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Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
Published on: January 16, 2019
Sudden death associated with short-QT syndrome linked to mutations in HERG
Ramon Brugada1, Kui Hong, Robert Dumaine
1Molecular Genetics Program, Masonic Medical Research Laboratory, 2150 Bleecker St, Utica, NY 13501, USA. brugada@mmrl.edu
Insights
Genetic mutations in the KCNH2 gene cause a new form of short-QT syndrome, leading to sudden cardiac death in young individuals. This discovery offers insights into diagnosis and treatment for these rare heart conditions.
Area of Science:
- Cardiology
- Genetics
- Molecular Biology
Background:
- Sudden cardiac death affects over 300,000 Americans annually.
- A subset of these deaths results from malignant ventricular arrhythmias in hearts without structural abnormalities.
- This study identifies a genetic basis for a syndrome of sudden death and short-QT intervals.
Purpose of the Study:
- To describe the genetic basis of a novel clinical entity characterized by sudden death and short-QT intervals.
- To investigate the molecular mechanisms underlying hereditary short-QT syndrome.
Main Methods:
- Studied three families with hereditary short-QT syndrome.
- Identified missense mutations in the cardiac IKr channel HERG (KCNH2) gene.
- Analyzed the functional consequences of these mutations on ion channel activity.
Main Results:
- Two families had distinct mutations in KCNH2, both causing an N588K amino acid change.
- These mutations significantly increased the IKr current, abbreviating cardiac action potential duration.
- The mutations reduced the affinity of HERG channels for IKr blockers.
Conclusions:
- A novel genetic and biophysical mechanism involving KCNH2 mutations causes sudden death in young individuals.
- Gain-of-function mutations in KCNH2 may be linked to sudden infant death syndrome.
- Findings may improve understanding of drug interactions with KCNH2 and inform diagnosis and therapy for arrhythmogenic diseases.
Background:
Sudden cardiac death takes the lives of more than 300 000 Americans annually. Malignant ventricular arrhythmias occurring in individuals with structurally normal hearts account for a subgroup of these sudden deaths. The present study describes the genetic basis for a new clinical entity characterized by sudden death and short-QT intervals in the ECG.
Methods And Results:
Three families with hereditary short-QT syndrome and a high incidence of ventricular arrhythmias and sudden cardiac death were studied. In 2 of them, we identified 2 different missense mutations resulting in the same amino acid change (N588K) in the S5-P loop region of the cardiac IKr channel HERG (KCNH2). The mutations dramatically increase IKr, leading to heterogeneous abbreviation of action potential duration and refractoriness, and reduce the affinity of the channels to IKr blockers.
Conclusions:
We demonstrate a novel genetic and biophysical mechanism responsible for sudden death in infants, children, and young adults caused by mutations in KCNH2. The occurrence of sudden cardiac death in the first 12 months of life in 2 patients suggests the possibility of a link between KCNH2 gain of function mutations and sudden infant death syndrome. KCNH2 is the binding target for a wide spectrum of cardiac and noncardiac pharmacological compounds. Our findings may provide better understanding of drug interaction with KCNH2 and have implications for diagnosis and therapy of this and other arrhythmogenic diseases.
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