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

Identification of an episignature for CHD3-related Snijders Blok-Campeau syndrome reveals heterogeneity in the CHARGE syndrome episignature: towards a better characterization of chromatinopathies. | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Identification of an episignature for CHD3-related Snijders Blok-Campeau syndrome reveals heterogeneity in the CHARGE syndrome episignature: towards a better characterization of chromatinopathies. Amandine Santini, Angelo Tognon, Anne-Claire Richard, Guillaume Velasco, and 35 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6706576/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract 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. A European cohort of 22 patients displaying typical Snijders Blok-Campeau syndrome traits and carrying pathogenic/likely pathogenic CHD3 variants was analysed using the Illumina EPIC array, identifying 139 differentially methylated positions distinguishing patients from 79 healthy matched controls. These regions serve as diagnostic tools for complex cases or variants of uncertain significance and help uncover deregulated pathways linked to this syndrome. Three patients carrying pathogenic/likely pathogenic variants but atypical clinical presentation as well as 5 patients with variants of uncertain significance were analysed as testing set. Comparing methylomes of patients carrying pathogenic variants in CHD3, CHD7 (CHARGE syndrome, ORPHA:138), or CHD8 (Intellectual developmental disorder with autism and macrocephaly, ORPHA:642675) genes allows us to identify distinct subgroups with unique methylation profiles. This robust CHD3 DNA methylation signature aids in reclassifying variants and diagnosing atypical cases. 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. Rare Diseases CHD3 episignature DNA methylation Figures Figure 1 Figure 2 Figure 3 Figure 4 Full Text Additional Declarations Tables 1 to 5 are available in the Supplementary Files section. No competing interests reported. Supplementary Files Table1CHD3patientphenotypes.xlsx Table2DMPandDMR.xlsx Table3CHD3CHD7CHD8clinicalsigns.xlsx Table4ListofpublishedDMPsforCHARGEandAUTS18.xlsx Table5CHD7patientclinicaltable.xlsx SupplementalinformationCHD3.docx Supplementaltable1TopenrichedbiologicalprocessesDMPs.xlsx 20250520SuppFigures.pptx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 05 Sep, 2025 Reviews received at journal 20 Jul, 2025 Reviews received at journal 06 Jul, 2025 Reviewers agreed at journal 04 Jul, 2025 Reviewers agreed at journal 22 Jun, 2025 Reviewers invited by journal 03 Jun, 2025 Editor assigned by journal 02 Jun, 2025 Submission checks completed at journal 21 May, 2025 First submitted to journal 20 May, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6706576","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":459656653,"identity":"034a06f6-9691-4d49-bda0-082ba0dd90cd","order_by":0,"name":"Amandine Santini","email":"","orcid":"","institution":"Univ Rouen Normandie, Normandie Univ, Inserm U1245","correspondingAuthor":false,"prefix":"","firstName":"Amandine","middleName":"","lastName":"Santini","suffix":""},{"id":459656654,"identity":"601d1438-d31c-44d4-9b8c-1de7b24a9487","order_by":1,"name":"Angelo Tognon","email":"","orcid":"","institution":"INSERM U1163, Université de Paris, Imagine Institute","correspondingAuthor":false,"prefix":"","firstName":"Angelo","middleName":"","lastName":"Tognon","suffix":""},{"id":459656655,"identity":"86ddc195-6361-4808-93a7-d6270f52b225","order_by":2,"name":"Anne-Claire Richard","email":"","orcid":"","institution":"Univ Rouen Normandie, Normandie Univ, Inserm U1245","correspondingAuthor":false,"prefix":"","firstName":"Anne-Claire","middleName":"","lastName":"Richard","suffix":""},{"id":459656656,"identity":"13ad654f-60b5-4e3e-85ad-001fafc3897c","order_by":3,"name":"Guillaume Velasco","email":"","orcid":"","institution":"Université Paris Cité, CNRS UMR7216","correspondingAuthor":false,"prefix":"","firstName":"Guillaume","middleName":"","lastName":"Velasco","suffix":""},{"id":459656658,"identity":"cd7facb2-b58b-41af-9b5b-8d8c3f6e12c7","order_by":4,"name":"Gilles Phan","email":"","orcid":"","institution":"Université Paris Cité, CNRS, UMR 8038","correspondingAuthor":false,"prefix":"","firstName":"Gilles","middleName":"","lastName":"Phan","suffix":""},{"id":459656659,"identity":"8edb862a-7e76-42da-a35a-0a8608265426","order_by":5,"name":"Pauline Marzin","email":"","orcid":"","institution":"Hôpital Necker - Enfants Malades, Assistance Publique - Hôpitaux de Paris, Université de Paris Cité","correspondingAuthor":false,"prefix":"","firstName":"Pauline","middleName":"","lastName":"Marzin","suffix":""},{"id":459656660,"identity":"c455d6b6-4da2-49b6-9f7b-87b30c28ff5e","order_by":6,"name":"Fabien Maury","email":"","orcid":"","institution":"INSERM U1163, Université de Paris, Imagine Institute","correspondingAuthor":false,"prefix":"","firstName":"Fabien","middleName":"","lastName":"Maury","suffix":""},{"id":459656662,"identity":"18495f68-b5b2-4567-a0e2-fd14c5170bbf","order_by":7,"name":"Angèle May","email":"","orcid":"","institution":"Univ Rouen Normandie, Normandie Univ, Inserm U1245","correspondingAuthor":false,"prefix":"","firstName":"Angèle","middleName":"","lastName":"May","suffix":""},{"id":459656664,"identity":"b1b479f1-aeda-4c23-af97-36e4efa6fb13","order_by":8,"name":"Caroline Michot","email":"","orcid":"","institution":"Hôpital Necker - Enfants Malades, Assistance Publique - Hôpitaux de Paris, Université de Paris Cité","correspondingAuthor":false,"prefix":"","firstName":"Caroline","middleName":"","lastName":"Michot","suffix":""},{"id":459656666,"identity":"5b19eb39-6f95-44ef-8474-e34ba7727fd3","order_by":9,"name":"Adela Chirita-Emandi","email":"","orcid":"","institution":"University of Medicine and Pharmacy \"Victor Babes\"","correspondingAuthor":false,"prefix":"","firstName":"Adela","middleName":"","lastName":"Chirita-Emandi","suffix":""},{"id":459656668,"identity":"628d18b0-b50e-4282-8439-394eb6ec626b","order_by":10,"name":"Jorge Saraiva","email":"","orcid":"","institution":"Hospital Pediátrico de Coimbra, Unidade Local de Saúde de Coimbra","correspondingAuthor":false,"prefix":"","firstName":"Jorge","middleName":"","lastName":"Saraiva","suffix":""},{"id":459656670,"identity":"fea2c82d-6057-4353-a55c-54393d06c10a","order_by":11,"name":"Maria Juliana Ballesta Martinez","email":"","orcid":"","institution":"Sección Genética Médica. 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U1245","correspondingAuthor":false,"prefix":"","firstName":"Camille","middleName":"","lastName":"Charbonnier","suffix":""},{"id":459656700,"identity":"c09b1464-5dc1-4617-942c-aabc731c47de","order_by":38,"name":"Maud de Dieuleveult","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABH0lEQVRIie3PsWqDQBjA8e84MEuw6xVL8gQFRbAO0me5Q3DKUCgEh6KRwvUNin2LdOtoOTCLxFXoEpdOHexS6NL2TgIdqsna4f5w4un98BNAp/unETDkVci1U9sJoB3dv+qOkv4kxtjeE5QfJMUvMQgcIOd3ldPAMgBzg0tCYzGzxUkZt0/J7OK+QLfxX+JVC9eHbQSnwogIrYRrC2w0TN6cvVCUVQOkWHgEcZGuxdQjjEds3RNesNyik3Y1QOo3Rb5BzvNB2FeUKnLFeJJKgrIh0vRfKSSZGoStAqoGA8YxJaPk9dqn21D9i+vTMnAeBHblhMLJLZYNkjp8bLrlJZi1aJvuhszNTda+f/JkTqzweYj00ZHnaAzodDqd7kg/UqNnwci5YagAAAAASUVORK5CYII=","orcid":"","institution":"INSERM U1163, Université de Paris, Imagine Institute","correspondingAuthor":true,"prefix":"","firstName":"Maud","middleName":"","lastName":"de Dieuleveult","suffix":""}],"badges":[],"createdAt":"2025-05-20 10:08:40","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6706576/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6706576/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":83438702,"identity":"e2875646-7af8-48d7-a939-12fa23ecd07a","added_by":"auto","created_at":"2025-05-26 09:05:35","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":271966,"visible":true,"origin":"","legend":"\u003cp\u003eA. Description of the cohort of individuals carrying pathogenic variants in the CHD3 gene B \u0026amp; C. Schematic diagram of the CHD3 protein depending on the severe, moderate and \u0026nbsp;mild clinical phenotype with the functional domains design with IBS 2.0 [42]. Missense \u0026nbsp;mutations are in yellow and truncated mutations are in black. \u0026nbsp;D. Mapping of CHD3 mutations. The mutated residues are in red sphere on the structural \u0026nbsp;model of CHD3 (AlphaFold code AF-Q12873-F1-v4: Chromo domain, Helicase domain, \u0026nbsp;Helicase C-term domain and CHDCT2 domain are in orange, dark green, green and cyan \u0026nbsp;respectively), superposed with the structure of the nucleosome complex with CHD1 in \u0026nbsp;blue (PDB code 5O9G). ATP analogue AMP-PNP (Adenylyl-imidodiphosphate) is shown in \u0026nbsp;yellow sphere. Structural details of highly conserved residues R966, R1169 and R1172 \u0026nbsp;show hydrogen bonds between R1169 and R1172 with ATP analogue in the active site of \u0026nbsp;Helicase domain.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6706576/v1/1f1e626bc9d0f881019da120.png"},{"id":83438696,"identity":"23f7aeef-af0a-483d-b5a3-f02259c745dc","added_by":"auto","created_at":"2025-05-26 09:05:35","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":302379,"visible":true,"origin":"","legend":"\u003cp\u003eA. Barplot representing the Gene Ontology (GO) enrichment analysis of differentially \u0026nbsp;methylated genes for DMPs of the CHD3 signature. The x-axis represents the number of \u0026nbsp;genes associated with each Biological Process category. The colour gradient indicates the \u0026nbsp;adjusted p-value, with lower p-values (higher significance) shown in pink and higher p-values in blue.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eB. Barplot representing the Gene Ontology (GO) enrichment analysis of differentially \u0026nbsp;methylated genes for DMRs of the CHD3 signature. The x-axis represents the number of \u0026nbsp;genes associated with each Biological Process category. The colour gradient indicates the \u0026nbsp;adjusted p-value, with lower p-values (higher significance) shown in pink and higher p-values in blue. \u0026nbsp;C. Principal component analysis of adjusted methylation levels, after correcting for \u0026nbsp;expected methylation based on age, sex, and estimated blood cell counts. Status is \u0026nbsp;indicated by colour: green for controls, red for CHD3 typical, purple for CHD3 atypical, \u0026nbsp;blue for CHD3 VUS, while phenotype is determined based on point size, with small points \u0026nbsp;representing controls, mild phenotypes, and not available; medium-sized points \u0026nbsp;representing moderate phenotypes; and large points representing severe phenotypes. \u0026nbsp;The percentage of explained variance is provided for each axis. \u0026nbsp;D. Heatmap of adjusted methylation levels displays hierarchical clustering of controls and \u0026nbsp;patients with CHD3 LP/P variants and CHD3 VUS. Blue indicates hypo-methylated \u0026nbsp;positions while red indicates hyper-methylated positions with respect to expected \u0026nbsp;methylation levels at equivalent age, sex and inferred blood cell composition. Status is \u0026nbsp;indicated by colour: green for controls, red for CHD3 typical, purple for CHD3 atypical, \u0026nbsp;and blue for CHD3 VUS. The technology used for each sample is also indicated: yellow for \u0026nbsp;EPIC v1 and orange for EPIC v2. E. Pathogenicity scores for each patient with CHD3 LP/P variants were obtained by leave-one-out, and pathogenicity scores for CHD3 atypical and CHD3 VUS were derived from a \u0026nbsp;prediction model based on the complete training set, using a support vector machine \u0026nbsp;predictor. Colours follow the same rules as in panels A and B.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6706576/v1/39fd4148e1980d6bc7dc59bd.png"},{"id":83438701,"identity":"67f073e4-4566-4059-b9f1-c1e212960f3c","added_by":"auto","created_at":"2025-05-26 09:05:35","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":386919,"visible":true,"origin":"","legend":"\u003cp\u003eA. Breakdown histogram showing the number of clinical phenotypes associated with each \u0026nbsp;disease based on data from the MONDO database (https://monarchinitiative.org/). B. Principal component analysis of adjusted methylation levels, after correcting for \u0026nbsp;expected methylation based on age, sex, and inferred blood cell composition. The probes \u0026nbsp;used correspond to the union of the CHD7, CHD8 (previously published), and CHD3 (newly identified DMPs) signatures. Status is indicated by colour: green for controls, red \u0026nbsp;for CHD3 typical patients, purple for CHD8 patients, and orange for CHD7 patients, with a \u0026nbsp;further separation into two subgroups among CHD7 patients, one of which is outlined in \u0026nbsp;black. \u0026nbsp;C. Heatmap of adjusted methylation levels, displaying hierarchical clustering of controls \u0026nbsp;and CHD3 typical, CHD8, and CHD7 patients. Hypomethylated regions are shown in blue, \u0026nbsp;while hypermethylated regions appear in red, relative to the expected methylation levels \u0026nbsp;for individuals of the same age, sex, and inferred blood cell composition. Colours follow \u0026nbsp;the same scheme as in the principal component analysis above. \u0026nbsp;D. Raincloud plot illustrating the distribution of adjusted methylation levels. For each \u0026nbsp;category, a mean methylation level is computed per block and per individual, generating \u0026nbsp;a density plot for each group. Below each density distribution, a boxplot visualises the \u0026nbsp;spread of individual data points. Colours follow the same scheme as in the plots on the \u0026nbsp;left. P-values were determined using the Wilcoxon test. Each patient category was \u0026nbsp;compared to the controls, and the two CHD7 subgroups were also compared to each other.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6706576/v1/3c5d4679e07f177df98d3109.png"},{"id":83438705,"identity":"5e4ed569-7e80-4025-b5c8-1a667826f5e3","added_by":"auto","created_at":"2025-05-26 09:05:35","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":163166,"visible":true,"origin":"","legend":"\u003cp\u003eA, B, C, D, E. IGV visualization examples showing DMPs, DMRs, and CHD3 ChIP-seq results \u0026nbsp;(public data, see Mat \u0026amp; Meth), which often colocalize at gene promoters. F. Venn diagram representing the common positions between DMPs and DMRs of the \u0026nbsp;CHD3 signature and CHD3 ChIP-seq. \u0026nbsp;G. Barplot representing the Gene Ontology (GO) enrichment analysis of differentially \u0026nbsp;methylated genes common to DMP probes, DMRs, and ChIP-seq. The x-axis represents the \u0026nbsp;number of genes associated with each Biological Process category. The colour gradient \u0026nbsp;indicates the adjusted p-value, with lower p-values (higher significance) shown in pink \u0026nbsp;and higher p-values in blue.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-6706576/v1/7ab373fd41f28c655ac0e85c.png"},{"id":83440088,"identity":"4df9753e-6cd2-47f1-a05d-afb453ef05d1","added_by":"auto","created_at":"2025-05-26 09:21:38","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":985792,"visible":true,"origin":"","legend":"","description":"","filename":"20250519CHD3manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6706576/v1_covered_e1ecd5a2-3c5a-4883-bca6-fabad8bb67e9.pdf"},{"id":83438700,"identity":"32850222-3aa3-425b-8553-aaaf33bdaed0","added_by":"auto","created_at":"2025-05-26 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09:05:35","extension":"xlsx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":8096,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementaltable1TopenrichedbiologicalprocessesDMPs.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6706576/v1/ddb06d6b2a77aaffc8cc3ce2.xlsx"},{"id":83438711,"identity":"8b7f4459-3b6a-4c3f-b788-896f46d31259","added_by":"auto","created_at":"2025-05-26 09:05:35","extension":"pptx","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":11723652,"visible":true,"origin":"","legend":"","description":"","filename":"20250520SuppFigures.pptx","url":"https://assets-eu.researchsquare.com/files/rs-6706576/v1/fb5214c48a1ba9f5b99f18f4.pptx"}],"financialInterests":"\u003cp\u003eTables 1 to 5 are available in the Supplementary Files section.\u003c/p\u003e\n\u003cp\u003eNo competing interests reported.\u003c/p\u003e","formattedTitle":"Identification of an episignature for CHD3-related Snijders Blok-Campeau syndrome reveals heterogeneity in the CHARGE syndrome episignature: towards a better characterization of chromatinopathies.","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"genome-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Genome Medicine](https://genomemedicine.biomedcentral.com/)","snPcode":"13073","submissionUrl":"https://submission.springernature.com/new-submission/13073/3","title":"Genome Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Rare Diseases, CHD3, episignature, DNA methylation","lastPublishedDoi":"10.21203/rs.3.rs-6706576/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6706576/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"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.\nDiseases 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.\nA European cohort of 22 patients displaying typical Snijders Blok-Campeau syndrome traits and carrying pathogenic/likely pathogenic CHD3 variants was analysed using the Illumina EPIC array, identifying 139 differentially methylated positions distinguishing patients from 79 healthy matched controls. These regions serve as diagnostic tools for complex cases or variants of uncertain significance and help uncover deregulated pathways linked to this syndrome. Three patients carrying pathogenic/likely pathogenic variants but atypical clinical presentation as well as 5 patients with variants of uncertain significance were analysed as testing set.\nComparing methylomes of patients carrying pathogenic variants in CHD3, CHD7 (CHARGE syndrome, ORPHA:138), or CHD8 (Intellectual developmental disorder with autism and macrocephaly, ORPHA:642675) genes allows us to identify distinct subgroups with unique methylation profiles. This robust CHD3 DNA methylation signature aids in reclassifying variants and diagnosing atypical cases.\nOur 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.","manuscriptTitle":"Identification of an episignature for CHD3-related Snijders Blok-Campeau syndrome reveals heterogeneity in the CHARGE syndrome episignature: towards a better characterization of chromatinopathies.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-26 09:05:30","doi":"10.21203/rs.3.rs-6706576/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-09-05T16:14:45+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-20T14:24:38+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-06T19:01:42+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"254847812853233567098349905466203111341","date":"2025-07-04T22:53:28+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"148497174524322341021310473194028450288","date":"2025-06-22T16:20:05+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-03T13:42:16+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-02T14:06:14+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-05-21T05:20:38+00:00","index":"","fulltext":""},{"type":"submitted","content":"Genome Medicine","date":"2025-05-20T10:05:31+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"genome-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Genome Medicine](https://genomemedicine.biomedcentral.com/)","snPcode":"13073","submissionUrl":"https://submission.springernature.com/new-submission/13073/3","title":"Genome Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"20eaded3-7697-4ab4-8aef-ee3b44b478f8","owner":[],"postedDate":"May 26th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-03-27T11:26:11+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-26 09:05:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6706576","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6706576","identity":"rs-6706576","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}