The c.913_915delTTC pathogenic vari

The c.913_915delTTC pathogenic variant has been identified in the KCNQ2 gene. The c.913_915delTTC variant was initially reported as a confirmed de novo variant in a child reported to have normal development and a history of neonatal-onset tonic and tonic-clonic seizures that resolved by six months of age (Ishii et al., 2009). The c.913_915delTTC variant was also reported as an assumed de novo variant in identical twins with neonatal epileptic encephalopathy with a burst suppression pattern on EEG, profound developmental delay, and spasticity (Millichap et al., 2016). In vitro functional studies indicate that the c.913_915delTTC variant significantly impairs potassium channel function (Ishii et al., 2009). The c.913_915delTTC variant results in an in-frame deletion of one amino acid, denoted p.Phe305del. However, the c.913_915delTTC variant is not predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. The c.913_915delTTC variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Furthermore, this deletion occurs at a conserved position predicted to be within the transmembrane segment S6. Therefore, the presence of c.913_915delTTC is consistent with the diagnosis of a KCNQ2-related disorder in this individual. (less)