From gene-specific to function-specific risk stratification in long QT syndrome Type 2: implications for clinical management

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Graphical Abstract

The graphical abstract represents three possible functional conditions. On the left is a cell with no disease-causing variant in the potassium voltage-gated channel subfamily H member 2 ( KCNH2) gene, and therefore, potassium channels are composed by four wild-type (WT) subunits (blue small circles). In the middle panel is a cell with haploinsufficiency (HI): there are less potassium channels available, but all with WT subunits. On the right panel is a cell with a mutation causing a dominant-negative (DN) effect: channels are composed by a random mix of WT and mutant subunits (red small circles). The amount of rapid component of the delayed rectifier potassium current (IKr) is progressively decreasing going from WT to HI to DN with an opposite increase in QT interval corrected for heart rate (QTc) and arrhythmic risk.

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NOS1AP is a genetic modifier of the long-QT syndrome.

Althea Goosen, Maria Cristina Monti, Anna Peljto … (2009)

In congenital long-QT syndrome (LQTS), a genetically heterogeneous disorder that predisposes to sudden cardiac death, genetic factors other than the primary mutation may modify the probability of life-threatening events. Recent evidence indicates that common variants in NOS1AP are associated with the QT-interval duration in the general population. We tested the hypothesis that common variants in NOS1AP modify the risk of clinical manifestations and the degree of QT-interval prolongation in a South African LQTS population (500 subjects, 205 mutation carriers) segregating a founder mutation in KCNQ1 (A341V) using a family-based association analysis. NOS1AP variants were significantly associated with the occurrence of symptoms (rs4657139, P=0.019; rs16847548, P=0.003), with clinical severity, as manifested by a greater probability for cardiac arrest and sudden death (rs4657139, P=0.028; rs16847548, P=0.014), and with greater likelihood of having a QT interval in the top 40% of values among all mutation carriers (rs4657139, P=0.03; rs16847548, P=0.03). These findings indicate that NOS1AP, a gene first identified as affecting the QTc interval in a general population, also influences sudden death risk in subjects with LQTS. The association of NOS1AP genetic variants with risk for life-threatening arrhythmias suggests that this gene is a genetic modifier of LQTS, and this knowledge may be clinically useful for risk stratification for patients with this disease, after validation in other LQTS populations.

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Increased risk of arrhythmic events in long-QT syndrome with mutations in the pore region of the human ether-a-go-go-related gene potassium channel.

Anthony J W Hall, Tawnya Peterson, Elizabeth S Kaufman … (2002)

The hereditary long-QT syndrome is characterized by prolonged ventricular repolarization and a variable clinical course with arrhythmia-related syncope and sudden death. Mutations involving the human ether-a-go-go-related gene (HERG) channel are responsible for the LQT2 form of long-QT syndrome, and in cellular expression studies these mutations are associated with reduction in the rapid component of the delayed rectifier repolarizing current (I(Kr)). We investigated the clinical features and prognostic implications of mutations involving pore and nonpore regions of the HERG channel in the LQT2 form of this disorder. A total of 44 different HERG mutations were identified in 201 subjects, with 14 mutations located in the pore region (amino acid residues 550 through 650). Thirty-five subjects had mutations in the pore region and 166 in nonpore regions. Follow-up extended through age 40 years. Subjects with pore mutations had more severe clinical manifestations of the genetic disorder and experienced a higher frequency (74% versus 35%; P<0.001) of arrhythmia-related cardiac events occurring at earlier age than did subjects with nonpore mutations. Multivariate Cox proportional hazard regression analysis revealed that pore mutations dominated the risk, with hazard ratios in the range of 11 (P<0.0001) for QTc at 500 ms, with a 16% increase in the pore hazard ratio for each 10-ms increase in QTc. Patients with mutations in the pore region of the HERG gene are at markedly increased risk for arrhythmia-related cardiac events compared with patients with nonpore mutations.

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Calmodulin mutations and life-threatening cardiac arrhythmias: insights from the International Calmodulinopathy Registry.

Lia Crotti, Carla Spazzolini, David J. Tester … (2019)

Calmodulinopathies are rare life-threatening arrhythmia syndromes which affect mostly young individuals and are, caused by mutations in any of the three genes (CALM 1-3) that encode identical calmodulin proteins. We established the International Calmodulinopathy Registry (ICalmR) to understand the natural history, clinical features, and response to therapy of patients with a CALM-mediated arrhythmia syndrome.

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Lia Crotti:

ORCID: https://orcid.org/0000-0001-8739-6527

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Journal ID (nlm-ta): Europace

Journal ID (iso-abbrev): Europace

Journal ID (publisher-id): europace

Title: Europace

Publisher: Oxford University Press (US )

ISSN (Print): 1099-5129

ISSN (Electronic): 1532-2092

Publication date Collection: April 2023

Publication date (Electronic): 01 March 2023

Publication date PMC-release: 01 March 2023

Volume: 25

Issue: 4

Pages: 1320-1322

Affiliations

Istituto Auxologico Italiano IRCCS, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics , Via Pierlombardo 22, 20135, Milan, Italy

Department of Medicine and Surgery, University of Milano-Bicocca , Via Cadore 48, 20900, Monza, Italy

Author notes

The opinions expressed in this article are not necessarily those of the Editors of Europace or of the European Society of Cardiology.

Corresponding author. Tel: 02/619112374. E-mail address: liacrotti@ 123456yahoo.it or l.crotti@ 123456auxologico.it

Conflict of interest: None declared.

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Lia Crotti https://orcid.org/0000-0001-8739-6527

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Publisher ID: euad035

DOI: 10.1093/europace/euad035

PMC ID: 10105882

PubMed ID: 36857538

SO-VID: 1b033626-0a15-4e7a-a8d1-89bc7c4d35d7

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This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

From gene-specific to function-specific risk stratification in long QT syndrome Type 2: implications for clinical management

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Karger: Cardiovascular System

Most cited references 15

NOS1AP is a genetic modifier of the long-QT syndrome.

Increased risk of arrhythmic events in long-QT syndrome with mutations in the pore region of the human ether-a-go-go-related gene potassium channel.

Calmodulin mutations and life-threatening cardiac arrhythmias: insights from the International Calmodulinopathy Registry.

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