Related Experiment Video
Updated: May 24, 2025
07:15
Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
Published on: January 16, 2019
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ATP1A3 Variants, Variably Penetrant Short QT Intervals, and Lethal Ventricular Arrhythmias
Mary E Moya-Mendez1, Minu-Tshyeto Bidzimou1, Padmapriya Muralidharan1
1Department of Pediatrics, Division of Pediatric Cardiology, Duke University School of Medicine, Durham, North Carolina.
JAMA Pediatrics
|March 3, 2025
Summary
Alternating hemiplegia of childhood (AHC) linked to ATP1A3 variants can cause short QT intervals. The D801N variant is associated with ventricular arrhythmias and may explain sudden unexplained death in AHC patients.
Area of Science:
- Cardiology
- Genetics
- Neurology
Background:
- Alternating hemiplegia of childhood (AHC) is a rare neurological disorder often caused by pathogenic variants in the ATP1A3 gene.
- While primarily neurological, AHC is associated with sudden unexplained death (SUD), potentially due to cardiac arrhythmias.
Purpose of the Study:
- To investigate the impact of ATP1A3 variants on cardiac electrophysiology in AHC patients.
- To determine if specific ATP1A3 variants are linked to lethal ventricular arrhythmias and SUD in AHC.
Main Methods:
- An international, multicenter case-control study involving 148 AHC patients and 74 controls.
- Analysis of QT intervals and corrected QT intervals (QTc) from electrocardiograms.
- Generation of induced pluripotent stem cell cardiomyocytes from patients with the ATP1A3 D801N variant for in vitro studies.
Main Results:
- Patients with the ATP1A3 D801N variant exhibited significantly shorter QTc intervals compared to other variants and controls (P < .001).
- Nearly 70% of D801N variant carriers had short QTc (<370 milliseconds).
- Three D801N-positive individuals experienced major cardiac events, unlike any in other groups (P = .02).
Conclusions:
- The ATP1A3 D801N variant is strongly associated with short QTc and ventricular arrhythmias in AHC.
- These cardiac electrophysiological abnormalities may be the underlying cause of sudden unexplained death in AHC patients.
- Targeted cardiac evaluation is crucial for AHC patients with ATP1A3 variants.
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