title: Exome Analyses of Long QT Syndrome Reveal Candidate Pathogenic Mutations in Calmodulin-Interacting Genes.
abstract: Long QT syndrome (LQTS) is an arrhythmogenic disorder that can lead to sudden death. To date, mutations in 15 LQTS-susceptibility genes have been implicated. However, the genetic cause for approximately 20% of LQTS patients remains elusive. Here, we performed whole-exome sequencing analyses on 59 LQTS and 61 unaffected individuals in 35 families and 138 unrelated LQTS cases, after genetic screening of known LQTS genes. Our systematic analysis of familial cases and subsequent verification by Sanger sequencing identified 92 candidate mutations in 88 genes for 23 of the 35 families (65.7%): these included eleven de novo, five recessive (two homozygous and three compound heterozygous) and seventy-three dominant mutations. Although no novel commonly mutated gene was identified other than known LQTS genes, protein-protein interaction (PPI) network analyses revealed ten new pathogenic candidates that directly or indirectly interact with proteins encoded by known LQTS genes. Furthermore, candidate gene based association studies using an independent set of 138 unrelated LQTS cases and 587 controls identified an additional novel candidate. Together, mutations in these new candidates and known genes explained 37.1% of the LQTS families (13 in 35). Moreover, half of the newly identified candidates directly interact with calmodulin (5 in 11; comparison with all genes; p=0.042). Subsequent variant analysis in the independent set of 138 cases identified 16 variants in the 11 genes, of which 14 were in calmodulin-interacting genes (87.5%). These results suggest an important role of calmodulin and its interacting proteins in the pathogenesis of LQTS.
authors.affiliation: Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: Daichi
authors.initials: D
authors.lastname: Shigemizu
authors.affiliation: Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Aiba
authors.affiliation: Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: Hidewaki
authors.initials: H
authors.lastname: Nakagawa
authors.affiliation: Laboratory for Cardiovascular Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: Kouichi
authors.initials: K
authors.lastname: Ozaki
authors.affiliation: Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: Fuyuki
authors.initials: F
authors.lastname: Miya
authors.affiliation: Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Satake
authors.affiliation: Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Toda
authors.affiliation: Department of Preventive Cardiology, National Cerebral and Cardiovascular Center, Suita, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Miyamoto
authors.affiliation: Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Fujimoto
authors.affiliation: Department of Computational Biology, Division of Biosystem Sciences, University of Tokyo, Chiba, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.affiliation: Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Tsunoda
authors.affiliation: Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan; Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Shimizu
authors.affiliation: Laboratory for Cardiovascular Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Department of Human Genetics and Disease Diversity, Tokyo Medical and Dental University Graduate School of Medical and Dental Sciences, Tokyo, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Tanaka
mesh_terms: D000293:Adolescent; D000328:Adult; D002148:Calmodulin-Binding Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D059472:Exome; D005260:Female; D005799:Genes, Dominant; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008133:Long QT Syndrome / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree
chemical_list: D002148:Calmodulin-Binding Proteins