Abstracts

Rationale: KCNQ2 and KCNQ3 encode voltage-gated ion channel subunits mediating a subthreshold potassium current important in limiting neuronal excitability. Loss-of-function variants in KCNQ3 are known to cause Benign Neonatal Epilepsy characterized by seizures in newborns with normal subsequent development1, although rare families with more severe phenotypes have also been described2. While a KCNQ3 gain-of-function variant, R230C, has been found in individual patients with epileptic encephalopathy3, intellectual disability4,5, or cerebral visual impairment6, relatively little is known about the electroclinical phenotype associated with KCNQ3 gain-of-function variants. Here, we describe the electroclinical phenotype and treatment response in three patients with novel KCNQ3 gain-of-function variants. Methods: Retrospective case series of patients and whole-cell patch-clamp electrophysiology recordings. Results: A 30 month old boy, diagnosed at 21 months with autism, hypotonia and mild motor delays, and minimal subsequent gains despite Applied Behavioral Analysis (ABA) and other therapies, presented with concern for seizures. Long-term continuous video-EEG monitoring did not record seizures but demonstrated high amplitude sleep-potentiated multifocal epileptiform discharges, meeting criteria for electrical status epilepticus of sleep (ESES). Treatment with high-dose diazepam led to an immediate electrographic resolution with the first dose and dramatic improvements were subsequently noted across multiple developmental domains by his therapists.Whole exome sequencing (WES) revealed a KCNQ3 R230H de novo variant. We investigated other patients with genetic variation at this site. A second R230H patient was identified, with profound intellectual disability, hypotonia and epileptiform discharges worsening in sleep. Strong phenotypic overlap - autism, motor delays with hypotonia and ESES responsive to benzodiazepine therapy with a similar age of onset - was noted in a patient with a de novo R230S variant. Patch clamp analysis of R230H and R230S - variants neutralizing the second arginine within the S4 voltage sensor, similarly to the previously described R230C variant,2  demonstrated a gain-of-function effect characterized by increased potassium current density and loss of voltage-dependence. Conclusions: Our findings add to growing evidence for unique gain-of-function phenotypes imparted by KCNQ2 and KCNQ3 gain-of-function variants7. Particularly, gain-of-function affecting R230 of KCNQ3 can cause autism and neurodevelopmental disability even in the absence of seizures.While autism is a heterogeneous spectrum disorder, monogenic subtypes are increasingly appreciated, each with particular clinical associations8,9. We suggest that KCNQ3 gain-of-function is a monogenic form of autism associated with ESES. As ESES may interfere with development in the absence of seizures, and treatment with benzodiazepines may lead to significant clinical improvement, our results support the clinical utility of WES and sleep EEG recording in autism.1.      Sands TT, et al. Epilepsia. 2016;57(12):2019-2030.2.      Miceli F, et al. J Neurosci. 2015;35(9):3782-3793.3.      Epi 4KC Nature. 2013;501(7466):217-221.4.      Rauch A, et al. Lancet 2012; 3801674-825.      Grozeva D et al. Hum Mutat. 2015;36(12):1197-1204.6.      Bosch DG et al. Eur J Hum Genet. 2016;24(5):660-665.7.      Mulkey SB, et al. Epilepsia. 2017;58(3):436-445.8.      van Bon BW, et al. Mol Psychiatry. 2016;21(1):126-132.9.      Bernier R, et al. Cell. 2014;158(2):263-276. Funding: MT: Telethon ggp15113EC: NIH R01 NS49119, KCNQ2 Cure Foundation, and the Jack Pribaz Foundation