EP Tips & Techniques

Precision Cardiology: Lessons From Long QT Syndrome

Makoto Ono1, MD, PhD, Sidney Johnson, MS1, Samy Claude Elayi, MD2, Brian P. Delisle, PhD1

1Department of Physiology, Cardiovascular Research Center, Center for Muscle Biology, University of Kentucky, Lexington, Kentucky

2CHI Saint Joseph Hospital, Lexington, Kentucky

Makoto Ono1, MD, PhD, Sidney Johnson, MS1, Samy Claude Elayi, MD2, Brian P. Delisle, PhD1

1Department of Physiology, Cardiovascular Research Center, Center for Muscle Biology, University of Kentucky, Lexington, Kentucky

2CHI Saint Joseph Hospital, Lexington, Kentucky

Congenital long QT syndrome (LQTS) is an arrhythmogenic disorder primarily caused by mutations that alter the cardiac ion channel function by delaying ventricular repolarization.1 A prolongation in ventricular depolarization increases the probability for early afterdepolarizations, which can generate into life-threatening polymorphic ventricle tachycardia (torsade de pointes) and sudden cardiac death. LQTS occurs in about 1 out of 2,500 patients and is identified in patients all over the world from all ethnic groups. Most patients diagnosed with LQTS can be successfully treated with drugs that block β-adrenergic receptors (β-blockers) and lifestyle interventions (eg, avoiding QT-prolonging drugs, and preventing hypokalemia and hypomagnesemia). Cardiac sympathetic denervation and implantable cardioverter-defibrillators are only recommended for patients with high-risk clinical features.2-4 

Precision medicine has the promise of improving the diagnostic and therapeutic value of genetic testing. This article briefly summarizes the history of precision medicine in LQTS. While there are some successes, several challenges remain.

The first known case report of LQTS dates back to 1856 when Meissner documented the sudden death of a girl with congenital deafness.5 Almost a century later, Herrlin and Möller described the LQTS features on an ECG (including the abnormally long QT interval),6 Jervell and Lange-Nielson gave the first clinical descriptions for autosomal recessive LQTS (Jervell and Lange-Nielson syndrome)7, and Romano and Ward identified the much more common autosomal dominant form of LQTS (Romano-Ward syndrome) (Figure 1).8,9 

In 1979, Moss and Schwartz began an international LQTS registry.10 This registry revealed common phenotypic traits among LQTS families, and led to a phenotypic scoring system to identify new LQTS patients based on the ECG, symptoms, and family history.11,12 During the 1990s, Keating identified the first genetic links for LQTS, and the three major alleles for the major causes of LQTS were identified: KCNQ1 (LQT1), KCNH2 (LQT2), and SCN5A (LQT3).13-19 All of these genes encode cardiac ion channel proteins critical for normal cardiac electrical activity. Generally speaking, LQTS-linked mutations cause a net decrease in the repolarizing ionic current during the ventricular action potential. This results in a prolongation of the action potential duration and an increase in the heart rate corrected QT interval on the ECG. 

Clinicians soon recognized specific genotype-phenotype characteristics between LQT1, LQT2, and LQT3 patients. These included gene-specific triggers for life-threatening events and responsiveness to β-blockers.20,21 LQT1 patients tend to suffer arrhythmias with exercise; LQT2 patients tend to suffer events when startled (eg, alarm clocks and telephones); and LQT3 patients often have symptoms during sleep.22 Understanding the types of LQTS has led to personalized improvements in risk stratification and management. Current recommendations limit genetic testing for LQTS to phenotypically positive or borderline patients — mostly represented by a relatively clear QT prolongation when an ECG is performed, sudden cardiac arrest, and/or sudden cardiac death in the family — in what is named a “phenotype-first” approach.23 Diagnosing borderline patients is restricted to those with an “unequivocal” LQTS-causing mutation, where a specific mutation is known and clearly linked to LQTS. 

Unfortunately, mortality rates are still high every year because LQTS is not always diagnosed before a life-threatening arrhythmia. This occurs for several reasons: (1) the QT on the ECG can often not be accurately and objectively determined; (2) some LQTS patients have a QT on the ECG similar to non-LQTS patients; and (3) many patients have never had an ECG until after a life-threatening event occurs.2,24-26 The “phenotype-first” method has many limitations and does not incorporate the use of increasingly available patient genetic data (eg, whole exome or genome sequencing).25 On the other hand, a “genetic-first” method, where genetic screening could facilitate the early identification and prophylactic treatment of LQTS, seems very attractive. However, genetic screening often identifies novel, rare variants of uncertain pathological significance (VUS) at a frequency that far outpaces the incidence of disease. Thus, most of these variants are probably benign, and they limit our ability to identify which variants likely confer a high risk for the disease. It is therefore critical to bridge the gap between our knowledge of causative genes in LQTS and improve our ability to decipher the functional consequences for the large number of variants in the major LQTS genes.

In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association of Molecular Pathology (AMP) worked to develop a predictive rubric that classifies gene variants in Mendelian-linked diseases as pathogenic, likely pathogenic, uncertain significance, likely benign, and benign.27 Genetic variants are segregated into these five categories based on population data (mean allelic frequency of the variant), computational data, functional data, and segregation data. This rubric can be applied to variants identified in LQT1, LQT2, and LQT3 alleles, and allows clinician scientists to delineate which variants confer a high risk for LQTS.28 Patients with high-risk variants can then be proactively screened for LQTS before they suffer a life-threatening event. This strategy would allow identification and treatment of unrecognized LQTS in patients before a life-threatening event occurs, and potentially save more lives.

Despite the major progress accomplished over the last few decades, several challenges remain. One challenge is that the absolute penetrance of LQTS is not exactly clear. By genetically sequencing only phenotype-positive patients, we have likely overestimated penetrance of the disease. Large-scale genetic screening of patients without LQTS will help us determine the percentage of ostensibly healthy people who harbor pathogenic variants. Although LQT1, LQT2, and LQT3 are considered Mendelian diseases, variants can impact the function of mutant ion channel proteins with varying degrees of severity. For example, some variants might not disrupt the ion channel function to cause LQTS, but they can modify the function of the ion channel to increase a patient’s susceptibility for drug-induced QT prolongation (acquired long QT). Lastly, the ACMG/AMP guidelines are very broad, which might lead to misclassification of variants to under- or overestimate the risk. Future studies that can tailor the guidelines specifically for LQTS genes will improve the precision with which clinician scientists can start with genetic data and delineate which variants are benign, and which confer a high risk for congenital LQTS or increased risk for drug-induced acquired long QT. 

Disclosures: The authors have no conflicts of interest to report regarding the content herein.

References
  1. Moss AJ. Long QT syndrome. JAMA. 2003;289(16):2041-2044.
  2. Priori SG, Wilde AA, Horie M, et al. Executive summary: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Heart Rhythm. 2013;10(12):e85-e108.
  3. Schwartz PJ, Crotti L, Insolia R. Long-QT syndrome: from genetics to management. Circ Arrhythm Electrophysiol. 2012;5(4):868-877.
  4. Wang Q, Chen Q, Towbin JA. Genetics, molecular mechanisms and management of long QT syndrome. Ann Med. 1998;30(1):58-65.
  5. Meissner FL. Deaf and Deaf Education [in German]. Leipzig and Heidelberg: Winter, 1856:119-120.
  6. Herrlin KM, Möller T. A case of cardiac syncope. Acta Paediatrica. 1953;42:391.
  7. Jervell A, Lange-Nielsen F. Congenital deaf-mutism, functional heart disease with prolongation of the Q-T interval and sudden death. Am Heart J. 1957;54(1):59-68.
  8. Romano C, Gemme G, Pongiglione R. [Rare cardiac arrythmias of the pediatric age. II. Syncopal attacks due to paroxysmal ventricular fibrillation. (Presentation of 1st case in italian pediatric literature)]. Clin Pediatr (Bologna). 1963;45:656-683.
  9. Ward OC. A new familial cardiac syndrome in children. J Ir Med Assoc. 1964;54:103-106.
  10. Moss AJ, Schwartz PJ. 25th anniversary of the International Long-QT Syndrome Registry: an ongoing quest to uncover the secrets of long-QT syndrome. Circulation. 2005;111(9):1199-1201.
  11. Schwartz PJ. Idiopathic long QT syndrome: progress and questions. Am Heart J. 1985;109(2):399-411.
  12. Schwartz PJ, Moss AJ, Vincent GM, Crampton RS. Diagnostic criteria for the long QT syndrome. an update. Circulation. 1993;88(2):782-784.
  13. Keating M, Atkinson D, Dunn C, Timothy K, Vincent GM, Leppert M. Linkage of a cardiac arrhythmia, the long QT syndrome, and the Harvey ras-1 gene. Science. 1991;252(5006):704-706.
  14. Sanguinetti MC, Jiang C, Curran ME, Keating MT. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell. 1995;81(2):299-307.
  15. Trudeau MC, Warmke JW, Ganetzky B, Robertson GA. HERG, a human inward rectifier in the voltage-gated potassium channel family. Science. 1995;269(5220):92-95.
  16. Wang Q, Curran ME, Splawski I, et al. Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nature Genetics. 1996;12(1):17-23.
  17. Donger C, Denjoy I, Berthet M, et al. KVLQT1 C-terminal missense mutation causes a forme fruste long-QT syndrome. Circulation. 1997;96(9):2778-2781.
  18. Curran ME, Splawski I, Timothy KW, Vincent GM, Green ED, Keating MT. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell. 1995;80(5):795-803.
  19. Wang Q, Shen J, Splawski I, et al. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell. 1995;80(5):805-811.
  20. Ellinor PT, Milan DJ, MacRae CA. Risk stratification in the long-QT syndrome. N Engl J Med. 2003;349(9):908-909. author reply 908-909.
  21. Priori SG, Schwartz PJ, Napolitano C, et al. Risk stratification in the long-QT syndrome. N Engl J Med. 2003;348(19):1866-1874.
  22. Ruan Y, Liu N, Napolitano C, Priori SG. Therapeutic strategies for long-QT syndrome: does the molecular substrate matter? Circulation. 2008;1(4):290-297.
  23. 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(8):1308-1339.
  24. Taggart NW, Haglund CM, Tester DJ, Ackerman MJ. Diagnostic miscues in congenital long-QT syndrome. Circulation. 2007;115(20):2613-2620.
  25. Kapa S, Tester DJ, Salisbury BA, et al. Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants. Circulation. 2009;120(18):1752-1760.
  26. Horner JM, Horner MM, Ackerman MJ. The diagnostic utility of recovery phase QTc during treadmill exercise stress testing in the evaluation of long QT syndrome. Heart Rhythm. 2011;8(11):1698-1704.
  27. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424.
  28. Adler A, Novelli V, Amin AA, et al. An international, multicentered, evidence-based reappraisal of genes reported to cause congenital long QT syndrome. Circulation. 2020;141(6):418-428.
/sites/eplabdigest.com/files/articles/images/Delisle.pdf