Risk of life-threatening cardiac events among patients with long QT syndrome and multiple mutations
Introduction
Genetic testing adds important information to the diagnosis, risk stratification, and management of long QT syndrome (LQTS). To date, more than 600 mutations have been identified in 13 LQTS genes. The LQT1, LQT2, and LQT3 genotypes comprise more than 95% of the patients with genotype-positive LQTS and approximately 75% of all patients with LQTS.1, 2 LQTS exhibits incomplete penetrance (ie, the likelihood that a disease-causing mutation will have a phenotypic expression in a mutation-positive subject) and variable expressivity (ie, the level of phenotypic expression). Thus, within the same LQTS family, some LQTS genotype-positive subjects may display a markedly prolonged corrected QT interval (QTc) and experience syncope, aborted cardiac arrest (ACA), or death whereas others have a normal QTc and may be asymptomatic.
Among the potential factors that may explain the incomplete penetrance and variable expressivity associated with LQTS is the presence of multiple mutations. Multiple mutations (ie,≥2 LQTS-associated mutations in the same individual) could involve either (1) the same allele of one LQTS-associated gene, (2) both alleles of the same LQTS-associated gene, or (3) different LQTS genes. Excluding patients with the autosomal recessive form of LQTS associated with deafness (Jervell and Lange-Nielsen syndrome [JLNS]), it has been suggested that the prevalence of multiple mutation status worldwide is between 8% and 11% among unrelated patients with LQTS and that patients with multiple LQTS mutation have a greater risk for cardiac events than those with a single LQTS mutation.3, 4, 5, 6
However, there are limited data on the risk for life-threatening cardiac events (including defibrillator shock, ACA, and sudden cardiac death [SCD]) among patients with multiple mutations.3, 5 In particular, there are no data comparing the risk of life-threatening cardiac events among important subgroups of patients with multiple mutations. Therefore, the present study aimed at (1) evaluating and comparing the risk for life-threatening cardiac events among patients with multiple mutations to those with a single LQTS mutation and (2) evaluating the effect of multiple mutation status involving the same gene vs multiple mutation status involving multiple genes on the patient’s clinical course.
Section snippets
Study population and data collection
The study population of 403 subjects was derived from 196 proband-identified families drawn from the US portion of the International LQTS Registry.7 Patients were divided into 2 groups based on the presence of either (1) multiple LQTS mutations or (2) a single LQTS-associated mutation. The group of patients with only 1 LQTS mutation (control group) was drawn from a group of patients consisting of (1) family members of patients with multiple mutations who were tested for all known family
Study population
The present study included 403 patients from 196 families. There were 346 patients with a single LQTS mutation (control group) from 188 families and 57 patients with multiple mutations from 23 families (54 patients had 2 mutations and 3 patients had 3 mutations). Of the 57 patients with multiple LQTS mutations, 24 had≥2 mutations in the same gene and 33 had≥2 mutations involving more than 1 gene. The spectrum of mutations as categorized by single/multiple mutations and LQTS gene and their
Discussion
The present study is the first to assess the risk of life-threatening cardiac events among patients with multiple LQTS mutations and to evaluate outcome among specific subsets of this group as compared with patients with a single mutation. Our findings provide several important implications useful in risk assessment and management of patients with LQTS. We have shown that (1) patients with multiple mutations have a significantly increased risk for life-threatening cardiac events (including ICD
Summary and clinical implications
Advances in genetic testing technology have led to a proliferation of new genetic tests and more cost-effective genetic testing that can establish a definitive molecular diagnosis for symptomatic patients suspected to have inherited arrhythmias. Specifically, genetic testing and genotype-phenotype correlations can add important information for predicting outcome and for selection of treatment among patients with the congenital LQTS.14, 15, 16, 17 The presence of multiple mutations is not
References (17)
- et al.
Long QT syndrome
J Am Coll Cardiol
(2008) - et al.
Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing
Heart Rhythm
(2005) - et al.
Long QT syndrome with compound mutations is associated with a more severe phenotype: a Japanese multicenter study
Heart Rhythm
(2010) Long QT syndrome: a double hit hurts more
Heart Rhythm
(2010)- et al.
Congenital deaf-mutism, functional heart disease with prolongation of the Q-T interval and sudden death
Am Heart J
(1957) - et al.
Long QT syndrome
Curr Probl Cardiol
(2008) - et al.
Mutation site-specific differences in arrhythmic risk and sensitivity to sympathetic stimulation in the LQT1 form of congenital long QT syndrome: multicenter study in Japan
J Am Coll Cardiol
(2004) - et al.
Risk stratification in the long-QT syndrome
N Engl J Med
(2003)
Cited by (37)
Congenital Long QT Syndrome
2022, JACC: Clinical ElectrophysiologyCitation Excerpt :This step-wise gradient is supported by findings of an increased HR for CE or SAE of ∼1.1 for every 10-ms increment in QTc interval.38,116,124,127,128 When dichotomized based on QTc interval, patients with a QTc interval ≥500 ms are ∼2 to 3 times more likely to experience CE or SAE compared with LQTS patients with a QTc interval <500 ms,110,111,114,123,125,129,130 including those who are medically managed with β-blockers.129 Pragmatically, the application of a QTc ≥500 ms is a reasonable approach for the identification of high-risk patients with LQTS, because this corresponds with a 1.9% to 2.1%/year incidence of CE and 0.5% to 1.3%/year incidence of SAE.112,131
Channelopathies That Lead to Sudden Cardiac Death: Clinical and Genetic Aspects
2019, Heart Lung and CirculationLong QT Syndrome and Torsade de Pointes
2017, Encyclopedia of Cardiovascular Research and MedicineIron Overload Leading to Torsades de Pointes in β-Thalassemia and Long QT Syndrome
2016, Cardiac Electrophysiology ClinicsCitation Excerpt :These parameters and risk markers were all included in the updated Schwartz score (in 2011).27 In a recent study done by Mullally and colleagues28 in evaluating predictors of life-threatening cardiac events, prior syncope and severe QT prolongation (QTc >500 ms) were associated with 15-fold and 4-fold increase in lethal events, respectively. LQTS patients should be advised to avoid medications that prolong the QT interval (https://www.crediblemeds.org/).
Genetic modulators of the phenotype in the long QT syndrome: state of the art and clinical impact
2015, Current Opinion in Genetics and DevelopmentCitation Excerpt :They found that carriers of two mutations had longer QTc intervals (an average of 17 ms) and were 3.5-fold more probably to have cardiac arrest (56% versus 27%) compared with probands with one or no identified mutation [15]. These results have been recently reproduced by Mullally et al. [16], who reported a multivariate analysis on fifty-seven LQTS patients with double mutations contrasted against a cohort of single mutation carriers (n = 346). The presence of two concurrent genetic defects was associated with a HR of 3.2 (95% CI: 1.30–7.61) for the occurrence of life-threatening events.
Polygenic case of long QT syndrome confirmed through functional characterization informs the interpretation of genetic screening results
2015, HeartRhythm Case ReportsCitation Excerpt :The KCNH2/hERG-S654G mutation is classified by the FAMILION genetic testing as class I. hERG-A913V is scored as class II by FAMILION. Both mutations have been potentially linked to arrhythmia, although they have not been functionally characterized.6,7 SCN5A-F1596I was scored as class I by FAMILION.
This work was supported in part by research grants HL-33843 and HL-51618 to the University of Rochester Medical Center from the National Institutes of Health, Bethesda, MD. Dr. Moss received a research grant from GeneDx. Dr. Kaufman received research grant from CardioDx and St Jude Medical. Dr. Ackerman has a consulting relationship and license agreement/royalty arrangement with Transgenomic and received consultant fees from Medtronic, Biotronik, Boston Scientific, and St Jude Medical.
This research was carried out while Dr. Barsheshet was a Mirowski-Moss Career Development Awardee at the University of Rochester Medical Center, Rochester, NY.