Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia (CPVT), ARVD, HCM and dilated cardiomyopathy (DCM) For exceptionally high-risk patients, primary prevention implantable cardioverter defibrillators (ICDs) may be offered although most electrophysiologists follow one or more ICDs that were placed in anticipation of a high-risk outcome before subsequent research helped downgrade the patient's risk in the patient's particular disease Therefore extensive risk-benefit consideration and patient counseling are required to help families understand the balance between the benefits of primary prevention ICDs and the potential risks of ICD placement, including infection, shocks, device malfunction, subsequent interventions, device failure, and psychosocial implications Other diagnoses found in surviving relatives call for therapy that does not directly impact acute arrhythmia risk, but may decrease long-term morbidity and mortality For example, early and severe atherosclerotic coronary heart disease on autopsy should trigger screening for familial hyperlipidemia Autopsy may also uncover conditions such as undiagnosed CHD, vascular malformations that may have ruptured or otherwise caused sudden death, toxicology findings consistent with overdose, or myocarditis While there are suggestions that there may be a heritable component to several of these disorders, the primary work to date has focused on channelopathies and cardiomyopathies, which are amenable to genetic testing for monogenetic autosomal dominant variants In summary, a sudden death event in a previously healthy young person is a dramatic signal that first-degree relatives—siblings, parents, and children— require risk stratification.77–79 Phenotype Screening Among First-Degree Relatives Several cardiac societies have endorsed a systematic approach to phenotype screening among first-degree relatives of a sudden “unexplained” death victim.77 Sudden unexplained death occurs when autopsy and toxicology do not identify a cause of death and toxicology does not suggest a toxic exposure The circumstances of the death should be investigated by interviews with relatives or in collaboration with the medical examiner or coroner's office An expert opinion on cardiac histology can be useful; slides can be mailed for a second opinion Overinterpretation of cardiomyopathy or inflammatory causes in unexperienced hands is more common than underinterpretation.80 The danger of overinterpretation is that it narrows the spectrum of further investigation in firstdegree relatives and puts the remainder of the family at risk for a missed diagnosis of a potentially heritable disorder.81 While phenotypic evaluation of the decedent is being completed by the coroner, medical examiner, or any consultants, an evaluation of first-degree relatives should begin as soon as the family is willing Doctors and families have the same priorities: first-degree relatives with symptoms, especially syncope, palpitations, or known arrhythmias, should be screened as quickly as feasible The initial steps are noninvasive, beginning with history and physical examination Testing should include an ECG in standard 12-lead position and an ECG in a modified position with V1 and V2 in the second intercostal space This position oversamples the right ventricular outflow tract, where Brugada syndrome and ARVD have their central focus of histopathology.77 Echocardiography provides information on ventricular dimensions and function Exercise stress electrocardiography provides information on exercise-sensitive arrhythmia, especially CPVT Myocardium with marginal perfusion can also be identified by exercise stress testing in some cases (e.g., severe premature coronary artery disease) A consensus statement endorses these noninvasive studies in first-degree relatives of a young sudden death victim as class I recommendations.82 More invasive or complex diagnostic studies have been used with varying efficacy They retain class IIA and IIB recommendations in the consensus statement because the test characteristics show neither excellent specificity nor excellent sensitivity As one example, a study from the Cardiac Arrest Survivors with Preserved Ejection Fraction (CASPER) registry performed provocative testing with sodium channel blockers among survivors of cardiac arrest or first-degree relatives with a family history of sudden death.82a In this slightly older cohort (47 years of age ±15 years), testing provoked a Brugada pattern in only 6.9% of subjects, less than half of which were uncovered in subjects with normal resting ECGs and only one of the induced cohort had a positive genotype In our center, we take a staged approach to screening firstdegree family members, beginning with history and physical, two ECGs, echocardiography, and exercise stress testing (class I indications) and only moving to more advanced testing if history and physical or initial testing suggests that further screening is required (see Fig 89.1 for a diagrammatic representation of our screening protocol) Although the consensus statement currently recommends discharging asymptomatic, fully grown adults with negative workups, a low rate of persistent events continues to occur in diagnosis- negative relatives and our understanding of the genetic etiologies remains imperfect.83 Therefore in our center, we continue to see phenotype-negative families at long follow-up intervals to revisit clinical testing as needed and reconsider the state of genotype testing in the family FIG 89.1 Protocol for screening first-degree relatives after a sudden unexplained death First-degree relatives are evaluated in the clinical pathway, beginning with history and physical (H&P), electrocardiography (ECG) in standard and modified right ventricular position, echocardiogram, and exercise stress test If the clinical history is suspicious for a specific etiology or initial testing demonstrates abnormalities, but does not result in a firm diagnosis, then additional clinical investigations are performed in the indeterminate pathway DNA extracted from the decedent is tested in the genetics pathway for a panel of genes associated with channelopathy and cardiomyopathy etiologies associated with sudden death (“molecular autopsy”) Results from molecular autopsy and results from the clinical testing protocol are used together to determine the optimal approach for family cascade screening cMRI, Cardiac magnetic resonance imaging; SAECG, signal-averaged electrocardiogram Genotype Screening Among First-Degree Relatives