GABRB1 encodes the beta1 subunit of GABAA receptors, pentameric ligand-gated chloride channels that mediate the brain's primary inhibitory neurotransmission 1. When activated by GABA, these receptors selectively permit chloride ion influx into postsynaptic neurons, reducing neuronal excitability and nerve transmission 1. Beta-containing GABAARs can simultaneously bind GABA and histamine, potentially regulating sleep-wake cycles. Pathogenic GABRB1 variants cause Developmental and Epileptic Encephalopathy 45 (DEE45), a severe neurodevelopmental disorder 2. Functional analysis reveals that gain-of-function (GoF) variants—characterized by increased GABA sensitivity—associate with severe early-onset disease including profound intellectual disability, hypotonia, early mortality, and cortical atrophy 3. Loss-of-function variants present with milder phenotypes such as genetic epilepsy with febrile seizures plus 3. GABRB1 mutations represent a significant genetic cause of Epilepsy of Infancy with Migrating Focal Seizures, occurring in approximately 69% of genetically solved cases 4. Beyond epilepsy, GABRB1 variants influence thalamus volume and modulate the relationship between thalamic structure and intelligence 5, and show association with alcohol dependence susceptibility 6. Treatment responses differ by variant type: GoF variants show resistance to GABAergic medications but may benefit from sodium-channel blockers, while vigabatrin causes life-threatening effects in GoF cases 3.