Phenotypic Variability of ANK2 Mutations in Patients With Inherited Primary Arrhythmia Syndromes

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 IP...

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Published in:Circulation Journal 2016/11/25, Vol.80(12), pp.2435-2442
Main Authors: Ichikawa, Mari, Aiba, Takeshi, Ohno, Seiko, Shigemizu, Daichi, Ozawa, Junichi, Sonoda, Keiko, Fukuyama, Megumi, Itoh, Hideki, Miyamoto, Yoshihiro, Tsunoda, Tatsuhiko, Makiyama, Takeru, Tanaka, Toshihiro, Shimizu, Wataru, Horie, Minoru
Format: Article
Language:English
Subjects:
Acquired long QT syndrome
Adult
ANK2
Ankyrin-B syndrome
Ankyrins - genetics
Arrhythmias, Cardiac - epidemiology
Arrhythmias, Cardiac - genetics
Asian Continental Ancestry Group
Bradycardia
Child
Exons
Female
Genetic Diseases, Inborn - epidemiology
Genetic Diseases, Inborn - genetics
Humans
Infant, Newborn
Inherited primary arrhythmia syndrome
Japan - epidemiology
Male
Middle Aged
Mutation
Prevalence
Syndrome
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Summary: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)
ISSN:1346-9843
1347-4820
DOI:10.1253/circj.CJ-16-0486