CACNA1H variants are not a cause of monogenic epilepsy
- 14 April 2020
- journal article
- research article
- Published by Hindawi Limited in Human Mutation
- Vol. 41 (6), 1138-1144
- https://doi.org/10.1002/humu.24017
Abstract
CACNA1H genetic variants were originally reported in a childhood absence epilepsy cohort. Subsequently, genetic testing for CACNA1H became available and is currently offered by commercial laboratories. However, the current status of CACNA1H as a monogenic cause of epilepsy is controversial, highlighted by ClinGen's recent re‐classification of CACNA1H as disputed. We analyzed published CACNA1H variants and those reported in ClinVar and found none would be classified as pathogenic or likely pathogenic per the ACMG classification criteria. Moreover, Cacna1h did not modify survival in a Dravet Syndrome mouse model. We observed a mild increase in susceptibility to hyperthermia‐induced seizures in mice with reduced Cacna1h expression. Overall, we conclude that there is limited evidence that CACNA1H is a monogenic cause of epilepsy in humans and that this gene should be removed from commercial genetic testing panels to reduce the burden of variants of uncertain significance for healthcare providers, families and patients with epilepsy.Keywords
Funding Information
- National Center for Advancing Translational Sciences (TL1 TR001423)
- National Institute of Neurological Disorders and Stroke (R00 NS089858, R01 NS084959)
- Dravet Syndrome Foundation
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