Relevance to Autism

Mutations in the KCNB1 gene are associated with epileptic encephalopathy-26 (EIEE26; OMIM 616056). de Kovel et al., 2017 examined the clinical spectrum associated with KCNB1 variation in a cohort of 26 patients. Developmental delay was reported in all patients, with intractable epilepsy (84%) and features of epileptic encephalopathy on EEG (95%) also frequently observed; ASD was reported in 10/20 patients (50%). Among the de novo variants in KCNB1 identified in patients with ASD were three predicted loss-of-function variants and a missense variant that was demonstrated to impair channel sensitivity and cooperativity. Parrini et al., 2017 identified a de novo nonsense variant in KCNB1 in a male patient presenting with West syndrome and autism spectrum disorder. Bar et al., 2019 presented genetic and phenotypic data from a cohort of 64 patients (37 previously unreported and 27 novel) with pathogenic KCNB1 variants and reported that behavioral issues were observed in 37/49 patients with available data, including autism spectrum disorder in 26 cases (53%). Kang et al., 2019 described clinical and functional analysis of KCNB1 variants identified in 32 patients, eight of whom were reported to present with ASD; pathogenic variants were found to display diverse functional effects, including altered current density and shifts in the voltage-dependence of activation and/or inactivaton, as well as reduced total protein expression and/or cell-surface expression. Bar et al., 2021 assessed the adaptive and behavioral features in a series of 25 individuals with a KCNB1 encephalopathy, using the the Social Communication Questionnaire (SCQ) to screen for autism spectrum disorder (ASD); the SCQ was filled by 18/21 caregivers according to the age criteria for this questionnaire (> 4 years), and thirteen out of 18 participants had a score above the threshold of risk for ASD. Five rare and potentially damaging missense variants, as well as two de novo loss-of-function variants, in the KCNB1 gene were reported in ASD proband from the Autism Sequencing Consortium, the MSSNG cohort, and the SPARK cohort in Zhou et al., 2022; a two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in this report identified KCNB1 as a gene reaching exome-wide significance (P < 2.5E-06).

Molecular Function

This gene encodes a member of the potassium channel, voltage-gated, shab-related subfamily. The voltage-gated potassium channel encoded by the KCNB1 gene mediates transmembrane potassium transport in excitable membranes, primarily in the brain, but also in the pancreas and cardiovascular system; it also contributes to the regulation of the action potential (AP) repolarization, duration and frequency of repetitive AP firing in neurons, muscle cells and endocrine cells and plays a role in homeostatic attenuation of electrical excitability throughout the brain. Mutations in the KCNB1 gene are associated with epileptic encephalopathy-26 (EIEE26; OMIM 616056).

External Links

References