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Updated: Jun 13, 2025
Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
Published on: January 16, 2019
Children and Adolescent Patients with Variants in the ATP1A3 -encoded Sodium-Potassium ATPase Alpha-3 Subunit
Insights
Individuals with the ATP1A3-D801N variant experience abnormal QT interval shortening at lower heart rates, increasing arrhythmia risk. This effect is worsened by sinus node dysfunction, highlighting a critical cardiac manifestation of Alternating Hemiplegia of Childhood.
Area of Science:
- Cardiology
- Genetics
- Neurology
Background:
- Alternating Hemiplegia of Childhood (AHC) is a rare disorder with neurological and cardiac symptoms.
- The ATP1A3-D801N variant is linked to a short QT interval and arrhythmia risk after bradycardia.
- The precise mechanism behind this cardiac risk remains unclear.
Purpose of the Study:
- To investigate the relationship between heart rate (HR), QT interval, and corrected QT (QTc) in individuals with the ATP1A3-D801N variant.
- To determine if impaired QT/QTc shortening at lower HR contributes to arrhythmia predisposition.
- To explore the prevalence of sinus node dysfunction in a broader cohort with ATP1A3-related phenotypes.
Main Methods:
- Retrospective observational study of AHC patients undergoing Holter monitoring and genetic testing.
- Inclusion of a healthy control cohort for comparison.
- Linear regression analysis to assess HR, QT, and QTc dynamics.
Main Results:
- Individuals with ATP1A3-D801N showed significantly impaired QT shortening and abnormal QTc prolongation at lower HR compared to healthy controls.
- Patients with ATP1A3-related phenotypes and a baseline QTc <350ms exhibited greater QT/QTc dynamic impairments.
- A small subset of worldwide cases with ATP1A3-related phenotypes required device implantation or experienced significant sinus pauses.
Conclusions:
- The ATP1A3-D801N variant causes paradoxical QT/QTc shortening at lower HR, elevating arrhythmia risk during bradycardia.
- Underlying sinus node dysfunction further exacerbates this cardiac risk in AHC patients.
- These findings elucidate a key cardiac mechanism in ATP1A3-related disorders.
Background:
Alternating hemiplegia of childhood (AHC) is a rare disorder with both neurologic and cardiac manifestations. The ATP1A3-D801N variant is associated with a pathologically short QT interval and risk of ventricular arrhythmia following bradycardia; however, the mechanism of this remains unknown. We investigated the relationship between heart rate (HR), QT, and QTc, hypothesizing that individuals with ATP1A3-D801N have abnormal, impaired shortening of QT and QTc at lower HR leading to arrhythmia predisposition.
Methods:
We performed a retrospective observational study of individuals who underwent clinical evaluation, Holter monitoring, and genetic testing for AHC at Duke University Hospitals. We also compiled a group of healthy individuals as a control cohort. A larger, worldwide cohort of individuals with ATP1A3 -related phenotypes was compiled to investigate sinus node dysfunction. Linear regression analysis was then performed.
Results:
The cohort consisted of 44 individuals with ATP1A3 -related phenotypes with 81 Holter recordings (52.27% female; mean age at first Holter 8.04 years, range 0.58 - 33 years), compared to 36 healthy individuals with 57 Holter recordings (52.78% female; mean age at first Holter 9.84 years, range 0.08 - 38 years). Individuals with ATP1A3-D801N had reduced prolongation of QT at lower HR, manifest as a significantly lower slope for HR vs QT compared to healthy (P<0.0001). This resulted in a significantly higher slope of the relationship for HR vs QTc compared to healthy (P<0.0001). Individuals with ATP1A3 -related phenotypes and baseline QTc <350 milliseconds (ms) had increased shortening of QT and QTc at lower HR compared to those with normal QTc (P=0.003; P=0.001). Among worldwide cases, 3 out of 131 individuals with ATP1A3 -related phenotypes required device implantation and/or had sinus pauses >4 seconds.
Conclusions:
Individuals with the ATP1A3-D801N variant exhibit paradoxical shortening of QT and QTc at lower HR, which contributes to an increased risk of arrhythmias during bradycardia. This is exacerbated by an underlying risk of sinus node dysfunction.
Clinical Perspective:
What is Known:Individuals with ATP1A3-D801N have a short baseline QTc.Two individuals with AHC experienced ventricular fibrillation following bradycardia.What the Study Adds:The QT and QTc shorten to a greater extent at lower heart rate in individuals with ATP1A3-D801N than in healthy individuals. Individuals with ATP1A3 -related phenotypes and QTc <350ms show greater impairment of QT and QTc dynamics than those with normal QTc. There is low prevalence of device implantation and significant sinus pauses in individuals with ATP1A3 -related phenotypes, with a relatively greater prevalence in those with ATP1A3-D801N.
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