magenis and Potocki-Lupski syndromes: a mirror perspective. Eur J Hum Genet (2025). https://doi.org/10.1038/s41431-025-01956-0
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DOI: https://doi.org/10.1038/s41431-025-01956-0
