Pediatrics International (2008) 50, 167–171 doi: 10.1111/j.1442-200X.2008.02539.x © 2008 Japan Pediatric Society Benign familial neonatal convulsion (BFNC; OMIM 121200) is an autosomal-dominantly inherited epilepsy of neonates that is characterized by unprovoked, generalized or multifocal tonic– clonic convulsions. Convulsions usually begin within the first few days of life and disappear spontaneously after several weeks or months. 1 Neurological examination, interictal electroencepha- lography (EEG) and subsequent neurodevelopment of these children are usually normal but, despite the normal neurodevel- opment, convulsions may recur later in life in some BFNC patients. 2 In addition, a wide range of phenotypic variability, from normal neurodevelopment without any convulsions to severe epileptic encephalopathy, may also be observed in BFNC families. 3 The first disease locus of BFNC, EBN1, was mapped to the long arm of chromosome 20. 4,5 Later, a second locus on chromo- some 8, EBN2, was described, suggesting clinical and genetic heterogeneity of the disease. 6–8 Two novel voltage-gated potassium channel genes, KCNQ2 on chromosome 20q13.3 and KCNQ3 on chromosome 8q24, were subsequently cloned and shown to be the responsible genes for the development of BFNC. 9–12 KCNQ2- and KCNQ3-specific transcripts are detectable in the central nervous system. 12 The corresponding proteins assem- ble to build a functional heterotetrameric channel that has an underlying M-current. 13–15 This M-current is a repolarizing cur- rent that limits repetitive firing during long-lasting depolarizing inputs and causes spike-frequency adaptation. 16 Thus, suppres- sion or stimulation of the M-current is a primary mechanism for increasing or decreasing neuronal excitability, respectively. 17 Many mutations in KCNQ2 and KCNQ3 that cause BFNC have been reported in various countries. 18 In Japan, several dif- ferent mutations have been identified in BFNC patients, namely c.481 + 1G>T in KCNQ2, c.910-2del, TTC or TTT in KCNQ2 and c.925T>C in KCNQ3. 19–21 Screening for mutations in KCNQ2 and KCNQ3 is helpful for confirmation of BFNC or differential diagnosis of convulsive disorders in the neonatal period. In the present report we describe a single novel mutation, c.683C>T, in KCNQ2 identified in a Japanese family with two siblings with BFNC. This mutation caused an amino acid change (p.R213W) Original Article Germ-line mutation of KCNQ2, p.R213W, in a Japanese family with benign familial neonatal convulsion Ahmad H. Sadewa, 1 Teguh H. Sasongko, 1 Gunadi, 1 Myeong J. Lee, 1 Kazunari Daikoku, 2 Akiyo Yamamoto, 3 Takemi Yamasaki, 3 Shigenori Tanaka, 4 Masafumi Matsuo 5 and Hisahide Nishio 1 1 Department of Public Health, Kobe University Graduate School of Medicine, Kobe, 2 Department of Pediatrics, Ootake Hospital, Hiroshima, 3 Hyogo Prefectural Children’s Hospital, 4 Kobe University Graduate School of Science and Technology and 5 Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan Abstract Background : Benign familial neonatal convulsion (BFNC) is an autosomal-dominantly inherited epilepsy of neonates. The KCNQ2 and KCNQ3 genes have been cloned as the responsible genes for BFNC. Detection of mutations in these genes is helpful for confirmation of BFNC or differential diagnosis of convulsive disorders in the neonatal period. Methods : A Japanese family with BFNC was investigated. Two siblings were clinically diagnosed as having BFNC. KCNQ2 and KCNQ3 were screened for mutations using a combination of polymerase chain reaction and denaturing high-performance liquid chromatography. Nucleotide substitutions were confirmed by direct sequencing. Results : In the affected siblings a C-to-T heterozygous substitution was detected at nucleotide 683 (c.683C>T) in KCNQ2, leading to substitution of arginine with tryptophan at amino acid position 213 (p.R213W) in the S4 voltage- sensing domain of the KCNQ2 protein. The detected mutation may disrupt this highly conserved region among potassium channel proteins. The c.683C>T substitution in KCNQ2 was not present in the parents. KCNQ3 was also analyzed and a single nucleotide polymorphism, c.1241A>G (National Center for Biotechnology Information (NCBI), SNP ID: rs2303995), was detected in the index family. Conclusions : Two siblings with BFNC had a novel heterozygous missense mutation, p.R213W, in KCNQ2. This mutation may affect potassium gating, leading to neuronal excitability or convulsions in the patients. Furthermore, neither of the parents had the p.R213W mutation, indicating that it was a germ-line mutation. The possibility of recurrence of such a germ-line mutation in the next siblings should be explained during genetic counseling. Key words benign familial neonatal convulsion, BFNC, germ–line mutation, KCNQ2, KCNQ3. Correspondence: Hisahide Nishio, MD, Department of Public Health, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. Email: nishio@med.kobe-u.ac.jp Received 16 May 2006; revised 30 January 2007; accepted 2 February 2007.