Since the first causative gene for cardiomyopathy was discovered in 1990, genetic testing has moved from basic science to clinical application. However, less than 10% of adult EP training deals with the approach to heritable channelopathies such as Long QT syndrome (LQTS). Therefore, a certain unease exists for many of us once these patients present in the afternoon clinic.

The most recent guidelines for genetic testing were just published this month by the Heart Rhythm Society and the European Heart Rhythm Association. The consensus statement provides guidance on 13 different genetic abnormalities of channelopathies and cardiomyopathies.(1) An important difference to other guideline documents is the paucity of randomized clinical trials and, as a result, the reliance on registry data and expert opinions.

The diagnostic yield of these current tests is quite variable, ranging from <20% for short QT, ~25% for Brugada, to >75% for the latest LQTS tests. It is important to remember that genetic tests are probabilistic and not deterministic. Most of us who have sent those tests out are painfully aware of this, especially when the results return as VUS (Variants of Uncertain Significance), which often creates further frustration or anxiety for the patients or family members. Thankfully, first studies have now emerged assessing the frequency of VUS in otherwise healthy volunteers and providing some helpful context for these cases.

Still, this document provides the treating EP with helpful guidance in many cases. For example, in LQTS, genetic testing would be recommended (class I) after a cardiologist (not PCP, interestingly) has a strong clinical suspicion after careful clinical assessment. Similarly, testing (class I) is recommended in asymptomatic, adult patients with QTC >500ms and lack of alternative QT-prolonging etiologies. Note that this is an interesting difference to the currently AHA/ACCF/HRS defined “prolonged QTc” cut-off of 450ms and 460ms in men and women, respectively. It is also important to keep in mind that several series have shown LQTS-associated mutations in 10-20% of patients with drug-induced LQTS cases.

Once a causative mutation in identified, at least all first-degree relatives should undergo mutation-specific LQTS testing, as a completely normal 12-lead ECG, uneventful exam, and history can be seen despite a deleterious mutation.

Beta blockers remain the primary treatment of the potassium-channel related LQT1 (IKs) and LQT2 (IKr), while LQT 3 (increased sodium-channel activity) is frequently treated with propranolol+mexiletine/flecainide combination. When discussing the potential need for an ICD, genetic testing should never be used as a decision maker, but always evaluated in the context of the patient and their history.

With the guidelines providing a detailed update on the always-evolving field of genetic testing, they provide a useful tool for quick reference on the most common genetic abnormalities, including when not to order genetic testing (e.g., atrial fibrillation).

These guidelines will also help us provide additional “genetic training” that is lacking in the curriculum of many EP fellows, and keep us current if the next “channelopathy patient” is waiting in clinic.

Reference
1. Ackerman MJ, Priori SG, Willems S, et al. HRS/EHRA Expert Consensus Statement on the State of Genetic Testing for the Channelopathies and Cardiomyopathies This document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Heart Rhythm 2011;8:1308.

Timm Dickfeld, MD, PhD is the Chief of Electrophysiology at the VA Baltimore, Associate Professor of Medicine at the University of Maryland, and Founder of the Maryland Arrhythmia and Cardiology Imaging Group (MACIG).