The diagnosis of cardiac Na channelopathies is established in the majority of cases by a high level of clinical suspicion on the part of the treating physician. While SCA/SCD in a previously healthy individual with a structurally normal heart is a definite and typical red flag sign, it has to be highlighted that more and more atypical presentations are being recognised. Although ventricular fibrillation and polymorphic ventricular tachycardia are the hallmarks of these diseases, other dysrhythmias such as monomorphic ventricular tachycardia, prolonged conduction intervals, atrial fibrillation, sinus bradycardia and sinus arrest, or a combination of these should prompt a 'channelopathic approach' to diagnosis. A thorough understanding of the genotype–phenotype correlations is essential to be able to spot an obvious association. For example, cardiac events occurring during rest/sleep are common in SCN5A related diseases such as BrS and LQT3, as opposed to exercise and emotional stress triggered arrhythmias in other inheritable arrhythmias. Fever associated arrhythmias in seemingly healthy young individuals are suggestive of loss-of-function Na channelopathies. The relevance of elucidating a complete and comprehensive family history in index patients cannot be overemphasised.
An ECG (resting ECG, 24 h ECG or drug challenge ECG) is quite often the most useful diagnostic tool in many cases. A systematic scrutiny of all aspects of the ECG should be carried out as atrial and/or ventricular depolarisation and repolarisation abnormalities may exist. In patients with symptoms suggestive of channelopathies and an apparently normal resting ECG, 24 h ECG or an implantable loop recorder may provide additional clues to diagnosis. A prolonged QTc in an individual with SCA during rest is suggestive of LQT3. Drug challenge with Na channel blockers such as flecainide and ajmaline is used to characterise better the not-so-typical ECG signs of BrS in patients with a convincing clinical picture. The role of electrophysiological testing in the diagnosis and prognosis of BrS patients has been an issue of debate and warrants further studies, particularly focusing on the various protocols used and their relation to inducibility of arrhythmias.
Echocardiography and cardiac imaging are conducted to either exclude or better delineate associated structural abnormalities of the heart. However, the presence of congenital cardiac defects in a patient could potentially mask or delay the identification of additional channelopathic disease. Genetic testing has a significant role in diagnosing and risk-stratifying this group of disorders. It is, however, an evolving tool that complements clinical evaluation. For example, only around 20–30% of patients with BrS have identifiable SCN5A mutations. While incomplete disease penetrance and genetic heterogeneity pose challenges to efficient diagnosis and treatment of the index patients and their family members, it is clear that knowing the genetic status of a family with inherited diseases is without doubt relevant in the appropriate management of each individual. Active cascade screening has proven effective in pre-symptomatic treatment of mutation carriers and should be an integral part of patient management in these potentially lethal disorders.