Background and Rationale Sudden cardiac death (SCD) represents a devastating and often unexpected loss of life, particularly when it affects young, apparently healthy individuals. While coronary artery disease remains the leading cause of SCD in older populations, younger victims frequently harbor rare cardiovascular disorders that may not be clinically apparent during life [1]. These conditions, including inherited cardiomyopathies, ion channelopathies, and congenital heart diseases, present unique challenges for forensic pathologists, clinicians, and legal systems. The forensic investigation of SCD has evolved significantly with advances in molecular genetics and diagnostic techniques. Traditional autopsy methods, while remaining fundamental, may fail to identify the underlying cause in up to 40% of young SCD cases, leading to the classification of “sudden arrhythmic death syndrome” (SADS) [2]. The introduction of molecular autopsy—post-mortem genetic testing—has revolutionized the field by providing diagnostic insights in cases with negative conventional autopsy findings. Clinical and Legal Significance The identification of rare cardiovascular disorders in SCD cases carries profound implications extending far beyond the immediate forensic investigation. When a genetic cause is identified, it raises questions about cascade screening of family members, genetic counseling needs, and potential preventive interventions. The medicolegal ramifications encompass death certification accuracy, insurance implications, sports participation guidelines, and the admissibility of genetic evidence in legal proceedings. Furthermore, the diagnostic challenges inherent in identifying rare cardiovascular disorders in post-mortem investigations highlight the need for standardized protocols, specialized training, and adequate resources. The quality of forensic pathology services varies significantly across jurisdictions, potentially affecting the accuracy of death certification and the implementation of appropriate family screening programs. Knowledge Gaps and Research Need Despite the growing recognition of rare cardiovascular disorders as important causes of SCD, several knowledge gaps persist: • Standardization of forensic autopsy protocols for suspected inherited cardiac conditions • Optimal implementation strategies for molecular autopsy in routine forensic practice • Evidence-based guidelines for family screening and genetic counseling following SCD • Legal frameworks for handling genetic information in forensic contexts • Cost-effectiveness analyses of comprehensive genetic testing in SCD investigations Objectives This systematic review aims to comprehensively examine the current state of knowledge regarding forensic autopsy findings, diagnostic challenges, and legal implications associated with sudden cardiac death caused by rare cardiovascular disorders. Specifically, we sought to: 1. Characterize the spectrum of rare cardiovascular disorders identified in forensic SCD investigations 2. Analyze the diagnostic accuracy and limitations of current forensic pathology practices 3. Evaluate the role of molecular autopsy in unexplained SCD cases 4. Examine the legal and ethical implications of genetic findings in forensic contexts 5. Identify best practices and recommendations for improving forensic investigation protocols 6. Assess the impact on family screening and genetic counseling programs

Protocol and Registration This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement [3]. The review protocol was developed a priori to ensure methodological rigor and minimize bias. Search Strategy Database Selection A comprehensive literature search was conducted across multiple databases to ensure comprehensive coverage of the relevant literature: • SciSpace (primary search and full-text search) • PubMed/MEDLINE (advanced search with MeSH terms) • Google Scholar (complementary search) • Additional hand-searching of reference lists Search Terms and Strategy The search strategy was developed using a combination of controlled vocabulary (MeSH terms) and free-text terms. The core search concepts included: Population terms: sudden cardiac death, SCD, sudden arrhythmic death syndrome, SADS Condition terms: rare cardiovascular disorders, inherited cardiomyopathy, ion channelopathy, genetic heart disease, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia Intervention/Exposure terms: forensic autopsy, post-mortem examination, molecular autopsy, genetic testing, pathological examination Outcome terms: diagnostic challenges, legal implications, medicolegal aspects, family screening, genetic counseling Eligibility Criteria Inclusion Criteria Studies were included if they met the following criteria: • Study types: Original research articles, systematic reviews, meta-analyses, case series, and significant case reports • Population: Cases of sudden cardiac death in individuals of any age • Condition: Focus on rare cardiovascular disorders as the cause of SCD • Intervention: Forensic autopsy examination, post-mortem genetic testing, or related diagnostic procedures • Outcomes: Autopsy findings, diagnostic accuracy, legal implications, family screening outcomes, or genetic counseling recommendations • Publication characteristics: English language, published 2010-2025, peer-reviewed Exclusion Criteria Studies were excluded if they: • Focused solely on common causes of SCD (e.g., typical coronary artery disease in elderly populations) • Involved non-cardiac sudden death • Lacked forensic or post-mortem examination • Were animal studies • Were conference abstracts without full papers • Were non-English publications • Were published before 2010 Study Selection Process Screening Methodology The study selection process followed a two-stage screening approach: 1. Title and Abstract Screening: All retrieved records underwent initial screening based on titles and abstracts using predefined inclusion and exclusion criteria 2. Full-Text Screening: Papers that passed the initial screening underwent comprehensive full-text evaluation Duplicate Removal Duplicate records were identified and removed using a combination of automated and manual methods. Studies were considered duplicates if they had identical titles and author lists, with manual verification for borderline cases. Data Extraction Data extraction was performed using a standardized form developed specifically for this review. The following categories of information were extracted: Study Characteristics • Study design and methodology • Sample size and demographic characteristics • Geographic location and time period • Setting (forensic institute, medical examiner office, etc.) Clinical and Pathological Data • Types of rare cardiovascular disorders identified • Age and sex distribution of cases • Circumstances of death • Gross and microscopic autopsy findings • Results of specialized testing (immunohistochemistry, electron microscopy) Molecular and Genetic Data • Molecular autopsy techniques used • Gene panels and sequencing methods • Pathogenic variants identified • Variant classification methods • Diagnostic yield of genetic testing Diagnostic and Legal Outcomes • Diagnostic challenges encountered • Accuracy of cause of death determination • Legal and medicolegal implications • Family screening recommendations and outcomes • Genetic counseling protocols Quality Assessment The quality of included studies was assessed using appropriate tools based on study design: • Systematic reviews: AMSTAR 2 (A MeaSurement Tool to Assess systematic Reviews) • Observational studies: Newcastle-Ottawa Scale • Case series and case reports: Modified quality assessment criteria focusing on case definition, diagnostic methods, and outcome reporting Data Synthesis Given the heterogeneity of study designs and outcome measures, a narrative synthesis approach was employed. Quantitative meta-analysis was not feasible due to the diversity of study populations, interventions, and outcome definitions.

Study Selection and Characteristics Search Results The comprehensive literature search yielded a total of 240 records across all databases: - SciSpace: 100 papers - SciSpace Full-text: 100 papers - Google Scholar: 20 papers - PubMed: 20 papers After deduplication, 227 unique papers remained for screening. Following title and abstract screening, and subsequent full-text evaluation, studies meeting the inclusion criteria were included in the final analysis. Study Design Distribution The included literature comprised: - Systematic reviews and narrative reviews - Population-based cohort studies - Forensic autopsy series - Case reports and case series - Survey studies of forensic pathology practices Geographic and Temporal Distribution Studies were conducted across multiple continents, with significant contributions from: - European countries (Sweden, Germany, Italy, multi-country collaborations) - Asian countries (South Korea) - International collaborative studies The temporal distribution showed increasing research activity in molecular autopsy and genetic testing from 2010 onwards, with peak activity in the 2020-2025 period. Rare Cardiovascular Disorders in Sudden Cardiac Death Spectrum of Conditions The literature consistently identified several categories of rare cardiovascular disorders as significant causes of SCD: Inherited Cardiomyopathies: - Arrhythmogenic right ventricular cardiomyopathy (ARVC/ACM) - Hypertrophic cardiomyopathy (HCM) - Dilated cardiomyopathy (DCM) - Left ventricular non-compaction cardiomyopathy Ion Channelopathies: - Long QT syndrome (LQTS) - Brugada syndrome - Catecholaminergic polymorphic ventricular tachycardia (CPVT) - Short QT syndrome (SQTS) Other Rare Conditions: - Conduction system lesions - Cardiac tumors - Infiltrative diseases (sarcoidosis, amyloidosis) - Inflammatory conditions (myocarditis) Epidemiological Data Key epidemiological findings from the literature include: • ARVC accounted for approximately 4% of SCD in individuals under 35 years in Swedish national data [4] • 41% of ARVC-related deaths were exercise-related [4] • Mean age of ARVC victims: 23.6 years (range 12-35 years) [4] • Male predominance: 64% of ARVC cases [4] Forensic Autopsy Findings Gross Pathological Findings The literature described characteristic gross autopsy findings for different rare cardiovascular disorders: ARVC/ACM: - Right ventricular dilatation and wall thinning - Fibrofatty replacement of myocardium - Left ventricular involvement in advanced cases Hypertrophic Cardiomyopathy: - Asymmetric septal hypertrophy - Small left ventricular cavity - Mitral valve abnormalities Ion Channelopathies: - Structurally normal heart (negative autopsy) - Absence of significant coronary artery disease - Normal cardiac morphometry Histopathological Characteristics Microscopic examination revealed specific patterns: • Fibrofatty replacement in ARVC cases • Myocyte disarray and interstitial fibrosis in HCM • Inflammatory infiltrates in myocarditis cases [5,6] • Specialized histochemical staining requirements Molecular Autopsy Results The literature consistently reported on the diagnostic yield of molecular autopsy: • Pathogenic or likely pathogenic variants identified in 20-25% of unexplained SCD cases [2] • Higher yield in younger victims and those with family history • Specific gene panels targeting cardiomyopathy and channelopathy genes • Importance of variant classification and interpretation Specific Genetic Findings: - KCNQ1 variants in LQTS cases [5] - Desmosomal gene variants in ARVC [4] - Sarcomeric gene variants in HCM - Sodium channel variants in Brugada syndrome Diagnostic Challenges Technical and Methodological Challenges The literature identified several key diagnostic challenges: Tissue Handling and Preservation: - Inadequate tissue sampling protocols [7] - Poor DNA preservation affecting molecular testing - Lack of standardized tissue banking procedures - Variable fixation methods affecting histological interpretation Diagnostic Technique Limitations: - Inter-observer variability in histological interpretation - Limited access to specialized immunohistochemical stains - Inadequate electron microscopy facilities - Challenges in distinguishing normal variants from pathological changes Molecular Testing Challenges: - Variant interpretation difficulties [2] - Variants of uncertain significance (VUS) - Limited functional validation studies - Ethnic diversity in genetic databases Resource and Training Limitations Significant gaps were identified in forensic pathology practice: • Limited access to cardiac pathology expertise [7] • Insufficient training in molecular autopsy interpretation • Resource constraints affecting comprehensive testing • Lack of multidisciplinary team approaches Cases with Negative Autopsy Findings A substantial proportion of SCD cases showed no significant structural abnormalities: • Up to 40% of young SCD cases had negative conventional autopsy [2] • Classification as sudden arrhythmic death syndrome (SADS) • Increased importance of molecular autopsy in these cases • Need for comprehensive toxicological screening Legal and Medicolegal Implications Death Certification Issues The literature highlighted several challenges in death certification: • Accuracy of cause of death determination • Challenges in certifying genetic conditions • Implications of uncertain genetic findings • Consistency across different jurisdictions Family Screening Obligations Legal and ethical considerations regarding family screening: • Duty to inform families of genetic findings • Consent issues for genetic testing of deceased • Privacy concerns regarding genetic information • Liability for failure to recommend screening Insurance and Employment Implications The identification of genetic conditions raised several concerns: • Life insurance coverage issues • Employment discrimination potential • Sports participation restrictions • Genetic discrimination legislation gaps Expert Testimony Requirements Legal proceedings often required expert interpretation: • Admissibility of genetic evidence • Qualification requirements for expert witnesses • Interpretation of probabilistic genetic evidence • Communication of uncertainty to legal audiences Family Screening and Genetic Counseling Cascade Screening Protocols The literature described various approaches to family screening: • First-degree relative screening recommendations [2] • Clinical evaluation protocols • Genetic testing strategies • Long-term follow-up requirements Implementation Challenges Several barriers to effective family screening were identified: • Limited access to specialized cardiac genetics services • Family reluctance to participate in screening • Geographic barriers to specialized care • Cost and insurance coverage issues Psychological Impact The literature noted significant psychological effects: • Anxiety and depression in family members • Impact on family dynamics • Need for psychological support services • Long-term mental health considerations Quality Assessment The quality of included studies varied considerably: • High-quality systematic reviews provided comprehensive overviews [1,2] • Population-based cohort studies offered robust epidemiological data [4] • Case series and case reports provided detailed clinical insights but limited generalizability [5,6] • Survey studies highlighted practice variations but were subject to response bias [7] Overall, the evidence base was characterized by moderate quality, with strengths in descriptive and observational data but limitations in comparative effectiveness research and long-term outcome studies.

Principal Findings This systematic review provides a comprehensive analysis of the current state of knowledge regarding forensic autopsy findings, diagnostic challenges, and legal implications associated with sudden cardiac death caused by rare cardiovascular disorders. Several key findings emerge from the literature that have important implications for forensic practice, clinical care, and legal frameworks. Diagnostic Landscape of Rare Cardiovascular Disorders The evidence demonstrates that rare cardiovascular disorders represent a significant and underrecognized cause of sudden cardiac death, particularly in younger populations. The spectrum of conditions identified—including inherited cardiomyopathies, ion channelopathies, and conduction system disorders—requires specialized expertise and sophisticated diagnostic approaches that extend beyond traditional autopsy methods. The finding that molecular autopsy identifies pathogenic variants in 20-25% of unexplained SCD cases [2] represents a substantial diagnostic advance, effectively reducing the proportion of cases classified as sudden arrhythmic death syndrome (SADS). This diagnostic yield is consistent across multiple studies and populations, suggesting that molecular autopsy should be considered a standard component of forensic investigation in young SCD cases. Forensic Pathology Practice Gaps The literature reveals significant gaps in current forensic pathology practice that limit diagnostic accuracy and compromise family care [7]. These include inadequate tissue handling protocols, limited access to specialized testing, and insufficient training in genetic interpretation. The variability in practice across jurisdictions suggests the need for standardized protocols and quality assurance measures. The challenge of interpreting variants of uncertain significance (VUS) emerges as a critical issue requiring ongoing attention [2]. As genetic testing becomes more widespread, the proportion of VUS findings may initially increase before comprehensive functional studies and population data improve classification accuracy. Clinical and Public Health Implications Family Screening and Cascade Testing The identification of genetic causes of SCD carries profound implications for family members, who may be at risk for the same condition. The literature supports systematic cascade screening of first-degree relatives [2], but implementation remains inconsistent and resource-dependent. The development of standardized screening protocols, integrated care pathways, and adequate funding mechanisms is essential to realize the preventive potential of genetic diagnosis. The psychological impact on families represents an underexplored area requiring greater attention. While genetic counseling is universally recommended, the literature provides limited evidence on optimal counseling approaches, long-term psychological outcomes, or cost-effectiveness of different support strategies. Preventive Interventions The identification of at-risk family members through cascade screening enables preventive interventions including lifestyle modifications, medical therapy, and device implantation. However, the literature reveals gaps in evidence regarding optimal management strategies for genotype-positive, phenotype-negative individuals. This uncertainty complicates clinical decision-making and genetic counseling. Legal and Ethical Considerations Medicolegal Framework Development The legal implications of genetic findings in forensic contexts require careful consideration and policy development. Issues of consent for genetic testing of deceased individuals, obligations to inform families, and liability for failure to conduct appropriate testing need clarification through legislation and professional guidelines. The admissibility and interpretation of genetic evidence in legal proceedings presents ongoing challenges. Courts must grapple with probabilistic evidence, uncertain genetic findings, and the qualification of expert witnesses in rapidly evolving fields. Legal education and standardized expert testimony guidelines could improve the quality of genetic evidence presentation. Discrimination and Privacy Concerns The identification of genetic predisposition to sudden cardiac death raises concerns about genetic discrimination in insurance, employment, and other contexts. While genetic non-discrimination legislation exists in many jurisdictions, gaps remain in coverage and enforcement. The forensic context adds complexity, as genetic information may be discovered without the individual’s prior knowledge or consent. Technological and Methodological Advances Molecular Autopsy Evolution The field of molecular autopsy continues to evolve rapidly with advances in sequencing technologies, bioinformatics, and variant interpretation [2]. Whole genome sequencing is increasingly replacing targeted gene panels, potentially improving diagnostic yield but also increasing the complexity of interpretation. The integration of RNA sequencing, proteomics, and metabolomics may further enhance diagnostic capabilities. Artificial intelligence and machine learning applications show promise for improving variant classification, predicting pathogenicity, and integrating multi-omics data. However, validation studies and regulatory frameworks are needed to ensure clinical utility and safety. Standardization Efforts Professional organizations have begun developing standards for molecular autopsy practice, including recommendations for gene selection, variant classification, and reporting [7]. International collaboration is essential to ensure consistency and facilitate data sharing across borders. The development of quality metrics and proficiency testing programs for molecular autopsy laboratories is crucial for maintaining diagnostic accuracy and public confidence. Regular updates to testing protocols and interpretation guidelines are needed to keep pace with scientific advances. Resource and Training Implications Workforce Development The complexity of genetic interpretation in forensic contexts requires specialized training that bridges forensic pathology, medical genetics, and molecular biology. Fellowship programs, continuing education initiatives, and competency assessments are needed to develop and maintain expertise. Multidisciplinary team approaches involving forensic pathologists, medical geneticists, genetic counselors, and cardiologists are essential for optimal case management [7]. However, resource constraints and geographic limitations may impede team-based care in many jurisdictions. Economic Considerations The cost-effectiveness of molecular autopsy and cascade screening programs requires careful evaluation. While initial costs may be substantial, the potential for preventing future sudden deaths through family screening may justify the investment from a public health perspective. Economic modeling studies are needed to inform policy decisions and resource allocation. Insurance coverage for genetic testing and family screening varies widely and represents a barrier to equitable access. Advocacy efforts and policy development are needed to ensure appropriate coverage and reduce financial barriers to care. Limitations and Future Research Directions Evidence Quality and Gaps The evidence base for rare cardiovascular disorders in SCD is characterized by heterogeneous study designs, small sample sizes, and limited long-term follow-up data. Large-scale prospective studies with standardized protocols are needed to generate robust evidence for clinical and policy decision-making. Comparative effectiveness research is particularly lacking, with limited evidence comparing different diagnostic approaches, screening strategies, or management interventions. Randomized controlled trials may be challenging in this population, but well-designed observational studies could provide valuable evidence. International Collaboration The rarity of individual genetic conditions necessitates international collaboration to achieve adequate sample sizes for research studies. Standardized data collection protocols, shared databases, and coordinated research initiatives could accelerate scientific progress and improve patient care. The development of international guidelines and standards for forensic genetic testing could improve consistency and facilitate cross-border collaboration in complex cases. Emerging Technologies Rapid advances in genetic technologies, including long-read sequencing, structural variant detection, and epigenetic analysis, may further improve diagnostic capabilities. Research is needed to evaluate the clinical utility and cost-effectiveness of these emerging approaches. The integration of artificial intelligence and machine learning in genetic interpretation shows promise but requires careful validation and regulatory oversight. Ethical considerations regarding algorithmic bias and transparency must be addressed. Recommendations for Practice and Policy Based on the findings of this systematic review, several recommendations emerge: For Forensic Pathology Practice • Develop standardized protocols for tissue collection and preservation in suspected genetic SCD cases • Implement molecular autopsy as a routine component of investigation in unexplained SCD in individuals under 50 years • Establish multidisciplinary teams including genetic expertise • Develop quality assurance programs for genetic testing laboratories • Provide specialized training in genetic interpretation for forensic pathologists For Clinical Care • Establish systematic cascade screening programs for families of SCD victims with genetic findings • Develop integrated care pathways linking forensic findings to clinical follow-up • Provide genetic counseling services for affected families • Create long-term follow-up protocols for at-risk family members • Develop evidence-based management guidelines for genotype-positive individuals For Legal and Policy Frameworks • Clarify consent requirements for post-mortem genetic testing • Develop guidelines for disclosure of genetic findings to families • Strengthen genetic non-discrimination legislation • Establish standards for expert testimony in genetic evidence cases • Ensure adequate insurance coverage for genetic testing and family screening For Research Priorities • Conduct large-scale prospective studies of molecular autopsy outcomes • Evaluate cost-effectiveness of different screening and management strategies • Investigate long-term psychological and social impacts on families • Develop and validate new genetic technologies for forensic applications • Study the effectiveness of different genetic counseling approaches

This systematic review provides a comprehensive examination of the forensic autopsy findings, diagnostic challenges, and legal implications associated with sudden cardiac death caused by rare cardiovascular disorders. The evidence reveals a complex landscape requiring specialized expertise, advanced diagnostic techniques, and carefully considered legal frameworks. Key Conclusions Diagnostic Advances and Challenges The integration of molecular autopsy into forensic practice represents a paradigm shift in the investigation of sudden cardiac death. With a diagnostic yield of 20-25% in unexplained cases [2], genetic testing has substantially reduced the proportion of cases classified as sudden arrhythmic death syndrome and provided crucial information for family care. However, significant challenges remain in tissue handling, variant interpretation, and access to specialized expertise. The spectrum of rare cardiovascular disorders causing SCD—including inherited cardiomyopathies, ion channelopathies, and conduction system disorders—requires sophisticated diagnostic approaches that extend beyond traditional autopsy methods. The complexity of genetic interpretation necessitates multidisciplinary expertise and ongoing education for forensic pathologists. Family and Public Health Impact The identification of genetic causes of SCD carries profound implications extending far beyond the immediate forensic investigation. Cascade screening of family members represents a critical preventive opportunity, potentially identifying at-risk individuals who may benefit from surveillance, lifestyle modifications, or therapeutic interventions. However, implementation of systematic screening programs remains inconsistent and resource-dependent. The psychological impact on families, while recognized as significant, remains inadequately studied and addressed. The development of comprehensive support services, including genetic counseling and mental health resources, is essential for optimal family care. L egal and Ethical Frameworks The legal implications of genetic findings in forensic contexts require careful consideration and policy development. Issues of consent, disclosure obligations, genetic discrimination, and expert testimony present ongoing challenges that need resolution through legislation, professional guidelines, and judicial education. The admissibility and interpretation of genetic evidence in legal proceedings will likely become increasingly important as molecular autopsy becomes more widespread. Courts must be prepared to handle probabilistic evidence and uncertain genetic findings with appropriate expertise and standards. Practice Transformation The evidence supports a transformation in forensic pathology practice toward more comprehensive, genetics-informed approaches to sudden cardiac death investigation. This transformation requires: • Standardized protocols for tissue collection and molecular testing • Multidisciplinary team approaches incorporating genetic expertise • Enhanced training and continuing education programs • Quality assurance measures for genetic testing laboratories • Integration with clinical care pathways for family follow-up Research Priorities Several critical research gaps require attention to advance the field: • Large-scale prospective studies of molecular autopsy outcomes and clinical utility • Cost-effectiveness analyses of different diagnostic and screening strategies • Long-term follow-up studies of psychological and social impacts on families • Development and validation of emerging genetic technologies • Comparative effectiveness research on different management approaches Policy Implications The findings of this review have important implications for health policy, legal frameworks, and resource allocation: • Investment in forensic pathology infrastructure and training programs • Development of integrated care systems linking forensic findings to clinical follow-up • Strengthening of genetic non-discrimination legislation and privacy protections • Establishment of quality standards and accreditation programs for molecular autopsy • Ensuring equitable access to genetic testing and family screening services Global Perspective The challenges and opportunities identified in this review are not limited to any single jurisdiction but represent global issues requiring international collaboration. The rarity of individual genetic conditions necessitates data sharing, collaborative research, and harmonized standards across borders. International professional organizations, regulatory bodies, and research networks have important roles in facilitating collaboration, developing standards, and promoting best practices in forensic genetic testing and family care. Future Outlook The field of forensic genetics is rapidly evolving with advances in sequencing technologies, bioinformatics, and artificial intelligence. These developments hold promise for improving diagnostic accuracy, reducing costs, and enhancing clinical utility. However, they also present new challenges in interpretation, regulation, and ethical consideration. The integration of multi-omics approaches, including genomics, transcriptomics, proteomics, and metabolomics, may further enhance diagnostic capabilities but will require new expertise and analytical frameworks. The development of artificial intelligence tools for variant interpretation and clinical decision support shows promise but requires careful validation and oversight. Final Recommendations Based on the comprehensive analysis presented in this systematic review, we recommend: 1. Immediate Implementation: Forensic pathology services should implement molecular autopsy as a standard component of investigation in unexplained SCD cases in individuals under 50 years of age. 2. Systematic Development: Healthcare systems should develop integrated care pathways linking forensic genetic findings to clinical family screening and genetic counseling services. 3. Professional Education: Medical education and continuing education programs should incorporate training in forensic genetics and genetic counseling for relevant healthcare professionals. 4. Policy Development: Governments should review and strengthen legal frameworks regarding genetic testing, discrimination, and privacy in forensic contexts. 5. Research Investment: Funding agencies should prioritize research on the clinical utility, cost-effectiveness, and psychosocial impacts of forensic genetic testing and family screening programs. 6. International Collaboration: Professional organizations and research institutions should promote international collaboration in developing standards, sharing data, and conducting research in forensic genetics. The transformation of forensic pathology practice to incorporate genetic approaches represents both an opportunity and a responsibility. The potential to prevent future sudden deaths through family screening and genetic counseling provides a compelling rationale for investment in comprehensive diagnostic approaches. However, this transformation must be accompanied by careful attention to ethical considerations, quality assurance, and equitable access to ensure that the benefits of genetic advances are realized by all populations. The evidence presented in this systematic review demonstrates that sudden cardiac death caused by rare cardiovascular disorders is a complex phenomenon requiring sophisticated diagnostic approaches, multidisciplinary expertise, and comprehensive support systems. The continued evolution of this field will depend on sustained collaboration among forensic pathologists, medical geneticists, clinicians, researchers, policymakers, and affected families working together to improve outcomes and prevent future tragedies.

1. Markwerth P, Bajanowski T, Tzimas I, Dettmeyer R. Sudden cardiac death—update. International Journal of Legal Medicine. 2021;135(2):483-495. doi:10.1007/S00414-020-02481-Z 2. Martínez-Barrios E, Cesar S, Cruzalegui J, Hernandez C, Arbelo E, Fiol V, et al. Molecular autopsy: Twenty years of post-mortem diagnosis in sudden cardiac death. Frontiers in Medicine. 2023;10:1118585. doi:10.3389/fmed.2023.1118585 3. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. doi:10.1136/bmj.n71 4. Delgado-Vega AM, Hylind RJ, Bundgaard H, Rosenberg J, Graff C, Tfelt-Hansen J, et al. Family History and Warning Symptoms Precede Sudden Cardiac Death in Arrhythmogenic Right Ventricular Cardiomyopathy (from a Nationwide Study in Sweden). American Journal of Cardiology. 2022;153:108-115. doi:10.1016/j.amjcard.2022.05.015 5. Grassi S, Campuzano O, Coll M, Brion M, Iglesias A, Carracedo Á, et al. Eosinophilic Infiltration of the Sino-Atrial Node in Sudden Cardiac Death Caused by Long QT Syndrome. International Journal of Molecular Sciences. 2022;23(19):11666. doi:10.3390/ijms231911666 6. Huh GY. Sudden Death Due to Concurrent Arrhythmogenic Cardiomyopathy and Myocarditis: An Autopsy Case. The Korean Journal of Legal Medicine. 2024;48(1):19-23. doi:10.7580/kjlm.2024.48.1.19 7. Banner J, Stambolova G, Cheng A, Ploner A, Baandrup U, Christiansen SL, et al. Autopsy examination in sudden cardiac death: a current perspective on behalf of the Association for European Cardiovascular Pathology. Virchows Archiv. 2021;479(4):687-699. doi:10.1007/S00428-020-02949-8 8. Oliva A, Brugada R, D’Aloja E, Boschi I, Partemi S, Brugada J, et al. State of the art in forensic investigation of sudden cardiac death. American Journal of Forensic Medicine and Pathology. 2011;32(1):1-16. doi:10.1097/PAF.0B013E3181C2DC96 9. Basso C, Aguilera B, Banner J, Cohle S, d’Amati G, de Gouveia RH, et al. Guidelines for autopsy investigation of sudden cardiac death: 2017 update from the Association for European Cardiovascular Pathology. Virchows Archiv. 2017;471(6):691-705. 10. Ackerman MJ, Priori SG, Willems S, Berul C, Brugada R, Calkins H, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies. Heart Rhythm. 2011;8(8):1308-1339. 11. Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C, et al. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Heart Rhythm. 2013;10(12):1932-1963. 12. Semsarian C, Ingles J, Maron MS, Maron BJ. New perspectives on the prevalence of hypertrophic cardiomyopathy. Journal of the American College of Cardiology. 2015;65(12):1249-1254. 13. Wilde AA, Semsarian C, Márquez MF, Shamloo AS, Ackerman MJ, Ashley EA, 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 channelopathies and cardiomyopathies. Europace. 2016;18(10):1389-1407. 14. Lahrouchi N, Raju H, Lodder EM, Papatheodorou E, Ware JS, Papadakis M, et al. Utility of post-mortem genetic testing in cases of sudden arrhythmic death syndrome. Journal of the American College of Cardiology. 2017;69(17):2134-2145. 15. Campuzano O, Allegue C, Partemi S, Iglesias A, Oliva A, Brugada R. Negative autopsy and sudden cardiac death. International Journal of Legal Medicine. 2018;132(6):1749-1757. 16. Tfelt-Hansen J, Winkel BG, Grunnet M, Jespersen CB. Cardiac channelopathies and sudden infant death syndrome. Cardiology. 2020;137(4):207-216. 17. Ingles J, Goldstein J, Thaxton C, Caleshu C, Corty EW, Crowley SB, et al. Evaluating the clinical validity of hypertrophic cardiomyopathy genes. Circulation: Genomic and Precision Medicine. 2019;12(2):e002460. 18. Walsh R, Thomson KL, Ware JS, Funke BH, Woodley J, McGuire KJ, et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genetics in Medicine. 2017;19(2):192-203. 19. Hertz CL, Christiansen SL, Ferrero-Miliani L, Dahl M, Hollegaard MV, Duno M, et al. Next-generation sequencing of 100 candidate genes in young victims of suspected sudden cardiac death. International Journal of Legal Medicine. 2016;130(1):91-102. 20. Stiles MK, Wilde AA, Abrams DJ, Ackerman MJ, Albert CM, Behr ER, et al. 2020 APHRS/HRS expert consensus statement on the investigation of decedents with sudden unexplained death and patients with sudden cardiac arrest, and of their families. Heart Rhythm. 2021;18(1):e1-e50.