Case report: Tripartite dissociation in survivors of sudden cardiac death—Diagnostic challenges of a long QT syndrome phenotype with structurally normal hearts and a DSP gene variant

Case report: Tripartite dissociation in survivors of sudden cardiac death—Diagnostic challenges of a long QT syndrome phenotype with structurally normal hearts and a DSP gene variant | 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 Case Report Case report: Tripartite dissociation in survivors of sudden cardiac death—Diagnostic challenges of a long QT syndrome phenotype with structurally normal hearts and a DSP gene variant Bin Ni, Yuchen Ye, Hailan Hu, Peng Dong This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6399080/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Etiological identification in young survivors of exercise-induced sudden cardiac death (SCD) frequently encounter challenges due to phenotype-genotype incongruity. Case presentation: We present a 21-year-old female survivor of aborted SCD caused by exercise-triggered ventricular fibrillation (VF). Comprehensive imaging studies ( echocardiography and cardiac magnetic resonance ) revealed no structural abnormalities. Ambulatory electrocardiography demonstrated prolonged QTc intervals (Schwartz score: 4.5), fulfilling the diagnostic criteria for long QT syndrome (LQTS). Intriguingly, the electrocardiographic findings also satisfied depolarization/repolarization abnormality indices per the 2010 revised Task Force Criteria for arrhythmogenic right ventricular cardiomyopathy (ARVC). Whole-exome sequencing identified heterozygous variants in the DSP (desmoplakin) and CFHR5 (complement factor H-related 5) genes, whereas no pathogenic variants were detected in 17 canonical LQTS-associated genes. Despite favourable outcomes with beta-blocker therapy, the exact trigger for VF remains elusive: the DSP variant suggests potential ARVC-related myocardial electrical substrate abnormalities, whereas the pathogenic importance of the CFHR5 variant in cardiomyopathy remains unestablished. Furthermore, the borderline LQTS phenotype lacked definitive genetic corroboration. Conclusions This case illustrates a "tripartite dissociation" among electrophysiological phenotype, cardiac structure, and genetic findings, challenging conventional disease classification frameworks in young SCD survivors. Prioritizing functional studies to investigate potential polygenic synergy in arrhythmogenesis may advance diagnostic paradigms and personalized SCD prevention strategies for atypical cases. Sudden cardiac death Long QT syndrome DSP gene CFHR5 gene Phenotype-genotype dissociation Figures Figure 1 Figure 2 Figure 3 Background Exercise-induced ventricular fibrillation (VF) constitutes a primary mechanism of sudden cardiac death (SCD) in young individuals, and is typically attributed to inherited ion channelopathies (e.g., long QT syndrome) or structural cardiomyopathies (e.g., arrhythmogenic right ventricular cardiomyopathy). However, clinical decision-making becomes complex when patients fulfill diagnostic criteria for multiple conditions but lack definitive structural or genetic evidence. For example, LQTS patients diagnosed via the Schwartz criteria frequently encounter diagnostic criteria, with approximately 25% of clinically diagnosed cases remaining genetically elusive[ 1 ]. The revised 2010 Task Force Criteria (TFC) permit diagnosis on the basis of electrocardiographic (ECG) and arrhythmic features even without overt structural abnormalities[ 2 , 3 ]. Recent studies suggest that desmosomal gene variants (e.g., DSPs) not only drive fibrofatty infiltration in ARVC but also alter myocardial coupling and ion channel function, creating a substrate for repolarization heterogeneity and arrhythmias[ 4 , 5 ]. This report describes a young SCD survivor with overlapping LQTS (Schwartz score: 4.5) and ARVC diagnostic criteria, but normal cardiac structure and the absence of canonical pathogenic mutations. By exploring the interplay between electrophysiological abnormalities and DSP variants, we challenge the prevailing "single-disease" diagnostic paradigm and propose that polygenic microeffects may underlie malignant arrhythmia susceptibility in atypical cases, guiding personalized SCD prevention strategies. Case Presentation A 21-year-old female SCD survivor was retrospectively analysed. The patient collapsed during a morning jog, losing consciousness without prodromal symptoms (e.g., seizures, incontinence). Bystanders initiated CPR and delivered two AED shocks. Emergency services recorded VF, administering amiodarone and achieving return of spontaneous circulation (ROSC) after repeated defibrillation. Upon admission, she was comatose (GCS 3) with no pupillary reflexes. Postresuscitation management included mechanical ventilation, esmolol infusion, and EICU monitoring. The patient was previously healthy and denied a history of sudden death or hereditary heart disease in the family. Examinations: ECG revealed sinus tachycardia, a QTc of 532ms (Bazett’s formula[ 6 ]), a reduced R-wave amplitude in V5–V6 and inferior leads, and T-wave inversion in precordial leads (Fig. 2 ). Holter: Frequent atrial ectopy, prolonged QT (390–610 ms), and one ventricular premature complex. Echocardiography/cardiac MRI revealed normal biventricular structure and function (LVEF 56% at follow-up). Laboratory tests revealed elevated cardiac enzymes (CK-MB 14.04 U/L, troponin-I normal) and lactate (14.6 mmol/L), ruling out metabolic or infectious triggers. Whole-exome sequencing (WES): revealed two variants of uncertain significance: DSP (NM_004415): c.2793 + 14T > G (heterozygous). CFHR5 (NM_030787.4): c.120C > A (p.Asn40Lys). No pathogenic mutations were detected in 17 LQTS-associated genes. Diagnostic criteria : LQTS: Schwartz score[ 7 ] 4.5 (QTc > 480 ms: 3.5 points; syncope without triggers: 1 point). ARVC: Met two major criteria (2010 Task Force): DSP variant (desmosomal gene). Diffuse T-wave inversion (Fig. 3 ). Endomyocardial biopsy was declined, and imaging revealed no right ventricular abnormalities. Discussion This case exemplifies the diagnostic complexity of overlapping channelopathy and cardiomyopathy phenotypes. While the patient met both the LQTS and ARVC criteria[ 2 ], the absence of structural abnormalities and canonical mutations[ 8 , 9 ] challenges traditional classifications. The DSP variant, although unclassified, may disrupt intercellular coupling and ion channel function, synergizing with latent repolarization abnormalities to precipitate VFs. Notably, amiodarone use during resuscitation complicates QT interpretation, but persistent QTc prolongation postrecovery supports intrinsic electrical pathology. LQTS is an autosomal dominant inherited primary arrhythmia disorder characterized by a prolonged QT interval on electrocardiogram (ECG), syncope, and an increased risk of sudden death due to polymorphic ventricular tachycardia (e.g., torsade’s de pointes). The diagnosis relies primarily on ECG findings: corrected QTc intervals > 450 ms in males and > 470 ms in females, often accompanied by delayed myocardial repolarization. Although mutations in ion channel genes are the most common etiology, approximately 20–25% of clinically diagnosed LQTS cases yield negative genetic testing results[ 1 ]. This "genotype-negative" phenomenon may stem from limitations in current detection methods (e.g., noncoding variants or large deletions not covered), polygenic interactions, or epigenetic dysregulation[ 10 , 11 ]. Even with whole-exome sequencing or functional studies, a significant proportion of LQTS patients lack identifiable monogenic causes, suggesting a potential polygenic contribution to arrhythmia susceptibility. Recent case-control studies indicate that a high polygenic risk score for QTc prolongation increases the likelihood of LQTS, particularly in patients without monogenic mutations. Thus, for genotype-negative LQTS patients, dynamic ECG monitoring, family screening (to detect low-penetrance variants), and long-term follow-up are critical, with diagnosis relying on clinical criteria rather than genetic confirmation. In this case, the Schwartz score played a pivotal role in confirming LQTS. Therapeutically, beta-blockers (e.g., propranolol) remain first-line empirical therapy, reducing repolarization dispersion and suppressing adrenergically triggered arrhythmias, even in genotype-negative patients[ 12 ]. For SCD survivors or high-risk LQTS patients with recurrent syncope despite beta-blocker therapy, implantable cardioverter-defibrillator (ICD) implantation is lifesaving[ 13 ]. ARVC is a genetic cardiomyopathy marked by progressive fibrofatty replacement of the right ventricular myocardium, with an estimated prevalence of 1:5,000–1:2,000[ 14 , 15 ]. The disease typically follows an insidious course, manifesting as ventricular arrhythmias, right ventricular dysfunction, heart failure, or SCD, particularly in young athletes[ 16 , 17 ]. Pathogenic variants in desmosomal genes (e.g., PKP2 , DSP , DSC2 , DSG2 , and JUP ) account for most reported ARVC cases[ 18 ]. Notably, DSP variants are associated with severe phenotypes, including increased risks of ventricular arrhythmias, SCD, and left ventricular involvement. However, genotype-phenotype discordance is common in young SCD survivors: some patients exhibit structural abnormalities on imaging without electrophysiological derangements, whereas others develop life-threatening arrhythmias before detectable histological or imaging changes[ 19 ]. Furthermore, genotype-positive ARVC patients may lack typical clinical features, and DSP variants exhibit marked phenotypic heterogeneity, even among carriers of identical mutations owing to incomplete penetrance[ 20 ]. Early-stage ARVC may present with malignant arrhythmias despite minimal structural remodelling. Consequently, identifying a DSP variant (even a pathogenic or likely pathogenic variant) in a patient with ARVC features strongly suggests cardiomyopathy but does not fully predict clinical manifestations or disease progression[ 21 ]. This underscores the challenges in the clinical interpretation of DSP variants, necessitating comprehensive evaluation of patient-specific factors. The patient in this case experienced sudden cardiac death (SCD) during exercise. Retrospective analysis revealed clinical features overlapping those of long QT syndrome (LQTS) and arrhythmogenic right ventricular cardiomyopathy (ARVC). Both the automated external defibrillator (AED) and hospital monitoring recorded ventricular fibrillation (VF) as the terminal arrhythmia during resuscitation. However, it remains uncertain whether torsades de pointes (TdP) serve as the triggering mechanism prior to syncope and SCD. Specifically, the debate centers on whether the fatal event originated from TdP secondary to LQTS progressing to VF or from malignant ventricular arrhythmias caused by DSP-related cardiomyopathy. Current evidence cannot definitively resolve this question. Notably, the CFHR5 gene variant identified in this case lacked documented associations with arrhythmias or SCD in the literature, leaving its pathogenicity unclear. However, further studies are needed to explore whether CFHR5 variants may contribute to arrhythmogenic risk. Conclusions This case exemplifies a unique "triad paradox": electrocardiographic features suggesting LQTS, genetic evidence pointing to ARVC, and normal cardiac structure on imaging. This complexity underscores the necessity for multidisciplinary evaluation in young SCD survivors, avoiding rigid adherence to single-disease classifications. Emerging evidence supports the "polygenic microeffect" model[ 22 , 23 ], where multiple weakly pathogenic variants collectively increase susceptibility to malignant arrhythmias. This model may explain some genetically elusive SCD cases and highlights the value of functional validation via patient-specific induced pluripotent stem cell (iPSC) cardiomyocyte models. Clinical management should emphasize individualized risk stratification, incorporating strict exercise restrictions, pharmacotherapy (e.g., β-blockers for LQT1), and early ICD implantation when warranted. This case provides critical insights for managing complex arrhythmia syndromes, although further mechanistic studies and case accumulation remain essential to clarify such overlapping phenotypes. Declarations Acknowledgements Not applicable. Author contributions YYY and HLH were major contributors to the conception, review and analysis of medical records. BN was a major contributor to the writing of the article. DP was a major contributor to the critical revision of the article. All the authors read and approved the final manuscript. Funding This work was supported by the Hangzhou Biomedicine and Health Industry Development Support Science and Technology Special Project (6th Phase) [Grant No. 2022WJC036] Data availability The datasets used and/or analysed during the current study are available from the corresponding author upon reasonable request. Ethics approval and consent to participate This study was approved by the Ethics Committee of Hangzhou Normal University Affiliated Hospital (Protocol No.: 2025(E2)-KS-110), and informed consent was obtained from the patients. Clinical trial number: not applicable. Consent for publication Written informed consent was obtained from the patient for the publication of the case report and accompanying images. Competing interests The authors declare that they have no competing interests. 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Desmoplakin Cardiomyopathy, a Fibrotic and Inflammatory Form of Cardiomyopathy Distinct From Typical Dilated or Arrhythmogenic Right Ventricular Cardiomyopathy. Circulation. 2020;141(23):1872–84. Garcia-Gras E, Lombardi R, Giocondo MJ, Willerson JT, Schneider MD, Khoury DS, Marian AJ. Suppression of canonical Wnt/beta-catenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy. J Clin Investig. 2006;116(7):2012–21. Beach SR, Celano CM, Noseworthy PA, Januzzi JL, Huffman JC. QTc prolongation, torsades de pointes, and psychotropic medications. Psychosomatics. 2013;54(1):1–13. Schwartz PJ, Crotti L, Insolia R. Long-QT syndrome: from genetics to management. Circulation Arrhythmia Electrophysiol. 2012;5(4):868–77. Wilde AAM, Semsarian C, Márquez MF, Shamloo AS, Ackerman MJ, Ashley EA, Sternick EB, Barajas-Martinez H, Behr ER, Bezzina CR et al. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases. Europace: European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology 2022, 24(8):1307–1367. Bohnen MS, Peng G, Robey SH, Terrenoire C, Iyer V, Sampson KJ, Kass RS. Molecular Pathophysiology of Congenital Long QT Syndrome. Physiol Rev. 2017;97(1):89–134. Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C, Blom N, Brugada J, Chiang CE, Huikuri H, et al. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart rhythm. 2013;10(12):1932–63. Schwartz PJ, Stramba-Badiale M, Crotti L, Pedrazzini M, Besana A, Bosi G, Gabbarini F, Goulene K, Insolia R, Mannarino S, et al. Prevalence of the congenital long-QT syndrome. Circulation. 2009;120(18):1761–7. Priori SG, Schwartz PJ, Napolitano C, Bloise R, Ronchetti E, Grillo M, Vicentini A, Spazzolini C, Nastoli J, Bottelli G, et al. Risk stratification in the long-QT syndrome. N Engl J Med. 2003;348(19):1866–74. Al-Khatib SM, Stevenson WG, Ackerman MJ, Bryant WJ, Callans DJ, Curtis AB, Deal BJ, Dickfeld T, Field ME, Fonarow GC, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2018;72(14):e91–220. Altmayer S, Nazarian S, Han Y. Left Ventricular Dysfunction in Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC): Can We Separate ARVC From Other Arrhythmogenic Cardiomyopathies? J Am Heart Association. 2020;9(23):e018866. de la Guía-Galipienso F, Ugedo-Alzaga K, Grazioli G, Quesada-Ocete FJ, Feliu-Rey E, Perez MV, Quesada-Dorador A, Sanchis-Gomar F. Arrhythmogenic Cardiomyopathy and Athletes: A Dangerous Relationship. Curr Probl Cardiol. 2023;48(9):101799. Ruwald AC, Marcus F, Estes NA 3rd, Link M, McNitt S, Polonsky B, Calkins H, Towbin JA, Moss AJ, Zareba W. Association of competitive and recreational sport participation with cardiac events in patients with arrhythmogenic right ventricular cardiomyopathy: results from the North American multidisciplinary study of arrhythmogenic right ventricular cardiomyopathy. Eur Heart J. 2015;36(27):1735–43. Emery MS, Kovacs RJ. Sudden Cardiac Death in Athletes. JACC Heart Fail. 2018;6(1):30–40. James CA, Jongbloed JDH, Hershberger RE, Morales A, Judge DP, Syrris P, Pilichou K, Domingo AM, Murray B, Cadrin-Tourigny J, et al. International Evidence Based Reappraisal of Genes Associated With Arrhythmogenic Right Ventricular Cardiomyopathy Using the Clinical Genome Resource Framework. Circulation Genomic precision Med. 2021;14(3):e003273. Steinmetz M, Krause U, Lauerer P, Konietschke F, Aguayo R, Ritter CO, Schuster A, Lotz J, Paul T, Staab W. Diagnosing ARVC in Pediatric Patients Applying the Revised Task Force Criteria: Importance of Imaging, 12-Lead ECG, and Genetics. Pediatr Cardiol. 2018;39(6):1156–64. Basso C, Corrado D, Bauce B, Thiene G. Arrhythmogenic right ventricular cardiomyopathy. Circulation Arrhythmia Electrophysiol. 2012;5(6):1233–46. Arbelo E, Protonotarios A, Gimeno JR, Arbustini E, Barriales-Villa R, Basso C, Bezzina CR, Biagini E, Blom NA, de Boer RA, et al. : 2023 ESC Guidelines for the management of cardiomyopathies. Eur Heart J. 2023;44(37):3503–626. Neubauer J, Haas C, Bartsch C, Medeiros-Domingo A, Berger W. Post-mortem whole-exome sequencing (WES) with a focus on cardiac disease-associated genes in five young sudden unexplained death (SUD) cases. Int J Legal Med. 2016;130(4):1011–21. Ye JZ, Delmar M, Lundby A, Olesen MS. Reevaluation of genetic variants previously associated with arrhythmogenic right ventricular cardiomyopathy integrating population-based cohorts and proteomics data. Clin Genet. 2019;96(6):506–14. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted 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. 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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-6399080","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":448671887,"identity":"217341a8-e1c3-4ee6-beed-1cf8292f5659","order_by":0,"name":"Bin Ni","email":"","orcid":"","institution":"Affiliated Hospital of Hangzhou Normal University","correspondingAuthor":false,"prefix":"","firstName":"Bin","middleName":"","lastName":"Ni","suffix":""},{"id":448671888,"identity":"f7ff1192-2855-48ae-a88e-4ff929820fe5","order_by":1,"name":"Yuchen Ye","email":"","orcid":"","institution":"Affiliated Hospital of Hangzhou Normal University","correspondingAuthor":false,"prefix":"","firstName":"Yuchen","middleName":"","lastName":"Ye","suffix":""},{"id":448671889,"identity":"7072dc26-4f4b-4def-9741-cc8bbada340b","order_by":2,"name":"Hailan Hu","email":"","orcid":"","institution":"Affiliated Hospital of Hangzhou Normal University","correspondingAuthor":false,"prefix":"","firstName":"Hailan","middleName":"","lastName":"Hu","suffix":""},{"id":448671890,"identity":"61ed68ac-e683-4a8e-b42b-1b46fdce637e","order_by":3,"name":"Peng Dong","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzUlEQVRIiWNgGAWjYBAC+wPnHz9I/MNmx9jeQKyeg2fYDB428CUz9xwgVsvhMwySDxvkGNtnJBCpg7Ht7AGDxB1mzLwzH2+8wVBjE01QCzPPuYQHiWfS+CRnpxVbMBxLy20gpIVN4oCBQQLbMWbD2TlmEowNhwlr4ZF/YCCRwPafcf/NM0RqkWA4YyCR2MbG2DiDh0gtBkDnGyScYUtm7AH6JYEYvxgwHD788EcFKCoPb7zxocaGsBYU7RIJpCiHaCFVxygYBaNgFIwMAABhDER3PnUcggAAAABJRU5ErkJggg==","orcid":"","institution":"Affiliated Hospital of Hangzhou Normal University","correspondingAuthor":true,"prefix":"","firstName":"Peng","middleName":"","lastName":"Dong","suffix":""}],"badges":[],"createdAt":"2025-04-08 04:23:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6399080/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6399080/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":82136558,"identity":"939f2922-f8fe-4a03-9127-c2991fc69e48","added_by":"auto","created_at":"2025-05-07 06:13:45","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":287598,"visible":true,"origin":"","legend":"\u003cp\u003eECG of partial ventricular fibrillation on an AED\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6399080/v1/55f04f3eda3e1e3d6d229614.png"},{"id":82136561,"identity":"15fab5f6-2aa5-4f18-9c7d-267dc63417ba","added_by":"auto","created_at":"2025-05-07 06:13:45","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":525165,"visible":true,"origin":"","legend":"\u003cp\u003eThe first 12-lead electrocardiogram (2024-5-15 10: 22) at admission revealed QTc prolongation.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6399080/v1/cf3807f6647808de62dab062.png"},{"id":82136563,"identity":"a5500fbc-5d3e-4d53-b6cf-ba2da1b01b6a","added_by":"auto","created_at":"2025-05-07 06:13:45","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":599116,"visible":true,"origin":"","legend":"\u003cp\u003eThe electrocardiogram (2024-5-16) on the second day of admission revealed QTc prolongation. The T-waves in leads II, III, avF and V1-V6 were inverted.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6399080/v1/2f5e0f04010d84e8b0a48c09.png"},{"id":82793180,"identity":"f00e1b0e-3069-4c2b-b8b4-ab6c6d0dab41","added_by":"auto","created_at":"2025-05-15 10:24:04","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1909553,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6399080/v1/88b4872c-f76a-4d7b-bbb3-220ec6b12ac5.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Case report: Tripartite dissociation in survivors of sudden cardiac death—Diagnostic challenges of a long QT syndrome phenotype with structurally normal hearts and a DSP gene variant","fulltext":[{"header":"Background","content":"\u003cp\u003eExercise-induced ventricular fibrillation (VF) constitutes a primary mechanism of sudden cardiac death (SCD) in young individuals, and is typically attributed to inherited ion channelopathies (e.g., long QT syndrome) or structural cardiomyopathies (e.g., arrhythmogenic right ventricular cardiomyopathy). However, clinical decision-making becomes complex when patients fulfill diagnostic criteria for multiple conditions but lack definitive structural or genetic evidence. For example, LQTS patients diagnosed via the Schwartz criteria frequently encounter diagnostic criteria, with approximately 25% of clinically diagnosed cases remaining genetically elusive[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The revised 2010 Task Force Criteria (TFC) permit diagnosis on the basis of electrocardiographic (ECG) and arrhythmic features even without overt structural abnormalities[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Recent studies suggest that desmosomal gene variants (e.g., DSPs) not only drive fibrofatty infiltration in ARVC but also alter myocardial coupling and ion channel function, creating a substrate for repolarization heterogeneity and arrhythmias[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. This report describes a young SCD survivor with overlapping LQTS (Schwartz score: 4.5) and ARVC diagnostic criteria, but normal cardiac structure and the absence of canonical pathogenic mutations. By exploring the interplay between electrophysiological abnormalities and DSP variants, we challenge the prevailing \"single-disease\" diagnostic paradigm and propose that polygenic microeffects may underlie malignant arrhythmia susceptibility in atypical cases, guiding personalized SCD prevention strategies.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eA 21-year-old female SCD survivor was retrospectively analysed. The patient collapsed during a morning jog, losing consciousness without prodromal symptoms (e.g., seizures, incontinence). Bystanders initiated CPR and delivered two AED shocks. Emergency services recorded VF, administering amiodarone and achieving return of spontaneous circulation (ROSC) after repeated defibrillation. Upon admission, she was comatose (GCS 3) with no pupillary reflexes. Postresuscitation management included mechanical ventilation, esmolol infusion, and EICU monitoring. The patient was previously healthy and denied a history of sudden death or hereditary heart disease in the family.\u003c/p\u003e\n\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003eExaminations:\u003c/h2\u003e\n \u003cp\u003eECG revealed sinus tachycardia, a QTc of 532ms (Bazett\u0026rsquo;s formula[\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e]), a reduced R-wave amplitude in V5\u0026ndash;V6 and inferior leads, and T-wave inversion in precordial leads (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003eHolter: Frequent atrial ectopy, prolonged QT (390\u0026ndash;610 ms), and one ventricular premature complex.\u003c/p\u003e\n \u003cp\u003eEchocardiography/cardiac MRI revealed normal biventricular structure and function (LVEF 56% at follow-up).\u003c/p\u003e\n \u003cp\u003eLaboratory tests revealed elevated cardiac enzymes (CK-MB 14.04 U/L, troponin-I normal) and lactate (14.6 mmol/L), ruling out metabolic or infectious triggers.\u003c/p\u003e\n \u003cp\u003eWhole-exome sequencing (WES): revealed two variants of uncertain significance: DSP (NM_004415): c.2793\u0026thinsp;+\u0026thinsp;14T\u0026thinsp;\u0026gt;\u0026thinsp;G (heterozygous). CFHR5 (NM_030787.4): c.120C\u0026thinsp;\u0026gt;\u0026thinsp;A (p.Asn40Lys). No pathogenic mutations were detected in 17 LQTS-associated genes.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Heading\"\u003e\u003cstrong\u003eDiagnostic criteria\u003c/strong\u003e:\u003c/div\u003e\n\u003cp\u003eLQTS: Schwartz score[\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e] 4.5 (QTc\u0026thinsp;\u0026gt;\u0026thinsp;480 ms: 3.5 points; syncope without triggers: 1 point).\u003c/p\u003e\n\u003cp\u003eARVC: Met two major criteria (2010 Task Force): DSP variant (desmosomal gene). Diffuse T-wave inversion (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). Endomyocardial biopsy was declined, and imaging revealed no right ventricular abnormalities.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis case exemplifies the diagnostic complexity of overlapping channelopathy and cardiomyopathy phenotypes. While the patient met both the LQTS and ARVC criteria[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], the absence of structural abnormalities and canonical mutations[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] challenges traditional classifications. The \u003cem\u003eDSP\u003c/em\u003e variant, although unclassified, may disrupt intercellular coupling and ion channel function, synergizing with latent repolarization abnormalities to precipitate VFs. Notably, amiodarone use during resuscitation complicates QT interpretation, but persistent QTc prolongation postrecovery supports intrinsic electrical pathology.\u003c/p\u003e \u003cp\u003eLQTS is an autosomal dominant inherited primary arrhythmia disorder characterized by a prolonged QT interval on electrocardiogram (ECG), syncope, and an increased risk of sudden death due to polymorphic ventricular tachycardia (e.g., torsade\u0026rsquo;s de pointes). The diagnosis relies primarily on ECG findings: corrected QTc intervals\u0026thinsp;\u0026gt;\u0026thinsp;450 ms in males and \u0026gt;\u0026thinsp;470 ms in females, often accompanied by delayed myocardial repolarization. Although mutations in ion channel genes are the most common etiology, approximately 20\u0026ndash;25% of clinically diagnosed LQTS cases yield negative genetic testing results[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. This \"genotype-negative\" phenomenon may stem from limitations in current detection methods (e.g., noncoding variants or large deletions not covered), polygenic interactions, or epigenetic dysregulation[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Even with whole-exome sequencing or functional studies, a significant proportion of LQTS patients lack identifiable monogenic causes, suggesting a potential polygenic contribution to arrhythmia susceptibility. Recent case-control studies indicate that a high polygenic risk score for QTc prolongation increases the likelihood of LQTS, particularly in patients without monogenic mutations. Thus, for genotype-negative LQTS patients, dynamic ECG monitoring, family screening (to detect low-penetrance variants), and long-term follow-up are critical, with diagnosis relying on clinical criteria rather than genetic confirmation. In this case, the Schwartz score played a pivotal role in confirming LQTS. Therapeutically, beta-blockers (e.g., propranolol) remain first-line empirical therapy, reducing repolarization dispersion and suppressing adrenergically triggered arrhythmias, even in genotype-negative patients[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. For SCD survivors or high-risk LQTS patients with recurrent syncope despite beta-blocker therapy, implantable cardioverter-defibrillator (ICD) implantation is lifesaving[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eARVC is a genetic cardiomyopathy marked by progressive fibrofatty replacement of the right ventricular myocardium, with an estimated prevalence of 1:5,000\u0026ndash;1:2,000[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The disease typically follows an insidious course, manifesting as ventricular arrhythmias, right ventricular dysfunction, heart failure, or SCD, particularly in young athletes[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Pathogenic variants in desmosomal genes (e.g., \u003cem\u003ePKP2\u003c/em\u003e, \u003cem\u003eDSP\u003c/em\u003e, \u003cem\u003eDSC2\u003c/em\u003e, \u003cem\u003eDSG2\u003c/em\u003e, and \u003cem\u003eJUP\u003c/em\u003e) account for most reported ARVC cases[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Notably, \u003cem\u003eDSP\u003c/em\u003e variants are associated with severe phenotypes, including increased risks of ventricular arrhythmias, SCD, and left ventricular involvement. However, genotype-phenotype discordance is common in young SCD survivors: some patients exhibit structural abnormalities on imaging without electrophysiological derangements, whereas others develop life-threatening arrhythmias before detectable histological or imaging changes[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Furthermore, genotype-positive ARVC patients may lack typical clinical features, and \u003cem\u003eDSP\u003c/em\u003e variants exhibit marked phenotypic heterogeneity, even among carriers of identical mutations owing to incomplete penetrance[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Early-stage ARVC may present with malignant arrhythmias despite minimal structural remodelling. Consequently, identifying a \u003cem\u003eDSP\u003c/em\u003e variant (even a pathogenic or likely pathogenic variant) in a patient with ARVC features strongly suggests cardiomyopathy but does not fully predict clinical manifestations or disease progression[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. This underscores the challenges in the clinical interpretation of \u003cem\u003eDSP\u003c/em\u003e variants, necessitating comprehensive evaluation of patient-specific factors.\u003c/p\u003e \u003cp\u003eThe patient in this case experienced sudden cardiac death (SCD) during exercise. Retrospective analysis revealed clinical features overlapping those of long QT syndrome (LQTS) and arrhythmogenic right ventricular cardiomyopathy (ARVC). Both the automated external defibrillator (AED) and hospital monitoring recorded ventricular fibrillation (VF) as the terminal arrhythmia during resuscitation. However, it remains uncertain whether torsades de pointes (TdP) serve as the triggering mechanism prior to syncope and SCD. Specifically, the debate centers on whether the fatal event originated from TdP secondary to LQTS progressing to VF or from malignant ventricular arrhythmias caused by DSP-related cardiomyopathy. Current evidence cannot definitively resolve this question. Notably, the CFHR5 gene variant identified in this case lacked documented associations with arrhythmias or SCD in the literature, leaving its pathogenicity unclear. However, further studies are needed to explore whether CFHR5 variants may contribute to arrhythmogenic risk.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis case exemplifies a unique \"triad paradox\": electrocardiographic features suggesting LQTS, genetic evidence pointing to ARVC, and normal cardiac structure on imaging. This complexity underscores the necessity for multidisciplinary evaluation in young SCD survivors, avoiding rigid adherence to single-disease classifications. Emerging evidence supports the \"polygenic microeffect\" model[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], where multiple weakly pathogenic variants collectively increase susceptibility to malignant arrhythmias. This model may explain some genetically elusive SCD cases and highlights the value of functional validation via patient-specific induced pluripotent stem cell (iPSC) cardiomyocyte models. Clinical management should emphasize individualized risk stratification, incorporating strict exercise restrictions, pharmacotherapy (e.g., β-blockers for LQT1), and early ICD implantation when warranted. This case provides critical insights for managing complex arrhythmia syndromes, although further mechanistic studies and case accumulation remain essential to clarify such overlapping phenotypes.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYYY and HLH were major contributors to the conception, review and analysis of medical records. BN was a major contributor to the writing of the article. DP was a major contributor to the critical revision of the article. All the authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Hangzhou Biomedicine and Health Industry Development Support Science and Technology Special Project (6th Phase) [Grant No. 2022WJC036]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Ethics Committee of Hangzhou Normal University Affiliated Hospital (Protocol No.: 2025(E2)-KS-110), and informed consent was obtained from the patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003enot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient for the publication of the case report and accompanying images.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eTester DJ, Benton AJ, Train L, Deal B, Baudhuin LM, Ackerman MJ. Prevalence and spectrum of large deletions or duplications in the major long QT syndrome-susceptibility genes and implications for long QT syndrome genetic testing. Am J Cardiol. 2010;106(8):1124\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMarcus FI, McKenna WJ, Sherrill D, Basso C, Bauce B, Bluemke DA, Calkins H, Corrado D, Cox MG, Daubert JP, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the Task Force Criteria. Eur Heart J. 2010;31(7):806\u0026ndash;14.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eQadri S, Anttonen O, Viikil\u0026auml; J, Sepp\u0026auml;l\u0026auml; EH, Myllykangas S, Alastalo TP, Holmstr\u0026ouml;m M, Heli\u0026ouml; T, Koskenvuo JW. Case reports of two pedigrees with recessive arrhythmogenic right ventricular cardiomyopathy associated with homozygous Thr335Ala variant in DSG2. BMC Med Genet. 2017;18(1):86.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSmith ED, Lakdawala NK, Papoutsidakis N, Aubert G, Mazzanti A, McCanta AC, Agarwal PP, Arscott P, Dellefave-Castillo LM, Vorovich EE, et al. Desmoplakin Cardiomyopathy, a Fibrotic and Inflammatory Form of Cardiomyopathy Distinct From Typical Dilated or Arrhythmogenic Right Ventricular Cardiomyopathy. Circulation. 2020;141(23):1872\u0026ndash;84.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGarcia-Gras E, Lombardi R, Giocondo MJ, Willerson JT, Schneider MD, Khoury DS, Marian AJ. Suppression of canonical Wnt/beta-catenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy. J Clin Investig. 2006;116(7):2012\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBeach SR, Celano CM, Noseworthy PA, Januzzi JL, Huffman JC. QTc prolongation, torsades de pointes, and psychotropic medications. Psychosomatics. 2013;54(1):1\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchwartz PJ, Crotti L, Insolia R. Long-QT syndrome: from genetics to management. Circulation Arrhythmia Electrophysiol. 2012;5(4):868\u0026ndash;77.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWilde AAM, Semsarian C, M\u0026aacute;rquez MF, Shamloo AS, Ackerman MJ, Ashley EA, Sternick EB, Barajas-Martinez H, Behr ER, Bezzina CR et al. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases. \u003cem\u003eEuropace: European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology\u003c/em\u003e 2022, 24(8):1307\u0026ndash;1367.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBohnen MS, Peng G, Robey SH, Terrenoire C, Iyer V, Sampson KJ, Kass RS. Molecular Pathophysiology of Congenital Long QT Syndrome. Physiol Rev. 2017;97(1):89\u0026ndash;134.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePriori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C, Blom N, Brugada J, Chiang CE, Huikuri H, et al. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart rhythm. 2013;10(12):1932\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchwartz PJ, Stramba-Badiale M, Crotti L, Pedrazzini M, Besana A, Bosi G, Gabbarini F, Goulene K, Insolia R, Mannarino S, et al. Prevalence of the congenital long-QT syndrome. Circulation. 2009;120(18):1761\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePriori SG, Schwartz PJ, Napolitano C, Bloise R, Ronchetti E, Grillo M, Vicentini A, Spazzolini C, Nastoli J, Bottelli G, et al. Risk stratification in the long-QT syndrome. N Engl J Med. 2003;348(19):1866\u0026ndash;74.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAl-Khatib SM, Stevenson WG, Ackerman MJ, Bryant WJ, Callans DJ, Curtis AB, Deal BJ, Dickfeld T, Field ME, Fonarow GC, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2018;72(14):e91\u0026ndash;220.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAltmayer S, Nazarian S, Han Y. Left Ventricular Dysfunction in Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC): Can We Separate ARVC From Other Arrhythmogenic Cardiomyopathies? J Am Heart Association. 2020;9(23):e018866.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ede la Gu\u0026iacute;a-Galipienso F, Ugedo-Alzaga K, Grazioli G, Quesada-Ocete FJ, Feliu-Rey E, Perez MV, Quesada-Dorador A, Sanchis-Gomar F. Arrhythmogenic Cardiomyopathy and Athletes: A Dangerous Relationship. Curr Probl Cardiol. 2023;48(9):101799.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRuwald AC, Marcus F, Estes NA 3rd, Link M, McNitt S, Polonsky B, Calkins H, Towbin JA, Moss AJ, Zareba W. Association of competitive and recreational sport participation with cardiac events in patients with arrhythmogenic right ventricular cardiomyopathy: results from the North American multidisciplinary study of arrhythmogenic right ventricular cardiomyopathy. Eur Heart J. 2015;36(27):1735\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEmery MS, Kovacs RJ. Sudden Cardiac Death in Athletes. JACC Heart Fail. 2018;6(1):30\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJames CA, Jongbloed JDH, Hershberger RE, Morales A, Judge DP, Syrris P, Pilichou K, Domingo AM, Murray B, Cadrin-Tourigny J, et al. International Evidence Based Reappraisal of Genes Associated With Arrhythmogenic Right Ventricular Cardiomyopathy Using the Clinical Genome Resource Framework. Circulation Genomic precision Med. 2021;14(3):e003273.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSteinmetz M, Krause U, Lauerer P, Konietschke F, Aguayo R, Ritter CO, Schuster A, Lotz J, Paul T, Staab W. Diagnosing ARVC in Pediatric Patients Applying the Revised Task Force Criteria: Importance of Imaging, 12-Lead ECG, and Genetics. Pediatr Cardiol. 2018;39(6):1156\u0026ndash;64.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBasso C, Corrado D, Bauce B, Thiene G. Arrhythmogenic right ventricular cardiomyopathy. Circulation Arrhythmia Electrophysiol. 2012;5(6):1233\u0026ndash;46.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArbelo E, Protonotarios A, Gimeno JR, Arbustini E, Barriales-Villa R, Basso C, Bezzina CR, Biagini E, Blom NA, de Boer RA, et al. : 2023 ESC Guidelines for the management of cardiomyopathies. Eur Heart J. 2023;44(37):3503\u0026ndash;626.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNeubauer J, Haas C, Bartsch C, Medeiros-Domingo A, Berger W. Post-mortem whole-exome sequencing (WES) with a focus on cardiac disease-associated genes in five young sudden unexplained death (SUD) cases. Int J Legal Med. 2016;130(4):1011\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYe JZ, Delmar M, Lundby A, Olesen MS. Reevaluation of genetic variants previously associated with arrhythmogenic right ventricular cardiomyopathy integrating population-based cohorts and proteomics data. Clin Genet. 2019;96(6):506\u0026ndash;14.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Sudden cardiac death, Long QT syndrome, DSP gene, CFHR5 gene, Phenotype-genotype dissociation","lastPublishedDoi":"10.21203/rs.3.rs-6399080/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6399080/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eEtiological identification in young survivors of exercise-induced sudden cardiac death (SCD) frequently encounter challenges due to phenotype-genotype incongruity.\u003c/p\u003e\u003ch2\u003eCase presentation:\u003c/h2\u003e \u003cp\u003eWe present a 21-year-old female survivor of aborted SCD caused by exercise-triggered ventricular fibrillation (VF). Comprehensive imaging studies (\u003cem\u003eechocardiography and cardiac magnetic resonance\u003c/em\u003e) revealed no structural abnormalities. Ambulatory electrocardiography demonstrated prolonged QTc intervals (Schwartz score: 4.5), fulfilling the diagnostic criteria for long QT syndrome (LQTS). Intriguingly, the electrocardiographic findings also satisfied depolarization/repolarization abnormality indices per the \u003cem\u003e2010 revised Task Force Criteria\u003c/em\u003e for arrhythmogenic right ventricular cardiomyopathy (ARVC). Whole-exome sequencing identified heterozygous variants in the \u003cem\u003eDSP\u003c/em\u003e (desmoplakin) and \u003cem\u003eCFHR5\u003c/em\u003e (complement factor H-related 5) genes, whereas no pathogenic variants were detected in 17 canonical LQTS-associated genes. Despite favourable outcomes with beta-blocker therapy, the exact trigger for VF remains elusive: the \u003cem\u003eDSP\u003c/em\u003e variant suggests potential ARVC-related myocardial electrical substrate abnormalities, whereas the pathogenic importance of the \u003cem\u003eCFHR5\u003c/em\u003e variant in cardiomyopathy remains unestablished. Furthermore, the borderline LQTS phenotype lacked definitive genetic corroboration.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThis case illustrates a \"tripartite dissociation\" among electrophysiological phenotype, cardiac structure, and genetic findings, challenging conventional disease classification frameworks in young SCD survivors. Prioritizing functional studies to investigate potential polygenic synergy in arrhythmogenesis may advance diagnostic paradigms and personalized SCD prevention strategies for atypical cases.\u003c/p\u003e","manuscriptTitle":"Case report: Tripartite dissociation in survivors of sudden cardiac death—Diagnostic challenges of a long QT syndrome phenotype with structurally normal hearts and a DSP gene variant","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-07 06:13:40","doi":"10.21203/rs.3.rs-6399080/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1ebadc6d-47f6-42d4-a230-acb7ded6d0a5","owner":[],"postedDate":"May 7th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-05-15T10:23:49+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-07 06:13:40","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6399080","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6399080","identity":"rs-6399080","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}