De novo KCNA1 KCNA1 variants in the PVP motif cause infantile epileptic encephalopathy and cognitive impairment similar to recurrent KCNA2 KCNA2 variants

摘要

Derangements in voltage‐gated potassium channel function are responsible for a range of paroxysmal neurologic disorders. Pathogenic variants in the KCNA1 gene, which encodes the voltage‐gated potassium channel Kv1.1, are responsible for Episodic Ataxia Type 1 (EA1). Patients with EA1 have an increased incidence of epilepsy, but KCNA1 variants have not been described in epileptic encephalopathy. Here, we describe four patients with infantile‐onset epilepsy and cognitive impairment who harbor de novo KCNA1 variants located within the Kv‐specific Pro‐Val‐Pro (PVP) motif which is essential for channel gating. The first two patients have KCNA1 variants resulting in (p.Pro405Ser) and (p.Pro405Leu), respectively, and a set of identical twins has a variant affecting a nearby residue (p.Pro403Ser). Notably, recurrent de novo variants in the paralogous PVP motif of KCNA2 have previously been shown to abolish channel function and also cause early‐onset epileptic encephalopathy. Importantly, this report extends the range of phenotypes associated with KCNA1 variants to include epileptic encephalopathy when the PVP motif is involved.