Under-recognized Cardiac Disease Burden in DDX3X Syndrome: Spectrum of Cardiovascular Abnormalities and Longitudinal Outcomes

Under-recognized Cardiac Disease Burden in DDX3X Syndrome: Spectrum of Cardiovascular Abnormalities and Longitudinal Outcomes | 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 Article Under-recognized Cardiac Disease Burden in DDX3X Syndrome: Spectrum of Cardiovascular Abnormalities and Longitudinal Outcomes Carlos Gallego-Navarro, Jeanne L. Theis, Radhika Dhamija, Lisa A. Schimmenti, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9059706/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Background DDX3X- syndrome is a rare neurodevelopmental disorder characterized by varying degrees of intellectual disability, predominantly affecting females. We present an institutional cohort supplemented by a systematic literature review, expanding the cardiovascular phenotype of DDX3X- syndrome. Methods We conducted a retrospective chart review of patients diagnosed with DDX3X -syndrome at Mayo Clinic. Additionally, we performed a systematic literature review to identify studies reporting cardiovascular abnormalities in patients with DDX3X -syndrome. Results A total of 200 patients with DDX3X -syndrome were analyzed, comprising 14 patients from our institutional cohort and 186 patients identified through a systematic review of 9 published studies. Our institutional cohort included 14 patients (12 females and 2 males) from 13 unrelated families diagnosed with DDX3X -syndrome, at a median age of 4.5 years (IQR 1.2–9.5). Echocardiogram was performed on nine patients, and cardiovascular abnormalities were found in 7 out of 9 patients who underwent echocardiography (78%), two of whom had major congenital heart defect (CHD) requiring surgical intervention. At the time of assessment, 13 individuals were still alive, while one had died at age six due to extracardiac complications. The systematic review included 9 studies involving 186 patients, of whom 32 (17.4%, 25 females and 7 males) had reported cardiovascular abnormalities, ranging from simple CHDs to more complex defects. Conclusion DDX3X -syndrome carries a significant cardiovascular burden, which is possibly higher than previously reported, including complex congenital heart disease requiring surgical repair. A thorough cardiovascular assessment, including an electrocardiogram and echocardiogram, should be universally recommended for all patients at the time of diagnosis. Health sciences/Cardiology Health sciences/Diseases Health sciences/Medical research DDX3X protein DDX3X syndrome X-linked genetic disease Neurodevelopmental disorder Intellectual disability rare diseases Congenital heart defects Full Text Additional Declarations No competing interests reported. Supplementary Files Supplementalfilefiguresandtables3.pdf Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 12 May, 2026 Reviews received at journal 05 May, 2026 Reviewers agreed at journal 05 May, 2026 Reviews received at journal 04 May, 2026 Reviewers agreed at journal 15 Apr, 2026 Reviewers agreed at journal 31 Mar, 2026 Reviewers invited by journal 30 Mar, 2026 Editor assigned by journal 29 Mar, 2026 Submission checks completed at journal 10 Mar, 2026 First submitted to journal 07 Mar, 2026 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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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-9059706","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":615400661,"identity":"2ba9ba04-1b9d-4848-98b1-2202e30a0be0","order_by":0,"name":"Carlos Gallego-Navarro","email":"","orcid":"","institution":"Mayo Clinic","correspondingAuthor":false,"prefix":"","firstName":"Carlos","middleName":"","lastName":"Gallego-Navarro","suffix":""},{"id":615400662,"identity":"7423668e-b215-4047-a98a-248c9b6fb614","order_by":1,"name":"Jeanne L. 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We present an institutional cohort supplemented by a systematic literature review, expanding the cardiovascular phenotype of \u003cem\u003eDDX3X-\u003c/em\u003esyndrome.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe conducted a retrospective chart review of patients diagnosed with \u003cem\u003eDDX3X\u003c/em\u003e-syndrome at Mayo Clinic. Additionally, we performed a systematic literature review to identify studies reporting cardiovascular abnormalities in patients with \u003cem\u003eDDX3X\u003c/em\u003e-syndrome.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 200 patients with \u003cem\u003eDDX3X\u003c/em\u003e-syndrome were analyzed, comprising 14 patients from our institutional cohort and 186 patients identified through a systematic review of 9 published studies. Our institutional cohort included 14 patients (12 females and 2 males) from 13 unrelated families diagnosed with \u003cem\u003eDDX3X\u003c/em\u003e-syndrome, at a median age of 4.5 years (IQR 1.2\u0026ndash;9.5). Echocardiogram was performed on nine patients, and cardiovascular abnormalities were found in 7 out of 9 patients who underwent echocardiography (78%), two of whom had major congenital heart defect (CHD) requiring surgical intervention. At the time of assessment, 13 individuals were still alive, while one had died at age six due to extracardiac complications. The systematic review included 9 studies involving 186 patients, of whom 32 (17.4%, 25 females and 7 males) had reported cardiovascular abnormalities, ranging from simple CHDs to more complex defects.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003e \u003cem\u003eDDX3X\u003c/em\u003e-syndrome carries a significant cardiovascular burden, which is possibly higher than previously reported, including complex congenital heart disease requiring surgical repair. A thorough cardiovascular assessment, including an electrocardiogram and echocardiogram, should be universally recommended for all patients at the time of diagnosis.\u003c/p\u003e","manuscriptTitle":"Under-recognized Cardiac Disease Burden in DDX3X Syndrome: Spectrum of Cardiovascular Abnormalities and Longitudinal Outcomes","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-01 20:11:38","doi":"10.21203/rs.3.rs-9059706/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"255956767758786557207666153747081547862","date":"2026-05-13T00:30:32+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-05T15:02:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"259750690321077102664981683334184027516","date":"2026-05-05T14:49:25+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-04T15:47:29+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"48570365522308370344653321793242801793","date":"2026-04-15T21:01:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"242914371074474225948212616128983707196","date":"2026-03-31T10:41:51+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-30T15:17:41+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-29T04:04:16+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-10T04:40:48+00:00","index":"","fulltext":""},{"type":"submitted","content":"npj Genomic Medicine","date":"2026-03-07T15:51:35+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"npj-genomic-medicine","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"npjgenmed","sideBox":"Learn more about [npj Genomic Medicine](http://www.nature.com/npjgenmed/)","snPcode":"41525","submissionUrl":"https://mts-npjgenmed.nature.com/","title":"npj Genomic Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"NPJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"580a0c30-46e7-49ca-ad14-f69057cd48e9","owner":[],"postedDate":"April 1st, 2026","published":true,"recentEditorialEvents":[{"type":"reviewerAgreed","content":"255956767758786557207666153747081547862","date":"2026-05-13T00:30:32+00:00","index":108,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-05T15:02:48+00:00","index":107,"fulltext":""},{"type":"reviewerAgreed","content":"259750690321077102664981683334184027516","date":"2026-05-05T14:49:25+00:00","index":106,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-04T15:47:29+00:00","index":91,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":65481823,"name":"Health sciences/Cardiology"},{"id":65481824,"name":"Health sciences/Diseases"},{"id":65481825,"name":"Health sciences/Medical research"}],"tags":[],"updatedAt":"2026-04-01T20:11:38+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-01 20:11:38","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9059706","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9059706","identity":"rs-9059706","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}