Circulation Journal
Online ISSN : 1347-4820
Print ISSN : 1346-9843
ISSN-L : 1346-9843
Arrhythmia/Electrophysiology
Phenotypic Variability of ANK2 Mutations in Patients With Inherited Primary Arrhythmia Syndromes
Mari IchikawaTakeshi AibaSeiko OhnoDaichi ShigemizuJunichi OzawaKeiko SonodaMegumi FukuyamaHideki ItohYoshihiro MiyamotoTatsuhiko TsunodaTakeru MakiyamaToshihiro TanakaWataru ShimizuMinoru Horie
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2016 Volume 80 Issue 12 Pages 2435-2442

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Abstract

Background:Mutations inANK2have been reported to cause various arrhythmia phenotypes. The prevalence ofANK2mutation carriers in inherited primary arrhythmia syndrome (IPAS), however, remains unknown in Japanese. Using a next-generation sequencer, we aimed to identifyANK2mutations in our cohort of IPAS patients, in whom conventional Sanger sequencing failed to identify pathogenic mutations in major causative genes, and to assess the clinical characteristics ofANK2mutation carriers.

Methods and Results:We screened 535 probands with IPAS and analyzed 46 genes including wholeANK2exons using a bench-top NGS (MiSeq, Illumina) or performed whole-exome-sequencing using HiSeq2000 (Illumina). As a result, 12 of 535 probands (2.2%, aged 0–61 years, 5 males) were found to carry 7 different heterozygousANK2mutations.ANK2-W1535R was identified in 5 LQTS patients and 1 symptomatic BrS and was predicted as damaging by multiple prediction software. In total, as to phenotype, there were 8 LQTS, 2 BrS, 1 IVF, and 1 SSS/AF. Surprisingly, 4/8 LQTS patients had the acquired type of LQTS (aLQTS) and suffered torsades de pointes. A total of 7 of 12 patients had documented malignant ventricular tachyarrhythmias.

Conclusions:VariousANK2mutations are associated with a wide range of phenotypes, including aLQTS, especially with ventricular fibrillation, representing “ankyrin-B” syndrome. (Circ J 2016; 80: 2435–2442)

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© 2016 THE JAPANESE CIRCULATION SOCIETY
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