Authors :
Atsushi Ishii, School of Medicine, Fukuoka University; Ayako Goto, School of Medicine, Fukuoka University; Mami Shibata, School of Medicine, Fukuoka University; Yukiko Ihara, School of Medicine, Fukuoka University; Kevin Moreira; and Shinichi Hirose
Rationale: KNCQ2 mutations are found in Benign Familial Neonatal Epilepsy (BFNE) and KCNQ2 Epileptic Encephalopathy (KCNQ2EE). While BFNE can be caused by a truncation or a missense mutation, KCNQ2EE is caused mostly by a missense mutation. The purpose of this study was to investigate if any specific regions of KCNQ2 missense variants can be used as a predictor of their consequent clinical phenotypes, i.e., BFNE or KCNQ2EE. Methods: Using our in-house data and two KCNQ2 specific disease databases, genetic and clinical information of all KCNQ2 missense variants associated with epilepsy were collected. KCNQ2 missense variants in control individuals were also collected using large control data bases. Irrelevant or duplicated variants were excluded. We then compared their cumulative distributions. Results: A total of 3106 missense variants (2963 in control
[H1] population, 46 in B(F)NE and 97 in KCNQ2EE) were eligible for study. Compared to the control, there was a significant accumulation of BFNE missense variants in the following five regions: c.304 to 394, c.460 to 482, c.587 to 916, c.998 to 1073 and c.1600 to 1764 while KCNQ2EE missense variants were accumulated significantly in the following three regions: c.523 to 1085, c.1578 to 1689, and c.1734 to 1742. In region c.460 to 482, BFNE missense variants were found more than those of KCNQ2EE. On the other hand, regions c.793 to 915 and c.917 to 973 contained more KCNQ2EE missense variants than BFNE missense variants. Conclusions: Missense variants in region c.460 to 482 are likely to cause BFNE and those in regions c.793 to 915 and c.917 to 973 are likely to cause KCNQ2EE. When a novel KCNQ2 missense variant is found, these specific regions are, therefore, useful to predict their resultant phenotypes. These regions also may be of interest as potential targets in developing precision medicine for KCNQ2 related epilepsy. Funding: This study was supported by the Ministry of Education, Culture, Sports, Science and Technology (MEXT), the Japan Agency for Medical Research and Development (AMED), the Ministry of Health, Labor and Welfare.