<i>ATP1A3</i> Mutations and Genotype-Phenotype Correlation of Alternating Hemiplegia of Childhood in Chinese Patients

<div><p>Alternating hemiplegia of childhood (AHC) is a rare and severe neurological disorder. <i>ATP1A3</i> was recently identified as the causative gene. Here we report the first genetic study in Chinese AHC cohort. We performed whole-exome sequencing on three trios and three unrelated patients, and screened additional 41 typical cases and 100 controls by PCR-Sanger sequencing. <i>ATP1A3</i> mutations were detected in 95.7% of typical AHC patients. At least 93.3% were <i>de novo</i>. Four late onset, atypical AHC patients were also mutation positive, suggesting the need for testing <i>ATP1A3</i> mutations in atypical cases. Totally, 13 novel missense mutations (T370N, G706R, L770R, T771N, T771I, S772R, L802P, D805H, M806K, P808L, I810N, L839P and G893R) were identified in our study. By homology modeling of the mutant protein structures and calculation of an extensive list of molecular features, we identified two statistically significant molecular features, solvent accessibility and distance to metal ion, that distinguished disease-associated mutations from neutral variants. A logistic regression classifier achieved 92.9% accuracy by the average of 100 times of five-fold cross validations. Genotype-phenotype correlation analysis showed that patients with epilepsy were more likely to carry E815K mutation. In summary, <i>ATP1A3</i> is the major pathogenic gene of AHC in Chinese patients; mutations have distinctive molecular features that discriminate them from neutral variants and are correlated with phenotypes.</p>