Elsevier

Heart Rhythm

Volume 10, Issue 3, March 2013, Pages 378-382
Heart Rhythm

Risk of life-threatening cardiac events among patients with long QT syndrome and multiple mutations

https://doi.org/10.1016/j.hrthm.2012.11.006Get rights and content

Background

Patients with long QT syndrome (LQTS) who harbor multiple mutations (i.e. ≥ 2 mutations in ≥ 1 LQTS-susceptibility gene) may experience increased risk for life-threatening cardiac events.

Objectives

The present study was designed to compare the clinical course of LQTS patients with multiple mutations to those with a single mutation.

Methods

The risk for life-threatening cardiac events (comprising aborted cardiac arrest, implantable defibrillator shock, or sudden cardiac death) from birth through age 40 years, by the presence of multiple vs. single mutations, was assessed among 403 patients from the LQTS Registry.

Results

Patients with multiple mutations (n=57) exhibited a longer QTc at enrollment compared with those with a single mutation (mean±SD: 506±72 vs. 480±56 msec, respectively; P=0.003) and had a higher rate of life threatening cardiac events during follow-up (23% vs. 11%, respectively; p=0.031). Consistently, multivariate analysis demonstrated that patients with multiple mutations had a 2.3-fold (P=0.015) increased risk for life threatening cardiac events as compared to patients with a single mutation. The presence of multiple mutations in a single LQTS gene was associated with a 3.2-fold increased risk for life threatening cardiac events (P=0.010) whereas the risk associated with multiple mutation status involving>1 LQTS gene was not significantly different from the risk associated with a single mutation (HR 1.7, P=0.26).

Conclusions

LQTS patients with multiple mutations have a greater risk for life-threatening cardiac events as compared to patients with a single mutation.

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)

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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.

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