KCNQ2-related disorders are caused by pathogenic variants in the KCNQ2 gene located on chromosome 20. KCNQ2 encodes for voltage gated potassium channel subunits which are widely expressed in the nervous system. These Kv7.2 subunits form homotetrameric or heterotetrameric channels with Kv7.3 subunits to generate the M-current (IKM), a non-inactivating K+ current that regulates the resting membrane potential and suppresses repetitive neuronal firing. In this way, it has a critical role in controlling neuronal excitability.
Pathogenic variants in KCNQ2 represent one of the most common causes of childhood-onset genetic epilepsies, with an incidence in young population of 1 per 17000 live births. Most disease-causing KCNQ2 variants cause loss-of-function and have been associated with a spectrum of neonatal-onset epilepsy phenotypes with or without developmental delay. More rarely, patients with loss-of-function variants and self-limiting infantile seizures or myokymia have been described. KCNQ2 variants with a gain-of-function effect are mainly characterized by developmental delay and autistic features with onset of seizures after the neonatal age or even without epilepsy. Behavioral disorders, like autism spectrum disorders or attention deficit hyperactivity disorder, are frequently associated with KCNQ2-related disorders.
Variants are inherited by an autosomal dominant mode. Mildly affected patients associated with self-limiting seizures without developmental delay often inherited the variant from an affected parent. In contrast, almost all severely affected individuals with developmental delay have a de novo pathogenic variant, but inheritance through a milder or unaffected parent carrying the variant in a mosaic state has been reported.
KCNQ2