KCNB2 mutations
KCNB2 (Potassium Voltage-Gated Channel Subfamily B Member 2) gene is located on chromosome 8q21.11 and contains 4 exons. Monoallelic missense mutations in KCNB2 are distributed throughout the coding sequence with no specific hot spots. Following is the distribution of the mutations across the KCNB2 gene: c.281G>A (p.Gly94Glu) in the N terminus; c.641C>T (p.Thr214Met) in the S1-S2 linker; c.827C>T (p.Pro276Leu) in the S3 transmembrane domain (TMD); c.911G>A (p.Arg304Gln) in the S4 TMD; c.994T>G (p.Tyr332Asp) in the S4-S5 linker; c.1141A>G (p.Thr381Ala) in the pore helix; and c.1937C>T (p.Ala646Val) in the C terminus.
Genotype-phenotype correlation
Although genotype-phenotype correlation for KCNB2-related neurodevelopmental disorders is not clear, the patient harbouring c.1141A>G (p.Thr381Ala) mutation, which has the most drastic effect on functional channel expression exhibited the most marked disease phenotype (global developmental delay, intellectual disability, epilepsy, etc.). Further analyses of the genotype-phenotype correlation are warranted.
Molecular-Pathomechanistic link
• KCNB2 knockout mice display hyperactivity but are viable, with no defects in body weight, gross or brain morphology (PMID: 39862856).
• Patients with point mutations in KCNB2 exhibit developmental delay. These include global developmental delay, speech, cognitive, language delay and delayed motor milestones. Some patients also exhibit intellectual disability, mild autism, ADHD, epilepsy and facial and limb dysmorphism.
• Molecular and biophysical characterisation of these mutations indicate loss of function phenotype either by loss or reduced functional expression of Kv2.2 ion channels (p.T381A and p.T214M variants) or due to increased channel inactivation (p.G94E, p.R304Q, p.Y332D and p.A646V variants).
Diagnostic testing
Variants were identified by trio exome sequencing. In some cases, whole genome sequencing and/or Sanger sequencing of the KCNB2 gene were also employed for validation. The cohort was assembled with the help of Matchmaker Exchange platform tools.
KCNB2