Comprehensive classification of HCN1 variants linked to neurodevelopmental disorders with and without epilepsy

HCN1

Loss of function (milder forms or no epilepsy) versus gain of function and mixed effects (DEE) of the HCN1 channel, across four biophysical classes

Forty-three HCN1 variants identified in patients with neurodevelopmental disorders, with or without epilepsy, were characterized by patch-clamp and confocal imaging in HEK293 cells. The authors derive four functional classes: low or no current, hyperpolarizing or depolarizing shift in voltage dependence, and generation of an instantaneous current. In 50 patients, functional class correlated strongly with clinical presentation: loss-of-function variants prevailed in milder forms or without epilepsy, the latter clustering in the selectivity filter, whereas gain-of-function and mixed variants were mainly associated with DEE. Allosteric modulators (peptides NB6 and TRIP8bnano, small molecule J&J12e) normalized channel function in vitro across three of the four classes.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

When interpreting an HCN1 variant found on the exome, the direction of the channel effect becomes a prognostic argument, not only a pathogenicity one. Functional data were obtained in a heterologous system, and rescue by modulators is shown only in vitro: class-based precision medicine remains to be validated in patients.

Analysis by Dr Thibaut Benquey