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

In HEK293 cells, 43 patient HCN1 variants segregate into four functional classes, with loss-of-function clustering in milder neurodevelopmental phenotypes and gain-of-function/mixed variants predominating in DEE.

• Why it matters: Genotype–phenotype links for HCN1 variants in neurodevelopmental disorders with or without epilepsy remain unclear, limiting interpretation of newly found variants for clinical risk and severity.
• What they did: Using patch-clamp electrophysiology and confocal imaging in HEK293 cells, the study functionally characterized 43 HCN1 variants and mapped them to four biophysical classes, supported by cryo-EM structure interpretation and clinical integration from 50 patients.
• The result: Across 50 patients, functional class correlated with clinical presentation: loss-of-function variants were common in milder cases or without epilepsy, while gain-of-function and mixed variants were predominantly associated with DEE; NB6, TRIP8b nano, and J&J12e normalized channel function across three classes in vitro.

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