Presentation Information
[OE3-5]A novel de novo variant in KCNH5 in a patient with refractory epileptic encephalopathy
○Akihiko Mitsutake1,2, Takashi Matsukawa1, Hiroyuki Ishiura1, Jun Mitsui3, Hiroaki Harada4, Keishi Fujio4, Jun Fujishiro5, Harushi Mori6, Shinichi Morishita7, Shoji Tsuji8, Tatsushi Toda1 (1.Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan, 2.Department of Neurology, International University of Health and Welfare Mita Hospital, Tokyo, Japan, 3.Department of Molecular Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan, 4.Department of Rheumatology and Allergy, The University of Tokyo Hospital, Tokyo, Japan, 5.Department of Pediatric Surgery, The University of Tokyo Hospital, Tokyo, Japan, 6.Department of Radiology, School of Medicine, Jichi Medical University, Tochigi, Japan, 7.Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan, 8.Institute of Medical Genomics, International University of Health and Welfare, Narita, Japan)
[Objective] We describe a novel de novo KCNH5 variant in a patient with epileptic encephalopathy. [Methods] Trio exome sequencing was performed. Candidate de novo variants were selected such that the number of alternative allele reads is at least 30% in the proband against reliable homozygous references in each parent. Candidates were validated by Sanger sequencing. [Results] The patient is a 24-year-old man. Developmental delay was noticed at the age of 9 months. Brain MRI showed cerebral atrophy and cerebellar hypoplasia. Epilepsy and regression worsened afterward, and he became bedridden. He was referred for a genetic diagnosis. We identified three de novo variants including a heterozygous p.K214Q variant in KCNH5. This variant was at a conserved position across vertebrates and not registered in databases. CADD Phred score was 26.0. Allele frequencies of the other two variants were high (0.32 and 0.13 in ToMMo). Other candidates were not detected from the conventional exome sequencing. [Discussion] Although KCNH5 has not been established as a causative gene for a specific disease, a heterozygous p.R327H variant in KCNH5 was reported in a case of epileptic encephalopathy by Veeramah (2013). Furthermore, Kv10.1 encoded by KCNH1 and Kv10.2 encoded by KCNH5 belong to the EAG K+ channel family. K214 residue in Kv10.2 corresponds to K217 in Kv10.1, and p.K217N has been described as pathogenic for Temple-Baraitser syndrome. Taken together, the p.K214Q variant is considered pathogenic. This study supports the notion that KCNH5 is a causative gene for epileptic encephalopathy.