title: Compound Mutations Cause Increased Cardiac Events in Children with Long QT Syndrome: Can the Sequence Homology-Based Tools be Applied for Prediction of Phenotypic Severity?
abstract: Long QT syndrome (LQTS) can cause syncope, ventricular fibrillation, and death. Recently, several disease-causing mutations in ion channel genes have been identified, and compound mutations have also been detected. It is unclear whether children who are carriers of compound mutations exhibit a more severe phenotype than those with single mutations. Although predicting phenotypic severity is clinically important, the availability of prediction tools for LQTS is unknown. To determine whether the severity of the LQTS phenotype can be predicted by the presence of compound mutations in children is needed. We detected 97 single mutations (Group S) and 13 compound mutations (Group C) between 1998 and 2012, age at diagnosis ranging 0-19 years old (median age is 9.0) and 18.0 years of follow-up period. The phenotypes and Kaplan-Meier event-free rates of the two groups were compared for cardiac events. This study investigated phenotypic severity in relation to the location of mutations in the protein sequence, which was analyzed using two sequence homology-based tools. In results, compound mutations in children were associated with a high incidence of syncope within the first decade (Group S: 32 % vs. Group C: 61 %), requiring an ICD in the second decade (Group S: 3 % vs. Group C: 56 %). Mortality in these patients was high within 5 years of birth (23 %). Phenotypic prediction tools correctly predicted the phenotypic severity in both Groups S and C, especially by using their coupling method. The coupling prediction method is useful in the initial evaluation of phenotypes both with single and compound mutations of LQTS patients. However, it should be noted that the compound mutation makes more severe phenotype.
authors.affiliation: Department of Pediatric Cardiology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjyuku-ku, Tokyo, 162-8666, Japan. gaku-izumi0920@med.hokudai.ac.jp.|Department of Pediatrics, Hokkaido University Graduate School of Medicine, North-15 West-7, Sapporo, 060-8638, Japan. gaku-izumi0920@med.hokudai.ac.jp.
authors.forename: Gaku
authors.initials: G
authors.lastname: Izumi
authors.affiliation: Department of Pediatric Cardiology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjyuku-ku, Tokyo, 162-8666, Japan.
authors.forename: Emiko
authors.initials: E
authors.lastname: Hayama
authors.affiliation: Department of Pediatrics, Hokkaido University Graduate School of Medicine, North-15 West-7, Sapporo, 060-8638, Japan.
authors.forename: Hirokuni
authors.initials: H
authors.lastname: Yamazawa
authors.affiliation: Department of Pediatric Cardiology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjyuku-ku, Tokyo, 162-8666, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Inai
authors.affiliation: Department of Pediatric Cardiology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjyuku-ku, Tokyo, 162-8666, Japan.
authors.forename: Mitsuyo
authors.initials: M
authors.lastname: Shimada
authors.affiliation: Department of Pediatric Cardiology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjyuku-ku, Tokyo, 162-8666, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Furutani
authors.affiliation: Department of Pediatric Cardiology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjyuku-ku, Tokyo, 162-8666, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nishizawa
authors.affiliation: Department of Pediatric Cardiology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjyuku-ku, Tokyo, 162-8666, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Furutani
authors.affiliation: Department of Pediatric Cardiology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjyuku-ku, Tokyo, 162-8666, Japan.
authors.forename: Rumiko
authors.initials: R
authors.lastname: Matsuoka
authors.affiliation: Department of Pediatric Cardiology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjyuku-ku, Tokyo, 162-8666, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Nakanishi
mesh_terms: D000293:Adolescent; D001145:Arrhythmias, Cardiac; D002648:Child; D002675:Child, Preschool; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D051657:KCNQ1 Potassium Channel; D008133:Long QT Syndrome; D009154:Mutation; D010641:Phenotype; D017385:Sequence Homology; D055815:Young Adult
chemical_list: D051657:KCNQ1 Potassium Channel
keywords: Compound mutation; ICD; LQT syndrome; Phenotypic prediction; Sudden death; Syncope