Whole-Exome Sequencing in NF1-Related West Syndrome Leads to the Identification of KCNC2 as a Novel Candidate Gene for Epilepsy

Annika Rademacher; Niklas Schwarz; Simone Seiffert; Manuela Pendziwiat; Axel Rohr; Andreas van Baalen; Ingo Helbig; Yvonne Weber; Hiltrud Muhle

doi:10.1055/s-0040-1710524

Neuropediatrics, Table of Contents

Neuropediatrics 2020; 51(05): 368-372
DOI: 10.1055/s-0040-1710524

Short Communication

Whole-Exome Sequencing in NF1-Related West Syndrome Leads to the Identification of KCNC2 as a Novel Candidate Gene for Epilepsy

Annika Rademacher^*

¹Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian-Albrechts University of Kiel, Kiel, Germany

,

Niklas Schwarz‡^*

²Department of Neurology and Epileptology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany

,

Simone Seiffert

²Department of Neurology and Epileptology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany

,

Manuela Pendziwiat

¹Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian-Albrechts University of Kiel, Kiel, Germany

,

Axel Rohr

³Department of Radiology and Neuroradiology, University Medical Center Schleswig-Holstein, Christian-Albrechts University of Kiel, Kiel, Germany

⁴Vancouver General Hospital, Vancouver, British Columbia, Canada

,

Andreas van Baalen

¹Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian-Albrechts University of Kiel, Kiel, Germany

,

Ingo Helbig

¹Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian-Albrechts University of Kiel, Kiel, Germany

⁵Children's Hospital of Philadelphia and Perelman School of Medicine University of Pennsylvania, Philadelphia, Pennsylvania, United States

,

Yvonne Weber‡^†

²Department of Neurology and Epileptology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany

⁶Department of Epileptology and Neurology, University of Aachen, Aachen, Germany

,

Hiltrud Muhle‡^†

¹Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian-Albrechts University of Kiel, Kiel, Germany

› Author Affiliations

Abstract

Patients with neurofibromatosis type 1 (NF1) have an increased risk for West syndrome (WS), but the underlying mechanisms linking NF1 and WS are unknown. In contrast to other neurocutaneous syndromes, intracerebral abnormalities explaining the course of infantile spasms (IS) are often absent and the seizure outcome is usually favorable. Several studies have investigated a potential genotype–phenotype correlation between NF1 and seizure susceptibility, but an association was not identified. Therefore, we identified three patients with NF1-related WS (NF1-WS) in a cohort of 51 NF1 patients and performed whole-exome sequencing (WES) to identify genetic modifiers. In two NF1 patients with WS and good seizure outcome, we did not identify variants in epilepsy-related genes. However, in a single patient with NF1-WS and transition to drug-resistant epilepsy, we identified a de novo variant in KCNC2 (c.G499T, p.D167Y) coding for Kv3.2 as a previously undescribed potassium channel to be correlated to epilepsy. Electrophysiological studies of the identified KCNC2 variant demonstrated both a strong loss-of-function effect for the current amplitude and a gain-of-function effect for the channel activation recommending a complex network effect. These results suggest that systematic genetic analysis for potentially secondary genetic etiologies in NF1 patients and severe epilepsy presentations should be done.

Keywords

neurofibromatosis type 1 - epilepsy - infantile spasms - whole-exome sequencing - KCNC2

Full Text

References

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Supplementary Material

Supplementary Material