Expanding the genetic and phenotypic relevance of KCNB1 variants in developmental and epileptic encephalopathies: 27 new patients and overview of the literature

Abstract

Developmental and epileptic encephalopathies (DEE) refer to a heterogeneous group of devastating neurodevelopmental disorders. Variants in KCNB1 have been recently reported in patients with early‐onset DEE. KCNB1 encodes the α subunit of the delayed rectifier voltage‐dependent potassium channel Kv2.1. We review the 37 previously reported patients carrying 29 distinct KCNB1 variants and significantly expand the mutational spectrum describing 18 novel variants from 27 unreported patients. Most variants occur de novo and mainly consist of missense variants located on the voltage sensor and the pore domain of Kv2.1. We also report the first inherited variant (p.Arg583*). KCNB1‐related encephalopathies encompass a wide spectrum of neurodevelopmental disorders with predominant language difficulties and behavioral impairment. Eighty‐five percent of patients developed epilepsies with variable syndromes and prognosis. Truncating variants in the C‐terminal domain are associated with a less‐severe epileptic phenotype. Overall, this report provides an up‐to‐date review of the mutational and clinical spectrum of KCNB1, strengthening its place as a causal gene in DEEs and emphasizing the need for further functional studies to unravel the underlying mechanisms.

Epilepsy and neurobehavioral abnormalities in mice with aKCNB1pathogenic variant that alters conducting and non-conducting functions of KV2.1

“…Neurobehavioral abnormalities were prominent in the Kcnb1 G379R mice and overlap with features reported in children with KCNB1 encephalopathy (Bar et al, 2019;Calhoun et al, 2017;de Kovel et al, 2017;Marini et al, 2017;Srivastava et al, 2018;Thiffault et al, 2015;Torkamani et al, 2014). Attention-deficit/hyperactivity disorder or hyperactivity with inattention has been reported in numerous cases of KCNB1 encephalopathy.…”

“…Previous work has identified heterozygous de novo KCNB1 pathogenic variants in individuals with DEE (Allen et al, 2016;Bar et al, 2019;Calhoun et al, 2017;de Kovel et al, 2017;Latypova et al, 2017;Marini et al, 2017;Miao et al, 2017;Saitsu et al, 2015;Thiffault et al, 2015;Torkamani et al, 2014). In addition to seizures, individuals with KCNB1 variants display comorbidities that include developmental delay, intellectual disability, features of autism spectrum disorder, ADHD and aggression (Bar et al, 2019;Calhoun et al, 2017;de Kovel et al, 2017;Marini et al, 2017). Since the initial reports of KCNB1 variants in early infantile epileptic encephalopathy type 26 (EIEE26), the phenotype has expanded to include cases with less severe and/or later onset epilepsy or no discrete seizures, and thus the term KCNB1 encephalopathy encompasses this broader phenotype spectrum.…”

Developmental and epilepsy spectrum of KCNB1 encephalopathy with long‐term outcome

“…Both variants were predicted to be damaging and thus considered pathogenic and contributing to the individual's phenotype. 16…”

“…[8][9][10][11][12][13][14][15] A few individuals had developmental delay without seizures. 11,16 Outcome data are sified as having developmental and epileptic encephalopathy (DEE) or developmental encephalopathy (DE). In addition, we reviewed published cases and provided the longterm outcome in patients older than 12 years from our series and from literature.…”

“…It has been suggested that truncating variants in the C-terminal domain correlate with less severe epilepsy outcome. 11,16 Here, we analyze a series of 36 individuals with pathogenic KCNB1 variants to delineate the phenotypic spectrum of KCNB1 encephalopathy. We explore genotype-phenotype correlations and long-term outcome to guide patient management and inform genetic and prognostic counseling.…”