ATP1A3 ‐Encoded Sodium‐Potassium ATPase Subunit Alpha 3 D801N Variant Is Associated With Shortened QT Interval and Predisposition to Ventricular Fibrillation Preceded by Bradycardia

Figures

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  Figure 1. Study design and genetic distribution of subjects involved in the study. A, Flowchart showing the design of this study and the distribution of subgroups used for analysis. Chart representing the study subgroups. B, Pie chart showing distribution of typical vs atypical alternating hemiplegia of childhood (AHC) in the study cohort. C, Genotype‐positive vs genotype‐negative individuals. D, Genes positive by panel genetic testing. Numbers represent the proportion of individuals present within each group among unrelated probands. Gene Neg indicates genotype‐negative; Gene Pos, genotype‐positive; QTc, corrected QT; and SCA, sudden cardiac arrest.

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  Figure 2. Comparison of corrected QT (QTc) measurements between study subgroups separated by genotype. A, ECG of an 8‐month‐old girl who carries the ATP1A3‐D801N variant; micron bar represents 0.4 seconds. B, ECG of a 16‐year‐old boy who is ATP1A3 genotype‐negative, typical alternating hemiplegia of childhood (AHC); micron bar represents 0.4 seconds. C, Chart with QTc (mean±SEM) for each study subgroup, including AHC (typical vs atypical, black fill), genotype (positive vs negative, dark gray fill), ATP1A3 genotype (positive vs negative, light gray fill), and ATP1A3 variant (D801N variant vs E815K and other variants, white fill). Examples from lead II of ECGs for an ATP1A3‐D801N female patient and an ATP1A3 genotype‐negative female patient are provided for comparison of QT/QTc measurements. Numbers on the bar graphs represent the total number of QTc measurements from each patient within the cohort. *P=0.034. **P<0.001. ***P<0.001. ****P<0.001. ATP1A3 indicates alpha‐3 subunit of the sodium‐potassium ATPase; ATP1A3‐D801N, D801N variant in the alpha‐3 subunit of the sodium‐potassium ATPase; Atyp, atypical AHC presentation; Neg, negative genotype; Pos, positive genotype; and Typ, typical AHC…

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  Figure 3. Scatter plots of corrected QT (QTc) (ms) as a function of age and linear regression model for (A) ATP1A3‐D801N–positive individuals separated by <10 years of age and ≥10 years of age, (B) ATP1A3‐positive individuals excluding those with the D801N variant separated by <10 years of age and ≥10 years of age, (C) genotype‐negative individuals separated by <10 years of age and ≥10 years of age, and (D) individuals with atypical alternating hemiplegia of childhood (AHC) separated by <10 years of age and ≥10 years of age. Light gray line denotes 370‐milliseconds threshold. ATP1A3 indicates alpha‐3 subunit of the sodium‐potassium ATPase; and ATP1A3‐D801N, D801N variant in the alpha‐3 subunit of the sodium‐potassium ATPase.

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  Figure 4. Venn diagram detailing the multifactorial contributions to sudden cardiac arrest (SCA) in patients carrying ATP1A3 variants. The upper left circle defines the central nervous system factors contributing to SCA such as the vagus nerve contributing to bradycardia. The upper right circle defines exogenous factors contributing to SCA such as medications. The lower circle represents the cardiac factors that contribute to the development of SCA such as dysfunction of cardiac myocytes. ATP1A3 indicates alpha‐3 subunit of the sodium‐potassium ATPase; and ATP1A3‐D801N, D801N variant in the alpha‐3 subunit of the sodium‐potassium ATPase.