A novel loss-of-function KCNB1 gene variant in a twin with global developmental delay and seizures

Human voltage-gated potassium (Kv) channels are expressed by a 40-member
family of genes essential for normal electrical activity and with numerous
associations and linkages to excitability disorders. Function-altering
sequence variants in the KCNB1 gene, which encodes the neuronally
expressed Kv2.1 channel, are associated with neurodevelopmental
disorders including developmental delay with or without
epileptic activity. Here, we describe a 40-month-old fraternal
twin who presented with severe neurodevelopmental delay.
Electroencephalogram recordings at 19 months of age revealed poor
sleep architecture and the presence of multifocal epileptiform
discharges. The individual’s fraternal twin was neurotypical and
there was no family history of neurodevelopmental delay or
seizures. Whole genome sequencing at 33 months of age for the
proband revealed a de novo variant in KCNB1
[c.1154C>T/p.Pro385Leu], encoding a proline to leucine substitution
at residue 385, in the extracellular region immediately preceding
Kv2.1 transmembrane segment 6 (S6). Cellular electrophysiological analysis
of the effects of the gene variant in heterologously expressed
Kv2.1 demonstrated that homozygous Kv2.1-P385L channels were
completely nonfunctional. Channels generated by 50/50 expression
of wild-type Kv2.1 and Kv2.1-P385L to mimic the
heterozygous status of the proband revealed a partially
dominant-negative, 81% reduction in current magnitude. The
dramatic loss of function in Kv2.1 is the most likely cause of the
severe developmental delay and seizure activity in the proband,
further enriching our phenotypic understanding of KCNB1
developmental encephalopathies.