De novo SCN8A and inherited rare CACNA1H variants associated with severe developmental and epileptic encephalopathy

Molecular Brain

卷:14

Lubica Lacinova¹  Bohumila Jurkovicova-Tarabova¹  Robin N. Stringer²  Norbert Weiss²  Waseem Mahmoud Fathalla³  Judy Ibrahim⁴  Jozef Hertecant⁴  Ivana A. Souza⁵  Gerald W. Zamponi⁵  Tomas Vacik⁶ 

[1] Center of Biosciences, Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences;

[2] Department of Pathophysiology, Third Faculty of Medicine, Charles University;

[3] Department of Pediatric Neurology, Mafraq Hospital;

[4] Department of Pediatrics, Tawam Hospital;

[5] Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary;

[6] Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University;

关键词: Ion channels;    Channelopathy;    Calcium channel;    CACNA1H;    Cav3.2 channel;    Sodium channel;   

DOI  :  10.1186/s13041-021-00838-y

来源: DOAJ

【 摘 要 】

Abstract Developmental and epileptic encephalopathies (DEEs) are a group of severe epilepsies that are characterized by seizures and developmental delay. DEEs are primarily attributed to genetic causes and an increasing number of cases have been correlated with variants in ion channel genes. In this study, we report a child with an early severe DEE. Whole exome sequencing showed a de novo heterozygous variant (c.4873–4881 duplication) in the SCN8A gene and an inherited heterozygous variant (c.952G > A) in the CACNA1H gene encoding for Nav1.6 voltage-gated sodium and Cav3.2 voltage-gated calcium channels, respectively. In vitro functional analysis of human Nav1.6 and Cav3.2 channel variants revealed mild but significant alterations of their gating properties that were in general consistent with a gain- and loss-of-channel function, respectively. Although additional studies will be required to confirm the actual pathogenic involvement of SCN8A and CACNA1H, these findings add to the notion that rare ion channel variants may contribute to the etiology of DEEs.

【 授权许可】

Unknown