Send to

Choose Destination
JAMA Neurol. 2017 Oct 1;74(10):1228-1236. doi: 10.1001/jamaneurol.2017.1714.

Neurodevelopmental Disorders Caused by De Novo Variants in KCNB1 Genotypes and Phenotypes.

Author information

Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
Department of Language and Genetics, Max Planck Institute for Psycholinguistics, Nijmegen, the Netherlands.
Division of Child Neurology and Inherited Metabolic Diseases, Department of General Pediatrics, Center for Pediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
Institute of Evolution, Systems and Genomics, Faculty of Medical and Human Sciences, University of Manchester, Manchester, England.
Manchester Centre For Genomic Medicine, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester, England.
Manchester Academic Health Science Centre, Manchester, England.
Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Department of Pediatrics, University Hospital of Hvidovre, Copenhagen, Denmark.
Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, Maryland.
Department of Neurology and Pediatrics, Johns Hopkins School of Medicine, Baltimore, Maryland.
Hugo Moser Research Institute, Kennedy Krieger Institute, Baltimore, Maryland.
Department of Neurology, Boston Children's Hospital, Boston, Massachusetts.
Department of Molecular Biology and Genetics, Bogaziçi University, Istanbul, Turkey.
Division of Child Neurology, Department of Pediatrics, School of Medicine, Dokuz Eylül University, İzmir, Turkey.
Center for Pediatric Genomic Medicine, Department of Pathology and Laboratory Medicine, Children's Mercy Hospital, Kansas City, Missouri.
Department of Pediatrics, Children's Mercy Hospital, Kansas City, Missouri.
Pediatric Pathology and Laboratory Medicine, University of Missouri-Kansas City School of Medicine, Kansas City.
Department of Medical Physiology, University Medical Center Utrecht, Utrecht, the Netherlands.
Department of Biomedical Sciences, University Medical Center Utrecht, Utrecht, the Netherlands.
Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian Albrechts University, Kiel, Germany.
Department of Physiology and Pharmacology, Tel Aviv University Medical School, Ramat Aviv, Israel.
Department of Neurology, Epilepsy Center Frankfurt Rhine-Main, Center of Neurology and Neurosurgery, University Hospital, Goethe-University Frankfurt, Frankfurt, Germany.
Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
University Medical Center Schleswig-Holstein, Christian Albrechts University, Kiel, Germany.
Epilepsiezentrum Bethel, Krankenhaus Mara, Kinderepileptologie, Bielefeld, Germany.
Department of Pediatric Neurology, Developmental Medicine and Social Pediatrics Dr. von Hauner's Children's Hospital, University of Munich, Munich, Germany.
Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.
Danish Epilepsy Centre, Dianalund, Denmark.
Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark.



Knowing the range of symptoms seen in patients with a missense or loss-of-function variant in KCNB1 and how these symptoms correlate with the type of variant will help clinicians with diagnosis and prognosis when treating new patients.


To investigate the clinical spectrum associated with KCNB1 variants and the genotype-phenotype correlations.

Design, Setting, and Participants:

This study summarized the clinical and genetic information of patients with a presumed pathogenic variant in KCNB1. 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.

Main Outcomes and Measures:

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.


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 KCNB1, 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.

Conclusions and Relevance:

De novo KCNB1 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 KCNB1 have a variable phenotype. However, the type and position of the variants in the protein are (imperfectly) correlated with the severity of the disorder.

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Silverchair Information Systems Icon for PubMed Central
Loading ...
Support Center