The HCN1 p.Ser399Pro variant causes epileptic encephalopathy with super-refractory status epilepticus

Yu Kobayashi; Jun Tohyama; Noriyuki Akasaka; Kei Yamada; Moemi Hojo; Eijun Seki; Masaki Miura; Noriko Soma; Takeshi Ono; Mitsuhiro Kato; Mitsuko Nakashima; Hirotomo Saitsu; Naomichi Matsumoto

doi:10.1038/s41439-023-00247-8

The HCN1 p.Ser399Pro variant causes epileptic encephalopathy with super-refractory status epilepticus

Hum Genome Var. 2023 Jun 23;10(1):20. doi: 10.1038/s41439-023-00247-8.

Authors

Affiliations

¹ Department of Child Neurology, National Hospital Organization Nishiniigata Chuo Hospital, Niigata, Japan.
² Department of Child Neurology, National Hospital Organization Nishiniigata Chuo Hospital, Niigata, Japan. tohyama.jun.um@mail.hosp.go.jp.
³ Department of Pediatrics, Niigata Prefecture Hamagumi Medical Rehabilitation Center for Disabled Children, Niigata, Japan.
⁴ Department of Pediatrics, Niigata University Medical and Dental Hospital, Niigata, Japan.
⁵ Department of Pediatrics, Showa University School of Medicine, Tokyo, Japan.
⁶ Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan.
⁷ Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Abstract

HCN1 is one of four genes encoding hyperpolarization-activated cyclic nucleotide-gated channels. The phenotypic spectrum associated with HCN1 variants ranges from neonatal developmental and epileptic encephalopathy to idiopathic generalized epilepsy. We report a Japanese patient with repetitive focal seizures and super-refractory status epilepticus since early infancy caused by a de novo HCN1 variant, NM_021072.4, c.1195T>C, p.(Ser399Pro). This variant might have a dominant-negative effect on channel function, leading to severe epileptic encephalopathy.