Abstract 13817: Clinical Significance of Whole Exome Analysis Using Next Generation Sequencing in the Genotype-negative Long-QT Syndrome
Background: Long-QT syndrome (LQTS) is characterized by QT prolongation of ECG and syncope or sudden unexpected death by lethal ventricular arrhythmias, and approximately 70% of patients with a clinically diagnosis has three major LQTS-genes such as KCNQ1, KCNH2 and SCN5A, whereas 30% of LQTS cases remains genetically elusive.
Next-generation sequencing (NGS) provides an unprecedented opportunity to assess genetic variation underlying human disease. Here, we investigated usefulness of the whole exon sequencing (WXS) by NGS for diagnosis in patients without identified major LQTS-genes by the Sanger sequencing method.
Methods: From 1815 Japanese LQTS cohort patients, WXS was performed in 400 (22%) consecutive genotype-negative/ phenotype-positive unrelated LQTS patients (196 probands and 204 families) in which major LQTS genes such as KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2 and KCNJ2 had already been screened. After WXS, 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 Japanese Riken database.
Results: Total 4 novel mutations in ANK2 gene, two AKAP9, one CAV3, and one SNTA1 mutations were identified from WXS using NGS. No significant difference was observed in the QTc interval between patients with ANK2 mutations and other genotype-negative LQTS (491±72 vs. 456±47 ms; p=NS). However, 3 of 4 patients with ANK2 mutations had symptoms (syncope or VF) while none in AKAP9, CAV3 and SNTA1 mutations had symptoms.
On the other hand, 3 KCNQ1, 2 KCNH2, and one SCN5A mutations, which could not be identified by the Sanger method, and 2 NOS1AP variants were identified and 8 (including 5 novel) mutations in RyR2 gene were also identified from WXS. 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: Whole exon sequencing by NGS revealed that small but not negligible number of patients have a mutation in the minor LQTS genes or RyR2 gene in the genotype-negative LQTS patients.
Author Disclosures: T. Aiba: None. K. Ishibashi: None. M. Wada: None. I. Nakajima: None. K. Miyamoto: None. H. Okamura: None. T. Noda: None. D. Shigemizu: None. W. Satake: None. T. Toda: None. K. Kusano: None. S. Kamakura: None. S. Yasuda: None. A. Sekine: None. Y. Miyamoto: None. T. Tanaka: None. H. Ogawa: None. W. Shimizu: None.
- © 2014 by American Heart Association, Inc.