Phenotypic Spectrum in a Family Sharing a Heterozygous KCNQ3 Variant

Abstract

Background and Purpose Mutations in KCNQ3 have classically been associated with benign familial neonatal and infantile seizures and more recently identified in patients with neurodevelopmental disorders and abnormal electroencephalogram (EEG) findings. We present 4 affected patients from a family with a pathogenic mutation in KCNQ3 with a unique constellation of clinical findings. Methods A family of 3 affected siblings and mother sharing a KCNQ3 pathogenic variant are described, including clinical history, genetic results, and EEG and magnetic resonance imaging (MRI) findings. Results This family shows a variety of clinical manifestations, including neonatal seizures, developmental delays, autism spectrum disorder, and anxiety. One child developed absence epilepsy, 2 children have infrequent convulsive seizures that have persisted into childhood, and their parent developed adult-onset epilepsy. An underlying c.1091G>A (R364H) variant in KCNQ3 was found in all affected individuals. Conclusions The phenotypic variability of KCNQ3 channelopathies continues to expand as more individuals and families are described, and the variant identified in this family adds to the understanding of the manifestations of KCNQ3-related disorders.

Lipophilic compounds restore wt function of neurodevelopmental-associated KCNQ3 mutations

“…Impairment of M-currents due to mutation of KCNQ3 increases neuronal excitability and delays the development of complex neuronal rhythms that contribute to a variety of NDDs, including different types of epilepsy and autism spectrum disorders 8, 9, 10, 11, 12 . The phenotypic heterogeneity of KCNQ3-associated NDDs is broad, ranging from benign familial neonatal seizures with normal cognition 13 to more severe epileptic encephalopathy with cognitive impairment 14, 15 .…”