Early Infantile Epileptic Encephalopathy 24 via the HCN1 Gene

Early infantile epileptic encephalopathy 24 is known as Dravet-like syndrome. Patients with a pathogenic variant in HCN1 have clinical symptoms resembling those of Dravet syndrome with progression toward atypical absences, intellectual disability and autistic traits (Nava et al. 2014). Patients have similar clinical features of seizures beginning at ages of 4 to 13 months and a combination of febrile and afebrile seizures, including hemiclonic and generalized seizures. These manifestations are initially suggestive of Dravet syndrome, but show different progression over time. Atypical absences, with or without myoclonic jerks, and focal seizures become predominant in older patients. All affected patients have mild to severe intellectual disability and major behavioral disturbances, including autistic traits (Nava et al. 2014).

Early infantile epileptic encephalopathy 24 is inherited in an autosomal dominant manner and is caused by pathogenic variants in HCN1 which encodes Hyperpolarization-activated cyclic nucleotide-gated potassium channel 1. HCN channels are activated by membrane hyperpolarization at voltages close to resting membrane potentials and carry the hyperpolarization-activated current, dubbed I_f (funny current) in heart and I_h in neurons (DiFrancesco et al. 2015). HCN1 is one of four genes (HCN1-4) with different biophysical properties expressed in the heart and brain.

The reported HCN1 pathogenic variants are missense variants (Human Gene Mutation Database). Most of the pathogenic missense variants have gain-of-function with possible dominant-negative effect (DiFrancesco et al. 2015). Some of the pathogenic variants occur de novo (Nava et al. 2014). Copy number variants (CNVs) encompassing HCN1 exons have been reported in healthy and intellectually disabled individuals at similarly low frequencies (Nava et al. 2014; Poduri et al. 2014). To date, no pathogenic large deletions/duplications have been reported in HCN1 (HGMD).

Pathogenic variants in HCN1 caused early infantile epileptic encephalopathy in roughly 2.5% of the cases in a screening cohort (Nava et al. 2014).

This test provides full coverage of all coding exons of the HCN1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.