Cardiogenetic screening of first-degree relatives after sudden cardiac death in the young: a population-based approach

This editorial refers to ‘Cardiogenetic screening of first-degree relatives after sudden cardiac death in the young: a population-based approach’ by A. Hendrix et al., on page 716. The term sudden unexpected death syndrome (SUDS) was first used by Professor Michael Davies 25 years ago to describe deaths that remain unexplained despite expert pathological review.1 He recommended that SUDS be made a specific diagnostic category on the death certificate to aid bereaved families and to promote research in the field. Sudden unexpected death syndrome or, as it is frequently termed, sudden arrhythmic death syndrome (SADS) represents a potentially avoidable cause of death in an otherwise healthy individual. The emotional and psychological consequences of these deaths are devastating for the families affected and this is compounded by the fact that a significant proportion are due to inherited conditions, hence raising complex questions regarding clinical and genetic screening and its consequences. Once one excludes acute myocardial infarction and structural heart disease (e.g. hypertrophic cardiomyopathy, aortic stenosis, and anomalous coronary arteries), the principal causes of sudden deaths are electrical-ion channelopathies: long QT syndrome, Brugada syndrome, cathecholaminergic polymorphic ventricular tachycardia, and concealed forms of cardiomyopathy such as arrhythmogenic right ventricular cardiomyopathy (ARVC). A cardiologist facing the task of screening families for these disorders must be prepared to keep an open mind and ensure that first-degree relatives are screened in a systematic manner as these disorders can still promote lethal ventricular arrhythmia in the absence of overt ECG abnormalities on a random resting ECG. For example, in long QT syndrome, the cumulative probability of life-threatening events in families with established disease in individuals with an apparently normal QTc on resting ECG is 4% between 0 and 40 years vs. 0.4% in unaffected relatives.2 Dynamic changes in QT interval may only manifest on exercise ECG testing (QT prolongation in recovery) or 24 h Holter recording when diurnal changes in autonomic tone lead to marked QT prolongation, e.g. at night in LQT3. In addition, the utilization of pharmacological testing is vital, e.g. ajmaline challenge testing to exclude Brugada syndrome. In two recent familial screening series, ajmaline challenge testing made a significant contribution to the diagnostic yield, facilitating appropriate monitoring, medication advice, and follow-up.3,4 This test should be routine in any SADS family screening programme following appropriate counselling. In this month's edition of the journal, Hendrix et al.5 describe the results of routine clinical screening of SUDS families and aborted sudden death victims in a district hospital setting. A proportion of deaths occurred in individuals with structural heart disease identified at post-mortem and therefore would not reach the definition of a SADS death, which requires the heart to be structurally normal ideally after expert pathological review. The study emphasizes a number of points in this difficult area. The diagnostic yield of family screening was low compared with other series, 14 vs. 33–55%, primarily because larger series employed a systematic approach, including pharmacological challenge testing, detailed Holter and exercise ECG testing, and advanced imaging if a cardiomyopathy was suspected. These higher diagnostic yields were achieved by an interdisciplinary approach between electrophysiologists and cardiologists with expertise in cardiomyopathy as well as geneticists to interpret the results of targeted gene testing. One could argue that these lower yields described by this population-based study represent real-world experience since tertiary centres screening for these conditions may have a selection bias of already screening families diagnosed at other centres. However, the higher diagnostic yields are primarily achieved through the utilization of ajmaline challenge testing and detailed cardiac imaging with the expansion of screening to first-degree relatives in the wider family. At present, SADS diagnostic yields are restricted to the 50% mark for a number of reasons. First of all the index case's death may be caused by a private mutation in that individual alone, and thus other relatives are unaffected, making family screening irrelevant in that case. There are likely to be other ion channelopathies responsible for lethal arrhythmia which are yet to be fully characterized–the emergence of J-wave syndromes as a recognized cause of idiopathic ventricular fibrillation is a case in point.6 Furthermore, ventricular arrhythmia in an index case may not arise as a result of a single ion channel mutation but a combination of mutations or polymorphisms in ion channel genes and structural proteins, to create a uniquely lethal arrhythmic substrate in that individual which is not necessarily relevant to other family members.7 A vital requirement to address some of these issues is to improve the collection and storage of genetic material at post-mortem. Recent pathological guidelines have highlighted the importance of performing a detailed, systematic post-mortem in SADS cases to ensure that early manifestations of hypertrophic cardiomyopathy, ARVC, conduction disease, etc. are not missed.8 These guidelines also recommend the collection and storage of DNA from EDTA blood or frozen spleen to facilitate molecular autopsy. Limited case series of such an approach demonstrate that a ‘molecular autopsy' can enable diagnosis of channelopathies, especially long QT and ryanodine receptor mutations responsible for catecholaminergic polymorphic ventricular tachycardia.9 Such information is invaluable since a recognized pathological mutation can be cascade screened throughout the family and appropriate preventative measures undertaken. It also means that resources do not have to be wasted in comprehensive clinical screening for all family members. However, the molecular approach is a double-edged sword. Inevitably, missense mutations or novel sequence changes will be identified which theoretically could produce structural changes in key ion channel or other myocyte proteins which could be arrhythmogenic. Such changes need to be evaluated using dedicated cell culture and animal models to establish their clinical relevance in conjunction with evaluating the familial phenotype. With the march of technology such as high throughput sequencing, it is now possible to sequence an individual's entire exome in a few days. This has already revealed that most healthy individuals harbour potentially pathological sequence variants in a number of genes which are not necessarily of any clinical relevance to that individual.10 Therefore, with this wealth of additional genetic data comes the responsibility of the clinician to weigh the evidence and balance the application of this information in the diagnosis, risk stratification, and management of the SADS victim's family. This will only be achieved by ensuring that clinicians involved in this field share their expertise, paying close attention to clinically characterizing the SADS family members, and apply the results of genetic testing judiciously in the light of clinical evidence. Conflict of interest: none declared. This research was funded by UCL NIHR, Medical Research Council, British Heart Foundation, Heart UK.