Author + information
- aDepartment of Forensic Pathology, New York City Office of Chief Medical Examiner, New York, New York
- bMolecular Genetics Laboratory, New York City Office of Chief Medical Examiner, New York, New York
- ↵∗Address for correspondence:
Dr. Barbara A. Sampson, New York City Office of Chief Medical Examiner, 520 First Avenue, New York, New York 10016.
Autopsy-negative sudden natural death in apparently healthy individuals is a vexing challenge facing medical examiners (MEs). Comprehensive studies commonly include scene investigation, gross and microscopic autopsy, detailed cardiopathologic and neuropathologic examination, as well as various laboratory tests, such as toxicology and microbiology tests. When all studies are negative, the cause of death is commonly certified as cardiac arrhythmia of unknown etiology.
Most ME offices around the world lack the means to routinely perform molecular testing on every autopsy-negative natural death case. The yields and utilities of molecular autopsy have been reported from national referral centers or academic institutes; however, it is difficult to compare the range of yields reported in various studies on different case populations and using different testing panels, ranging from a handful of genes to whole exome sequencing. Nonetheless, the study reported by Lahrouchi et al. (1) in this issue of the Journal highlighted the importance of stringent variant interpretation and emphasized the added value to molecular autopsy through family study.
Importance of Integrated Multidisciplinary Communication
Using American College of Medical Genetics (ACMG) sequence interpretation guidelines, Lahrouchi et al. (1) identified a pathogenic or likely pathogenic variant in 13% of 302 autopsy-negative cases, 88% Europeans, by testing 77 genes previously associated with primary cardiac electrical diseases or cardiomyopathies. Those variants are mostly found in RYR2 for catecholaminergic polymorphic ventricular tachycardia, and KCNQ1, KCNH2, and SCN5A for long QT and Brugada syndromes. ACMG guidelines emphasize: previously reported variants with genotype and phenotype cosegregation in families or unrelated, clinically affected individuals; functional evidence; concordance between mutation type and genetic mechanism of the disease; and minor allele frequency in the population. This leads to a substantial number of ultra-rare variants or novel variants that are predicted to be deleterious in these cardiac arrhythmogenic disease genes and to be classified as variants of uncertain significance (VUS). Although a VUS is not diagnostic without further familial or functional study, it is important to communicate this finding to the family, conveying the level of uncertainty of the role and significance of these variants, and the possibility that the VUS may be a rare benign variant or a likely pathogenic variant upon additional studies. From our own molecular testing experience, we often have found multiple coexisting VUS in a autopsy-negative case, and it is important to acknowledge that our understanding of variant interactions is limited.
Communicating such complex molecular testing information in a digestible fashion to the family, collecting and interpreting a detailed family history, and providing appropriate referrals to a cardiogenetic program for further genotype/phenotype evaluation and ongoing medical care, if needed, as well as offering psychosocial support and resources is best done by a certified genetic counselor. Integrated multidisciplinary communications—among the MEs, the families, the clinical programs, and researchers involved in functional study—are best coordinated and facilitated by a genetic counselor who not only understands the testing results and their diagnostic value and impact on at-risk family members, but also ensures that the familial or functional study results of VUS flow back to the medical examiner. This communication aids further understanding of a VUS’ clinical significance and its possible role in cardiac arrhythmia and death certification (Figure 1). This multidisciplinary communication is not commonly practiced, but it is essential to the ME who ultimately certifies the death, thereby providing these critical data to the public health system.
Shared Molecular Mechanisms Driving a Brain-Heart Connected Arrhythmia
An interesting finding from the study by Lahrouchi et al. (1) was the 21 cases with epilepsy patients who had a long-term history of syncope and seizures. Lahrouchi et al. (1) identified a likely cause of death in 5 cases: 2 pathogenic and 2 likely pathogenic variants in RYR2 and 1 pathogenic variant in KCNH2. It is possible, as the authors suggested, that the syncope and seizures are manifestations of the cardiac channel abnormalities. Although various arrhythmias occurring during and after seizures have been described, the converse phenomenon of arrhythmias causing seizures appears to be extremely rare and has only been reported in children after cardioinhibitory syncope (2).
Significantly, cardiac channelopathy genes, such as RYR2, KCNH2, KCNQ1, and SCN5A, have gene expression in the brain in addition to the heart, and epilepsy genes, such as SCN1A, SCN8A, and KCNA1, have gene expression in both the heart and brain (Table 1). A shared genetic susceptibility between brain and heart has been reported in numerous animal models or patient studies (2,3). Therefore, it is possible that both epilepsy and cardiac arrhythmia are the result of the same abnormal activity of the ion channel in the brain and the heart, respectively. Alternatively, it is possible that the abnormal channel activities in the brain cause seizures and syncope that then triggers and disturbs the electrical rhythm of a heart already predisposed to cardiac channel abnormality. The current conceptual paradigm of the epilepsy and cardiac arrhythmia connection was described by Ravindran et al. (3), who proposed that persistent seizures result in the activation of important central autonomic foci, creating the downstream effect of peripherally mediated autonomic stimulation, resulting in the generation of cardiac arrhythmia due to an ion channelopathy in the heart. A recent study of autopsy-negative sudden death through a whole exome study also identified likely pathogenic variants in a few epilepsy genes (4), highlighting the importance of including epilepsy genes in the molecular autopsy panel for autopsy-negative sudden natural death cases.
Implications for Future Directions
Numerous studies have proven the value of molecular autopsy in autopsy-negative sudden natural deaths. Applying stringent genetic variant interpretation will better separate the true pathogenic variants from background noise in the genes for cardiac channelopathy and epilepsy. This is essential for accurate cause of death determination. Additionally, combining familial and functional studies using various cell lines and animal models is expected to enhance our understanding of novel VUS found privately in a single small family. Although simply increasing the number of genes in the testing panel, such as genes for hypertrophic cardiomyopathy or dilated cardiomyopathy, is unlikely to increase the overall yield in autopsy-negative cases, including genes for arrhythmogenic cardiomyopathy, such as PKP2 (5), as well as cardiac arrhythmia and epilepsy genes is important. Furthermore, interrogating noncoding regions, such as the 5′ untranslated region promoter in SCN5A (6), and designing tests to identify large deletions and duplications may further increase the yield of molecular autopsy. To improve our understanding of the likely heterogeneous genetic architecture underlying such sudden deaths, future studies should recruit subjects from diverse ethnic backgrounds and include infants and their families.
Finally, with enhanced multidisciplinary communications among MEs, clinicians, families, and basic researchers mediated thorough a genetic counselor and harnessing the combined power of genomic, transcriptomic, and proteomic studies, we will be better positioned to improve public health through accurate diagnosis and death prevention.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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