Identification of an episignature for CHD3-related Snijders Blok-Campeau syndrome reveals heterogeneity in the CHARGE syndrome episignature: towards a better characterisation of chromatinopathies
Por:
Santini, A, Tognon, A, Richard, AC, Velasco, G, Phan, G, Marzin, P, Maury, F, May, A, Michot, C, Chirita-Emandi, A, Saraiva, JM, Ballesta-Martinez, MJ, Lyonnet, S, Sansovic, I, Barakat, TS, Brunelle, P, Ghoumid, J, Le Guillou, X, Le Tanno, P, Willems, M, Zenker, M, Schanze, I, Moortgat, S, Isidor, B, Paulet, A, Yeung, A, Levy, J, Ruscitti, F, Pias-Peleteiro LD, Rio, M, Courtin, T, Abdallah, HH, Ducreux, S, Laloy, JS, Rollier, P, Guerrot, AM, Chatron, N, Demurger, F, Goldenberg, A, Delanne, J, Faivre, L, Lecoquierre, F, Nicolas, G, Coussement, A, Collet, C, Herenger, Y, Defrance, M, Cormier-Daire, V, Charbonnier, C and de Dieuleveult, M
Publicada:
8 abr 2026
Ahead of Print:
1 abr 2026
Resumen:
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.
Filiaciones:
Santini, A:
Normandie Univ, Univ Rouen Normandie, Reference Ctr Dev Abnormal, Inserm,U1245, F-76000 Rouen, France
Normandie Univ, Univ Rouen Normandie, Dept Genet, Inserm,U1245, F-76000 Rouen, France
CHU Rouen, F-76000 Rouen, France
Tognon, A:
Univ Paris Cite, Imagine Inst, INSERM, U1163, Paris, France
Richard, AC:
Normandie Univ, Univ Rouen Normandie, Reference Ctr Dev Abnormal, Inserm,U1245, F-76000 Rouen, France
Normandie Univ, Univ Rouen Normandie, Dept Genet, Inserm,U1245, F-76000 Rouen, France
CHU Rouen, F-76000 Rouen, France
Velasco, G:
Univ Paris Cite, CNRS, Epigenet & Cell Fate, UMR7216, Paris, France
Phan, G:
Univ Paris Cite, Fac Pharm Paris, UMR 8038,CNRS, Lab CiTCoM Cibles Therapeut & Concept Medicaments, Paris, France
Marzin, P:
Univ Paris Cite, Hop Necker Enfants Malad, Assistance Publ Hop Paris, Fac Med,Serv Med Genom Malad Rares, Paris, France
Ctr Hosp Univ La Reunion, Serv Gynecol & Obstet, UF Genet Med, St Denis, La Reunion, France
Maury, F:
Univ Paris Cite, Imagine Inst, INSERM, U1163, Paris, France
May, A:
Normandie Univ, Univ Rouen Normandie, Reference Ctr Dev Abnormal, Inserm,U1245, F-76000 Rouen, France
Normandie Univ, Univ Rouen Normandie, Dept Genet, Inserm,U1245, F-76000 Rouen, France
CHU Rouen, F-76000 Rouen, France
Michot, C:
Univ Paris Cite, Hop Necker Enfants Malad, Assistance Publ Hop Paris, Fac Med,Serv Med Genom Malad Rares, Paris, France
Chirita-Emandi, A:
Univ Med & Farm Timisoara, Ctr Genom Med, Dept Microscop Morphol, Genet Discipline, Timisoara, Romania
Clin Emergency Hosp Children Louis Turcanu, Reg Ctr Med Genet Timis, Timisoara, Romania
Saraiva, JM:
Hosp Pediatr Coimbra, Med Genet Dept, Unidade Local Saude Coimbra, Coimbra, Portugal
Univ Coimbra, Univ Clin Pediat, Fac Med, Coimbra, Portugal
Clin Acad Ctr Coimbra, Hosp Pediatr Coimbra, Unidade Local Saude Coimbra, Coimbra, Portugal
Ballesta-Martinez, MJ:
Hosp Clin Univ Virgen Arrixaca, Serv Pediat, Secc Genet Med, Murcia, Spain
Lyonnet, S:
Univ Paris Cite, Imagine Inst, INSERM, U1163, Paris, France
Univ Paris Cite, Hop Necker Enfants Malad, Assistance Publ Hop Paris, Fac Med,Serv Med Genom Malad Rares, Paris, France
Sansovic, I:
Univ Zagreb, Childrens Hosp Zagreb, Dept Med & Lab Genet Endocrinol & Diabetol, Sch Med, Zagreb, Croatia
Barakat, TS:
Erasmus MC, Dept Clin Genet, Univ Med Ctr, Rotterdam, Netherlands
Brunelle, P:
Univ Lille, Inst Genet Med, CHU Lille, Lille, France
Ghoumid, J:
Univ Lille, ULR7364, Clin Genet, RADEME Malad RAres Dev Embryonnaire & Metabol, Lille, France
Le Guillou, X:
CHU Poitiers, Serv Genet Med, Poitiers, France
Le Tanno, P:
CHU Grenoble Alpes, Genet Genom & Procreat Dept, Grenoble, France
Willems, M:
CHRU Montpellier, Hop Arnaud Villeneuve, Dept Genet Clin, Montpellier, France
Univ Montpellier, Inst Neurosci Montpellier, INSERM, Montpellier, France
Zenker, M:
Univ Hosp Magdeburg, Inst Human Genet, Magdeburg, Germany
Schanze, I:
Univ Hosp Magdeburg, Inst Human Genet, Magdeburg, Germany
Moortgat, S:
Ctr Genet Humaine, Inst Pathol & Genet, Gosselies, Belgium
Isidor, B:
Ctr Hosp Univ Nantes, Dept Genet, Nantes, France
Paulet, A:
Univ Paris Cite, Hop Necker Enfants Malad, Assistance Publ Hop Paris, Fac Med,Serv Med Genom Malad Rares, Paris, France
Yeung, A:
Murdoch Childrens Res Inst, Victorian Clin Genet Serv, Melbourne, Australia
Levy, J:
Hop Robert Debre, Dept Genet, Paris, France
Lab Med Genom SeqOIA, Paris, France
Ruscitti, F:
Hop Robert Debre, Dept Genet, Paris, France
Pias-Peleteiro LD:
St Joan Deu Hosp, Dept Child Neurol, Dept Genet & Mol Med, Neurometab Disorders Unit, Barcelona, Spain
Rio, M:
Univ Paris Cite, Hop Necker Enfants Malad, Assistance Publ Hop Paris, Fac Med,Serv Med Genom Malad Rares, Paris, France
Courtin, T:
Univ Paris Cite, Hop Necker Enfants Malad, Assistance Publ Hop Paris, Fac Med,Serv Med Genom Malad Rares, Paris, France
Abdallah, HH:
Univ Paris Cite, Hop Necker Enfants Malad, Assistance Publ Hop Paris, Fac Med,Serv Med Genom Malad Rares, Paris, France
Ducreux, S:
Lab Med Genom SeqOIA, Paris, France
Laloy, JS:
Univ Paris Cite, Hop Necker Enfants Malad, Assistance Publ Hop Paris, Fac Med,Serv Med Genom Malad Rares, Paris, France
Rollier, P:
CHU Rennes, Genet Clin Ctr Reference Malad Rares CLAD Ouest, FHU GenOMedS, Rennes, France
Guerrot, AM:
Normandie Univ, Univ Rouen Normandie, Reference Ctr Dev Abnormal, Inserm,U1245, F-76000 Rouen, France
Normandie Univ, Univ Rouen Normandie, Dept Genet, Inserm,U1245, F-76000 Rouen, France
CHU Rouen, F-76000 Rouen, France
Chatron, N:
Hosp Civils Lyon, Genet Dept, Lyon, France
UCBL, UMR5261, Pathophysiol & Genet Neuron & Muscle PNMG, CNRS,INSERM, Lyon, France
Demurger, F:
CHBA, Serv Genet, Vannes, France
Goldenberg, A:
Normandie Univ, Univ Rouen Normandie, Reference Ctr Dev Abnormal, Inserm,U1245, F-76000 Rouen, France
Normandie Univ, Univ Rouen Normandie, Dept Genet, Inserm,U1245, F-76000 Rouen, France
CHU Rouen, F-76000 Rouen, France
Delanne, J:
Univ Bourgogne Europe, Ctr Reference Deficiences Intellectuelles Causes R, Ctr Reference Anomalies Dev & Syndromes Malformati, Ctr Genet,CHU Dijon Bourgogne,Inserm,CTM,UMR1231, Dijon, France
Faivre, L:
Univ Bourgogne Europe, Ctr Reference Deficiences Intellectuelles Causes R, Ctr Reference Anomalies Dev & Syndromes Malformati, Ctr Genet,CHU Dijon Bourgogne,Inserm,CTM,UMR1231, Dijon, France
Lecoquierre, F:
Normandie Univ, Univ Rouen Normandie, Reference Ctr Dev Abnormal, Inserm,U1245, F-76000 Rouen, France
Normandie Univ, Univ Rouen Normandie, Dept Genet, Inserm,U1245, F-76000 Rouen, France
CHU Rouen, F-76000 Rouen, France
Nicolas, G:
Normandie Univ, Univ Rouen Normandie, Reference Ctr Dev Abnormal, Inserm,U1245, F-76000 Rouen, France
Normandie Univ, Univ Rouen Normandie, Dept Genet, Inserm,U1245, F-76000 Rouen, France
CHU Rouen, F-76000 Rouen, France
Coussement, A:
Hop Cochin, AP HP, Serv Med Genom Malad Syst & Organes, Federat Genet & Med Genom, Paris, France
Collet, C:
Univ Paris Cite, Imagine Inst, INSERM, U1163, Paris, France
Univ Paris Cite, Hop Necker Enfants Malad, Assistance Publ Hop Paris, Fac Med,Serv Med Genom Malad Rares, Paris, France
Herenger, Y:
Genet AG, Human Genet & Genet Counselling Unit, Zurich, Switzerland
Defrance, M:
Univ Libre Bruxelles, Interuniv Inst Bioinformat Brussels, Brussels, Belgium
Cormier-Daire, V:
Univ Paris Cite, Imagine Inst, INSERM, U1163, Paris, France
Univ Paris Cite, Hop Necker Enfants Malad, Assistance Publ Hop Paris, Fac Med,Serv Med Genom Malad Rares, Paris, France
Charbonnier, C:
Normandie Univ, Univ Rouen Normandie, Reference Ctr Dev Abnormal, Inserm,U1245, F-76000 Rouen, France
CHU Rouen, F-76000 Rouen, France
Normandie Univ, Univ Rouen Normandie, Dept Biostat, Inserm,U1245, Rouen, France
de Dieuleveult, M:
Univ Paris Cite, Imagine Inst, INSERM, U1163, Paris, France
Green Submitted, gold
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