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

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 Na(v)1.6 voltage-gated sodium and Ca(v)3.2 voltage-gated calcium channels, respectively. In vitro functional analysis of human Na(v)1.6 and Ca(v)3.2 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13041-021-00838-y.