KCNQ3-related disorders are rare disorders caused by pathogenic variants in the KCNQ3 gene located on chromosome 8. KCNQ3 encodes for voltage gated potassium channel subunits which are widely expressed in the nervous system. These Kv7.3 subunits form heterotetrameric channels with Kv7.2 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.

Heterozygous pathogenic variants in KCNQ3 leading to loss-of-function have been associated with self-limiting neonatal or infantile-onset epilepsy, while bi-allelic loss-of-function variants lead to neonatal epilepsy with developmental delay. KCNQ3 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.

Mildly affected patients associated with self-limiting seizures and normal development often inherited the variant from an affected parent by an autosomal dominant mode. In contrast, almost all severely affected individuals with developmental delay inherited pathogenic (loss-of-function) variants from both parent (recessive inheritance) or carry a de novo (gain-of-function) pathogenic variant.