Long QT Syndrome Clinic and the Windland Smith Rice Sudden Death Genomics Laboratory

Michael J. Ackerman, M.D., Ph.D., Director, Windland Smith Rice Sudden Death Genomics Laboratory.

Long QT syndrome (LQTS) affects 1 in 2,500 people. In 5% to 10% of cases, the first symptom is sudden death, often related to physical exertion or auditory triggers such as an alarm clock. Many cases can be diagnosed following warning signs, however, such as sudden fainting spells or a family history that suggests its potential presence and from objective data derived from electrocardiography, exercise or epinephrine QT stress testing, and genetic testing.

The condition was first clinically described in 1957, but the first LQTS genes were not identified until 1995. The first genetic test for LQTS became clinically available in North America in 2004.

Hundreds of mutations have now been identified in 12 LQTS-susceptibility genes. Of these 12 genes, 9 are minor contributors to the disease, collectively accounting for less than 5% of LQTS. The 3 canonical LQTS-susceptibility genes cause about 70% to 75% of LQTS:

• LQT1 (KCNQ1-encoded potassium channel [IKs] mutations)
• LQT2 (KCNH2-encoded potassium channel [IKr] mutations)
• LQT3 (SCN5A-encoded sodium channel mutations)

Given the potential risk of sudden cardiac death and the genetic nature of this collection of familial heart rhythm syndromes known as the cardiac channelopathies, the challenge is to incorporate and decipher the information derived from all the available clinical tools to accurately diagnose disease, predict risk, and develop a personalized treatment plan.

Currently, 40% of patients who arrive at Mayo Clinic with the diagnosis of LQTS leave Mayo reclassified as otherwise normal. Others arrive having been advised of an urgent need for an implantable defibrillator and leave Mayo effectively managed without a device for their low-risk substrate. Still others have received videoscopic denervation therapy as a potent antifibrillatory intervention as part of their personalized treatment program.

Genetic tests are interpreted comprehensively, and the probabilistic nature of genetic testing has been brought into sharp focus here. Identification of the subset of patients with a negative genetic test has enabled the Mayo Clinic Windland Smith Rice Sudden Death Genomics Laboratory to discover the last 4 of the 12 LQTS-susceptibility genes.

Since its inception in 2000, Mayo Clinic's Long QT Syndrome Clinic has provided comprehensive evaluations for more than 1,000 unique patients and actively manages the care of more than 500 patients with genetically proven LQTS, making Mayo one of the most experienced centers in the world.

The Long QT Syndrome Clinic and the Windland Smith Rice Sudden Death Genomics Laboratory at Mayo Clinic have one of the most comprehensive bedside-to-bench programs internationally for families affected with this condition. It is one of the premier research laboratories for this syndrome worldwide.