Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare but potentially fatal inherited arrhythmia syndrome characterized by adrenergically induced ventricular tachyarrhythmias in otherwise structurally normal hearts. CPVT-related sudden cardiac death (SCD) often occurs in children and adolescents during physical or emotional stress; however, conventional autopsies frequently reveal no gross or microscopic abnormalities. In such cases, the absence of structural anomalies may lead to inconclusive diagnosis of the cause of death. Although postmortem genetic testing has not yet become a routine tool in forensic practice in South Korea, it is increasingly gaining attention as a valuable approach for investigating sudden unexplained deaths. The present report describes an autopsy case of SCD in an adolescent in whom postmortem genetic analysis confirmed CPVT, providing the definitive cause of death and relevant information for family-based risk assessments.

The deceased was a 15-year-old boy (height, 171 cm; weight, 66 kg) who suddenly collapsed during an outdoor climbing activity. His medical history included attention deficit hyperactivity disorder, for which he was taking methylphenidate. Notably, he experienced an episode of exertional syncope several years before death but had not undergone extensive cardiac evaluation or received a formal diagnosis. At the time of collapse, the patient exhibited hyperventilation, followed by cardiac arrest. Emergency medical services were called immediately and cardiopulmonary resuscitation was initiated onsite. Electrocardiography (ECG) revealed ventricular fibrillation (VF) as the initial rhythm (Fig. 1). Despite three defibrillation attempts, he died at the hospital.

External examination revealed no significant injuries apart from resuscitation-related marks. The heart weighed 345 g and exhibited no gross congenital or acquired structural abnormalities (Fig. 2A). The left ventricular wall measured 1.2 cm, the interventricular septum 1.4 cm, and the right ventricular wall 0.3 cm, all of which were within normal limits. An examination of the sinoatrial and atrioventricular nodes revealed no microscopic abnormalities. Histological evaluation of the ventricular myocardium revealed multiple foci of contraction band necrosis, a nonspecific reperfusion injury consistent with VF in the agonal stage (Fig. 2B). The other organs were grossly and microscopically unremarkable. Toxicology screening detected therapeutic blood levels of methylphenidate. Laboratory analysis of vitreous humor was within normal limits, exhibiting no metabolic or electrolyte imbalance.

Heart blood was collected during autopsy and submitted to a commercial laboratory for postmortem next-generation sequencing (NGS). Targeted sequencing was performed using an arrhythmia gene panel covering 19 genes (191,040 base pairs) on an Illumina platform (Illumina, San Diego, CA, USA). The mean depth of coverage was 122.35×, with 98.3% of bases covered at ≥10× depth. A pathogenic mutation, c.7202G>T in the RYR2 gene, was identified. This variant results in an amino acid substitution at codon 2401, which changes arginine to leucine (p.Arg2401Leu). This substitution is predicted to alter the conformation and regulatory function of the receptor, leading to abnormal calcium release and increased vulnerability to stress-induced ventricular arrhythmias. The resulting disruption of calcium homeostasis is consistent with the known pathophysiology of CPVT type 1.

Based on negative autopsy findings and the identification of a pathogenic RYR2 mutation by NGS, the cause of death was determined to be SCD due to CPVT, likely triggered by physical exertion during climbing. Genetic counseling was recommended for families of decedents.

CPVT is a rare—but potentially fatal—inherited arrhythmia that primarily affects children and adolescents. It is characterized by adrenergically triggered polymorphic or bidirectional ventricular tachycardia occurring in hearts that are otherwise structurally and histologically normal. The estimated prevalence of CPVT is approximately 1 in 10,000, although the true prevalence may be higher due to underdiagnosis [1-3]. It accounts for approximately 12% of autopsy-negative sudden deaths and 1.5% of sudden infant deaths. The disease course can be severe, with untreated pediatric patients experiencing a mortality rate of up to 50%. Cardiac arrest is often the first symptom, occurring in nearly one-third of those affected. When syncope, aborted cardiac arrest, and SCD were considered together, the overall event rate among untreated individuals ranged from 54% to 58% [2]. Although traditionally considered to be a childhood-onset disorder, emerging data suggest a bimodal pattern of symptom onset. While most patients are diagnosed before 20 years of age (median age, 15 years), some develop symptoms between 32 and 48 years of age. Adult-onset CPVT is more frequently observed in females and less commonly associated with RYR2 mutation(s). In contrast, juvenile-onset CPVT often involves RYR2 variants and is associated with a higher incidence of sudden death. These findings indicate age-related differences in genetic and clinical characteristics [1,2].

Clinically, symptoms are typically triggered by adrenergic stimuli, such as exercise or emotional stress, while resting ECGs are frequently normal. The QT interval remains within normal limits and, although sinus bradycardia or supraventricular arrhythmias may be present, they are nonspecific. Diagnosis is often delayed, particularly in asymptomatic individuals or when sudden death is the first manifestation [1-3]. Exercise stress testing remains the primary diagnostic method, because it can induce bidirectional or polymorphic ventricular arrhythmias. However, a negative test result does not necessarily exclude a diagnosis. Additional tools, such as Holter monitoring and adrenergic stimulation testing, may offer supplementary insights. A definitive diagnosis often depends on genetic testing, particularly postmortem investigations. RYR2 mutations are the most common genetic cause and are typically inherited in an autosomal dominant manner. Calsequestrin 2 (CASQ2) and triadin (TRDN) are also implicated as genes that usually exhibit autosomal recessive inheritance.

The RYR2 gene encodes the cardiac ryanodine receptor 2, a critical calcium release channel located in the sarcoplasmic reticulum. This receptor facilitates the movement of calcium ions into the cytoplasm during cardiac excitation-contraction coupling. Pathogenic mutations in RYR2 result in gain-of-function mutations, leading to diastolic calcium leakage and delayed afterdepolarization during adrenergic stress. This underlies the arrhythmogenic phenotype of CPVT [2-4]. CPVT type 1, which is associated with RYR2 mutations, is the most common form of CPVT and has been identified in approximately 60% of clinically diagnosed patients. However, detection rates can vary widely, ranging from 5% to 38% in suspected populations. Moreover, approximately 15% of asymptomatic relatives identified through family screening harbor RYR2 variants [3]. Mutations in CASQ2 cause CPVT type 2, which is a less common but frequently more severe form. CASQ2 encodes cardiac calsequestrin, which serves as a calcium buffer in the sarcoplasmic reticulum. Defective calcium storage in this context increases susceptibility to arrhythmias. Other rare genes, such as calmodulin 1 (CALM1) and TRDN, have also been implicated, supporting the role of calcium dysregulation in CPVT pathogenesis. A locus on chromosome 7p14-p22 has also been suggested, although the responsible gene remains unidentified [2-4].

The c.7202G>T variant in the RYR2 gene identified in the case described is classified as pathogenic in ClinVar (ID: 201280) and is associated with autosomal dominant inheritance, as noted in the Online Mendelian Inheritance in Man database [1,5]. Although RYR2 mutations are well-established causes of CPVT, the p.Arg2401Leu variant is extremely rare and absent from population databases such as the Genome Aggregation Database and Korean Reference Genome Database, and has been previously reported in affected individuals. Experimental studies and computational predictions have consistently supported this deleterious effect [5,6]. Given the autosomal dominant inheritance and potential for familial transmission, genetic counseling and cascade screening are strongly recommended.

In forensic settings, CPVT presents a diagnostic challenge due to the absence of structural abnormalities on autopsy. When gross and microscopic findings fail to reveal the cause of death, postmortem genetic testing using NGS is a valuable alternative. Genetic testing can be used to identify pathogenic variants of key arrhythmia-related genes including RYR2, CASQ2, potassium voltage-gated channel subfamily Q member 1 (KCNQ1), potassium voltage-gated channel subfamily H member 2 (KCNH2), and sodium voltage-gated channel alpha subunit 5 (SCN5A). A significant proportion of sudden deaths in adolescents occur without anatomical findings, emphasizing the importance of postmortem genetic testing.

Several autopsy-based case reports have documented the diagnostic challenges and forensic implications of CPVT. D'Ovidio et al. [7] described a case involving a 16-year-old boy who died while playing football. A previous cardiological assessment revealed sinus bradycardia and rare ectopic beats. Autopsy findings were unremarkable, except for minor pulmonary edema. A rare RYR2 variant (c.463G>A, p.Gly155Arg) was identified postmortem, and maternal inheritance with incomplete penetrance was confirmed. Mahlke et al. [8] reported the sudden death of a 13-year-old girl who experienced repeated exertional syncope before her death. Autopsy revealed edematous lungs, pulmonary hemorrhage, and bloody fluid in the thoracic cavities, but no structural heart disease. Histological findings included marked alveolar hemorrhage and visceral congestion. Postmortem sequencing revealed a de novo RYR2 mutation (c.6497G>A, p.Gly2166Glu). Later, Itoh et al. [9] reported a case involving a 17-year-old boy who was diagnosed with CPVT after a resuscitated VF episode. He was treated with an implantable cardioverter defibrillator and beta-blockers but died at 21 years of age after an inappropriate shock and spontaneous VF. Genetic analysis revealed a de novo mosaic RYR2 variant (p.Gln4936Lys), and functional studies confirmed abnormal calcium handling. Most recently, Son et al. [10] investigated 249 Korean infants diagnosed with sudden infant death syndrome category IA. Among them, two male infants were found to harbor novel heterozygous RYR2 variants, p.Lys4392Arg (c.13175A>G) and p.Asn1551Ser (c.4652A>G), which are located in functionally important regions of the RYR2 gene and are classified as variants of uncertain significance. Collectively, these case studies demonstrate that CPVT can result in sudden death in individuals with structurally normal hearts, and often evade detection using standard clinical and pathological evaluations. Postmortem genetic testing has proven to be valuable in identifying pathogenic or likely pathogenic RYR2 variants, thus supporting accurate cause-of-death determination and family risk assessment.

Current clinical guidelines emphasize the role of genetic testing in the diagnosis of inherited arrhythmic syndromes. The 2017 guidelines from the American Heart Association, American College of Cardiology, and Heart Rhythm Society support genetic testing for conditions such as long QT syndrome (LQTS) and CPVT; however, molecular findings should be interpreted in conjunction with clinical features and family history [11]. More recent guidelines from the European Society of Cardiology in 2022 attribute greater diagnostic importance to genetic findings. According to these guidelines, the presence of a pathogenic variant in a known disease-related gene (e.g., RYR2 for CPVT or KCNQ1/KCNH2 for LQTS) may confirm a diagnosis even when ECG or structural markers are absent, provided there is an adequate clinical or familial context. It recommends comprehensive autopsy with histological and toxicological assessments in all cases of sudden unexplained death and encourages molecular testing when structural causes cannot be identified [12].

Despite advances in molecular testing, its routine application in forensic settings is limited by several factors. These include incomplete knowledge regarding the pathogenicity of genetic variants, variable penetrance, and expressivity, and the challenge of interpreting variants of uncertain significance. Additionally, the results of genetic testing can have broader implications for surviving relatives, raising ethical and legal questions that require careful management. Practical barriers also exist because many forensic institutions lack standardized testing protocols, and challenges related to funding, consent, and data privacy persist. For molecular testing to be effectively integrated into forensic practice, it must be supported by robust quality assurance, expert interpretation, a collaborative system with clinical institutions to provide genetic counseling, and appropriate legal frameworks.

The case described herein exemplifies the utility of postmortem genetic testing for identifying hereditary arrhythmias responsible for sudden unexplained deaths. The detection of a pathogenic RYR2 mutation provides a clear cause of death and enables family-based screening. However, in South Korea, genetic testing and counseling services are not yet systematically available within national forensic institutions, and families often encounter practical barriers to seeking testing on their own. Forensic authorities should work toward making genetic testing a standard component of autopsy protocols. This requires appropriate policies and financial commitments. The continued publication of postmortem genetic testing cases, such as the case described herein, is important for advocating institutional changes and demonstrating the benefits of incorporating genetics into forensic evaluations. With systematic implementation, postmortem genetic testing and family counseling can improve the early identification of inherited cardiac risks and help prevent arrhythmia-related deaths.

In summary, this case reinforces the diagnostic and preventive utility of postmortem genetic testing in CPVT, supports the integration of genetic testing into forensic protocols, and advocates for the development of family-centered genetic services in South Korea.