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Background <p>Recent advances in sequencing technologies have enhanced patient diagnosis; however, causal pathogenic variants remain unidentified for a significant number of patients due to limited understanding of certain variants, regulatory sequences, or sequencing challenges, such as complex rearrangements. Investigating the epigenetic landscape has become essential to improve the diagnostic yield. Diseases caused by pathogenic variants in epigenetic regulators, often associated with growth abnormalities, intellectual disability, and facial dysmorphism, are prime models for studying episignatures. Among them, Snijders Blok-Campeau syndrome (ORPHA:599082), caused by pathogenic variants in the <i>CHD3</i> gene, remains largely understudied.</p> Methods <p>A European cohort of 23 patients displaying typical Snijders Blok-Campeau syndrome traits and carrying pathogenic/likely pathogenic <i>CHD3</i> variants was analysed using the Illumina EPIC array, identifying 270 differentially methylated positions distinguishing patients from 62 healthy matched controls. A subset of these regions serves as diagnostic tools for complex cases or variants of uncertain significance and helps uncover deregulated pathways linked to this syndrome. Four patients carrying pathogenic/likely pathogenic variants but with atypical clinical presentation, as well as 10 patients with variants of uncertain significance, were analysed as the testing set.</p> Results <p>Comparing methylomes of patients carrying pathogenic variants in <i>CHD3</i>, <i>CHD7</i> (CHARGE syndrome, ORPHA:138), and <i>CHD8</i> (Intellectual developmental disorder with autism and macrocephaly, ORPHA:642675) genes allows us to identify distinct subgroups with unique methylation profiles. This <i>CHD3</i> DNA methylation signature aids in reclassifying variants and diagnosing atypical cases.</p> Conclusions <p>Our findings advance the field of epigenetic signatures in rare diseases. We have opened new avenues for further investigation into subtypes defined by methylome assays (such as in the context of chromatinopathies), which could refine the phenotype spectrum and help predict patient outcomes.</p>

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Identification of an episignature for CHD3-related Snijders Blok-Campeau syndrome reveals heterogeneity in the CHARGE syndrome episignature: towards a better characterisation of chromatinopathies

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月8日

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  • Amandine Santini,
  • Angelo Tognon,
  • Anne-Claire Richard,
  • Guillaume Velasco,
  • Gilles Phan,
  • Pauline Marzin,
  • Fabien Maury,
  • Angele May,
  • Caroline Michot,
  • Adela Chirita-Emandi,
  • Jorge M. Saraiva,
  • Maria Juliana Ballesta-Martinez,
  • Stanislas Lyonnet,
  • Ivona Sansović,
  • Tahsin Stefan Barakat,
  • Perrine Brunelle,
  • Jamal Ghoumid,
  • Xavier Le Guillou,
  • Pauline Le Tanno,
  • Marjolaine Willems,
  • Martin Zenker,
  • Ina Schanze,
  • Stéphanie Moortgat,
  • Bertrand Isidor,
  • Alix Paulet,
  • Alison Yeung,
  • Jonathan Levy,
  • Federica Ruscitti,
  • Leticia Pias-Peleteiro,
  • Marlène Rio,
  • Thomas Courtin,
  • Hamza Hadj Abdallah,
  • Stéphanie Ducreux,
  • Jean-Sérène Laloy,
  • Paul Rollier,
  • Anne-Marie Guerrot,
  • Nicolas Chatron,
  • Florence Demurger,
  • Alice Goldenberg,
  • Julian Delanne,
  • Laurence Faivre,
  • François Lecoquierre,
  • Gaël Nicolas,
  • Aurélie Coussement,
  • Corinne Collet,
  • Yvan Herenger,
  • Matthieu Defrance,
  • Valérie Cormier-Daire,
  • Camille Charbonnier,
  • Maud de Dieuleveult

摘要

Background

Recent advances in sequencing technologies have enhanced patient diagnosis; however, causal pathogenic variants remain unidentified for a significant number of patients due to limited understanding of certain variants, regulatory sequences, or sequencing challenges, such as complex rearrangements. Investigating the epigenetic landscape has become essential to improve the diagnostic yield. Diseases caused by pathogenic variants in epigenetic regulators, often associated with growth abnormalities, intellectual disability, and facial dysmorphism, are prime models for studying episignatures. Among them, Snijders Blok-Campeau syndrome (ORPHA:599082), caused by pathogenic variants in the CHD3 gene, remains largely understudied.

Methods

A European cohort of 23 patients displaying typical Snijders Blok-Campeau syndrome traits and carrying pathogenic/likely pathogenic CHD3 variants was analysed using the Illumina EPIC array, identifying 270 differentially methylated positions distinguishing patients from 62 healthy matched controls. A subset of these regions serves as diagnostic tools for complex cases or variants of uncertain significance and helps uncover deregulated pathways linked to this syndrome. Four patients carrying pathogenic/likely pathogenic variants but with atypical clinical presentation, as well as 10 patients with variants of uncertain significance, were analysed as the testing set.

Results

Comparing methylomes of patients carrying pathogenic variants in CHD3, CHD7 (CHARGE syndrome, ORPHA:138), and CHD8 (Intellectual developmental disorder with autism and macrocephaly, ORPHA:642675) genes allows us to identify distinct subgroups with unique methylation profiles. This CHD3 DNA methylation signature aids in reclassifying variants and diagnosing atypical cases.

Conclusions

Our findings advance the field of epigenetic signatures in rare diseases. We have opened new avenues for further investigation into subtypes defined by methylome assays (such as in the context of chromatinopathies), which could refine the phenotype spectrum and help predict patient outcomes.