Abstract 12257: Calmodulin Interacting Genes as a Novel Candidate for Pathogenesis of Long-QT Syndrome
Background: Approximately 30% of long-QT syndrome (LQTS) cases remains genetically elusive. Here, we investigated usefulness of the whole exon sequencing (WES) by next-generation sequencing for identification of novel pathogenic candidates which directly or indirectly interact with proteins encoded by known LQTS genes.
Methods: Of 1815 Japanese LQTS cohort patients, WES was performed in 59 LQTS patients and 61 unaffected individuals from 35 families and 138 unrelated LQTS cases, all were screened major LQTS genes such as KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2 and KCNJ2. After WES, the genes known as inherited arrhythmias were screened by the Human Gene Mutation Database, and the Sanger sequencing was also referred for validation of the mutations and common variants were excluded by the public (1000G, ESP6500 and dbSNP) and Riken database.
Results: Total 92 candidate mutations including 11 de novo, 5 recessive (2 homozygous and 3 compound heterozygous) and 73 dominant mutations in 88 genes were identified in 23 of the 35 families. Protein-protein interaction network analyses revealed ten new pathogenic candidates (WDR26, RYR2, UBR5, UBR4, KIF21B, CIT, SIRT6, PIK3CG, PI4KA and RIMS1) that directly or indirectly interact with proteins encoded by known LQTS genes. Furthermore, gene based association studies identified an additional novel candidate; SLC2A5. Taken together, mutations in these new candidates or known LQTS genes were identified in 13 of the 35(37%) genotype-unknown LQTS families. Moreover, 5 of the 11 newly identified candidates directly interact with calmodulin (CaM). Subsequent variant analysis in the independent set of 138 cases identified 16 variants in the 11 genes, of which, 14 (87.5%) were in the CaM-interacting genes and 8 of them were in RYR2. Many of the patients with RyR2 mutation had similar exercise-induced cardiac events (3 syncope, 2 VF) as LQTS patients, while the QTc interval was shorter in patients with RyR2 mutation than those with genotype-negative LQTS (441±32 vs. 487±47ms; p=0.01).
Conclusions: These findings suggest that CaM interacting genes have an important role on the pathogenesis of LQTS. In particular, RYR2 mutations may cause an overlap syndrome between catecholaminergic polymorphic ventricular tachycardia and LQTS.
Author Disclosures: T. Aiba: None. D. Shigemizu: None. H. Nakagawa: None. K. Ozaki: None. F. Miya: None. W. Satake: None. T. Toda: None. Y. Miyamoto: None. A. Fujimoto: None. Y. Suzuki: None. M. Kubo: None. T. Tsunoda: None. K. Kusano: None. S. Yasuda: None. H. Ogawa: None. T. Tanaka: None. W. Shimizu: None.
- © 2015 by American Heart Association, Inc.