Neurodevelopmental Disorders Caused by De Novo Variants in <i>KCNB1 </i>Genotypes and Phenotypes
Authors: Carolien G. F. de Kovel, Steffen Syrbe, Eva H. Brilstra, Nienke Verbeek, Bronwyn Kerr, Holly Dubbs, Allan Bayat, Sonal Desai, Sakkubai Naidu, Siddharth Srivastava, Hande Cagaylan, Uluc Yis, Carol Saunders, Martin Rook, Susanna Plugge, Hiltrud Muhle, Zaid Afawi, Karl-Martin Klein, Vijayakumar Jayaraman, Ramakrishnan Rajagopalan, Ethan Goldberg, Eric Marsh, Sudha Kessler, Christina Bergqvist, Laura K. Conlin, Bryan L. Krok, Isabelle Thiffault, Manuela Pendziwiat, Ingo Helbig, Tilman Polster, Ingo Borggraefe, Johannes R. Lemke, Marie-José van den Boogaardt, Rikke S. Møller, Bobby P. C. Koeleman
Journal: JAMA Neurology (2017)

<h3>Importance</h3> Knowing the range of symptoms seen in patients with a missense or loss-of-function variant in<i>KCNB1</i>and how these symptoms correlate with the type of variant will help clinicians with diagnosis and prognosis when treating new patients. <h3>Objectives</h3> To investigate the clinical spectrum associated with<i>KCNB1</i>variants and the genotype-phenotype correlations. <h3>Design, Setting, and Participants</h3> This study summarized the clinical and genetic information of patients with a presumed pathogenic variant in<i>KCNB1.</i> Patients were identified in research projects or during clinical testing. Information on patients from previously published articles was collected and authors contacted if feasible. All patients were seen at a clinic at one of the participating institutes because of presumed genetic disorder. They were tested in a clinical setting or included in a research project. <h3>Main Outcomes and Measures</h3> The genetic variant and its inheritance and information on the patient's symptoms and characteristics in a predefined format. All variants were identified with massive parallel sequencing and confirmed with Sanger sequencing in the patient. Absence of the variant in the parents could be confirmed with Sanger sequencing in all families except one. <h3>Results</h3> Of 26 patients (10 female, 15 male, 1 unknown; mean age at inclusion, 9.8 years; age range, 2-32 years) with developmental delay, 20 (77%) carried a missense variant in the ion channel domain of<i>KCNB1,</i>with a concentration of variants in region S5 to S6. Three variants that led to premature stops were located in the C-terminal and 3 in the ion channel domain. Twenty-one of 25 patients (84%) had seizures, with 9 patients (36%) starting with epileptic spasms between 3 and 18 months of age. All patients had developmental delay, with 17 (65%) experiencing severe developmental delay; 14 (82%) with severe delay had behavioral problems. The developmental delay was milder in 4 of 6 patients with stop variants and in a patient with a variant in the S2 transmembrane element rather than the S4 to S6 region. <h3>Conclusions and Relevance</h3> De novo<i>KCNB1</i>missense variants in the ion channel domain and loss-of-function variants in this domain and the C-terminal likely cause neurodevelopmental disorders with or without seizures. Patients with presumed pathogenic variants in<i>KCNB1</i>have a variable phenotype. However, the type and position of the variants in the protein are (imperfectly) correlated with the severity of the disorder.