Scripps Translational Science Institute (STSI) have uncovered a previously unknown basis for a rare and severe form of epilepsy: defects in a gene involved in potassium regulation. STSI’s IDIOM (Idiopathic Diseases of Man) study aims to use whole genome sequencing (WGS) to hunt down the origin of diseases in both adult and pediatric cases – and the advent of modern sequencing methods means they’re uncovering genetic causes for conditions that have long been a mystery.
The research began with the case study of a nine-year old girl with a severe and complicated form of epileptic encephalopathy (EE) that had no known cause. EEs are a heterogeneous group of conditions with childhood onset, neurodevelopmental impairment and often a poor prognosis (1). Recent progress has seen 12 new causative genes identified for this group of conditions, and the number is still growing – WGS of the patient uncovered a de novo missense mutation in the gene KCNB1, which wasn’t previously associated with EE. KCNB1 encodes the kv2.1 voltage-gated potassium (K+) channel, which regulates the flow of K+ in neurons, affecting how cells communicate, and in the kidneys, affecting K+ excretion and fluid balance. Two further patients with the same condition were identified, and whole exome sequencing (WES) uncovered similar mutations. The Scripps researchers feel the identification of the mutations in three patients, along with previous functional studies demonstrating that mutations in the pore region of the channel can result in altered ion selectivity and therefore dysfunction, point to the fact that these mutations may be causative of EE.
They also suggest that clinical WES will be a valuable tool for molecular diagnosis of future cases (1). “We are continuing to learn the impressive power of whole genome sequencing for making a difficult – and heretofore impossible – diagnosis,” says Eric Topol, director of STSI. “These findings can serve as a model on how to treat this particular form of epilepsy in other patients. The KCNB1 mutations might also have a role as a diagnostic biomarker for this condition, and they could help to direct the discovery and testing of new drugs to treat epilepsy.” Uncovering the mutation also has a more immediate effect – the original patient’s physician feels this discovery has made a huge difference to her outlook, and believes expanded medical treatment and monitoring of hydration could see her condition improve over time.
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References
- A. Torkamani et al., “De Novo KCNB1 Mutations in Epileptic Encephalopathy” Ann. Neurol., 76, 529–540 (2014).
