Döring JH1, Schröter J1, Jüngling J2, Biskup S2 3, Klotz KA4 5, Bast T6 7, Dietel T7, Korenke GC8, Christoph S8, Brennenstuhl H9, Rubboli G10, Møller RS10 11, Lesca G12, Chaix Y13, Kölker S9, Hoffmann GF9, Lemke JR14 15, Syrbe S 1
Pathogenic variants in KCNA2, encoding for the voltage-gated potassium channel Kv1.2, have been identified as the cause for an evolving spectrum of neurological disorders. Affected individuals show early-onset developmental and epileptic encephalopathy, intellectual disability, and movement disorders resulting from cerebellar dysfunction. In addition, individuals with a milder course of epilepsy, complicated hereditary spastic paraplegia, and episodic ataxia have been reported. By analyzing phenotypic, functional, and genetic data from published reports and novel cases, we refine and further delineate phenotypic as well as functional subgroups of KCNA2-associated disorders. Carriers of variants, leading to complex and mixed channel dysfunction that are associated with a gain- and loss-of-potassium conductance, more often show early developmental abnormalities and an earlier onset of epilepsy compared to individuals with variants resulting in loss- or gain-of-function. We describe seven additional individuals harboring three known and the novel KCNA2 variants p.(Pro407Ala) and p.(Tyr417Cys). The location of variants reported here highlights the importance of the proline(405)-valine(406)-proline(407) (PVP) motif in transmembrane domain S6 as a mutational hotspot. A novel case of self-limited infantile seizures suggests a continuous clinical spectrum of KCNA2-related disorders. Our study provides further insights into the clinical spectrum, genotype-phenotype correlation, variability, and predicted functional impact of KCNA2 variants.
- Division of Paediatric Epileptology, Centre for Paediatric and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany.
- Praxis für Humangenetik Tübingen, 72076 Tuebingen, Germany.
- CEGAT GmbH, 72076 Tuebingen, Germany.
- Department of Neuropediatrics and Muscle Disorders, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
- Department of Epileptology, Medical Center, Faculty of Medicine, University of Freiburg, 79085 Freiburg, Germany.
- Medical Faculty, University Hospital Freiburg, 79085 Freiburg, Germany.
- Epilepsy Center Kork, Medical Faculty of the University of Freiburg, 77694 Kehl, Germany.
- Department of Neuropediatrics, University Children’s Hospital, Klinikum Oldenburg, 26133 Oldenburg, Germany.
- Division of Paediatric Neurology and Metabolic Medicine, Centre for Paediatric and Adolescent Medicine, University Hospital, 69120 Heidelberg, Germany.
- Danish Epilepsy Centre, 4293 Dianalund, Denmark.
- Department of Regional Health Research, University of Southern Denmark, 5230 Odense, Denmark.
- Department of Medical Genetics, Lyon University Hospital, University of Lyon, 69100 Lyon, France.
- Pediatric Neurology Unit, Children’s Hospital, Purpan University Hospital, 31300 Toulouse, France.
- Institute of Human Genetics, University of Leipzig Medical Center, 04103 Leipzig, Germany.
- Center for Rare Diseases, University of Leipzig Medical Center, 04103 Leipzig, Germany.