Non-missense ATP1A3 Variants in Children: Genotype-Phenotype Correlations and Molecular Modeling

Non-missense ATP1A3 variants are rare. Their phenotypic and molecular consequences in children remain to be characterized. We conducted a registry-based and computational structural modeling study. Phenotyping: 6 of 143 consecutive ATP1A3- related disease registry patients had non-missense variants. Their phenotypes ranged from mild or moderate alternating hemiplegia of childhood (c.2755_2757del-p.Val919del, c.2542+1G>A, c.388_390delGTG-p.Val130del, c.1297_2542del-exons 9-23del) to severe developmental and epileptic encephalopathy (c.2562_2565delTGGCinsG-p.Gly855del, c.2570_2572delTCT-p.Phe857del). Molecular modeling: in-frame deletions localized to transmembrane domains which are critical to Na + binding or ATPase conformational transitions. Splice-site and multi-exon deletion variants were predicted to result in truncation and loss of functional protein, consistent with a haploinsufficiency mechanism. This suggests that haploinsufficiency is a potential mechanism resulting in alternating hemiplegia of childhood (AHC) phenotypes, which is a novel conclusion, given that literature has hypothesized a dominant-negative mechanism for missense ATP1A3 mutations. Our study, while providing novel insights into genotype-phenotype correlations and underlying pathophysiology, also indicates that prognosis should be guided by the specific the clinical presentation and ATP1A3 variants rather than by variant class.