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Three cases of catecholaminergic polymorphic ventricular tachycardia with prolonged QT intervals including two cases of compound mutations.

ABSTRACT: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is one of the leading causes of sudden arrhythmic death in the young. The QT interval in CPVT patients is typically within the normal range. However, those with prolonged QT interval have often been diagnosed with mutation-negative long QT syndrome (LQTS). We report three CPVT patients with prolonged QT interval. Case 1 and 2 were diagnosed as LQTS at first. Genetic test using next-generation sequencing (NGS) revealed RyR2 mutations. We should consider genetic test using NGS to identify the genes responsible for CPVT in mutation-negative LQTS.

SUBMITTER: Saito A

PROVIDER: S-EPMC6010000 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Three cases of catecholaminergic polymorphic ventricular tachycardia with prolonged QT intervals including two cases of compound mutations.

Saito Aki A Ohno Seiko S Nuruki Norihito N Nomura Yuichi Y Horie Minoru M Yoshinaga Masao M

Journal of arrhythmia 20180406 3

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is one of the leading causes of sudden arrhythmic death in the young. The QT interval in CPVT patients is typically within the normal range. However, those with prolonged QT interval have often been diagnosed with mutation-negative long QT syndrome (LQTS). We report three CPVT patients with prolonged QT interval. Case 1 and 2 were diagnosed as LQTS at first. Genetic test using next-generation sequencing (NGS) revealed <i>RyR2</i> mutat ...[more]

PMID: 29951146

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Project description:RationaleAutosomal-dominant mutations in ryanodine receptor type 2 ( RYR2) are responsible for ≈60% of all catecholaminergic polymorphic ventricular tachycardia. Dysfunctional RyR2 subunits trigger inappropriate calcium leak from the tetrameric channel resulting in potentially lethal ventricular tachycardia. In vivo CRISPR/Cas9-mediated gene editing is a promising strategy that could be used to eliminate the disease-causing Ryr2 allele and hence rescue catecholaminergic polymorphic ventricular tachycardia.ObjectiveTo determine if somatic in vivo genome editing using the CRISPR/Cas9 system delivered by adeno-associated viral (AAV) vectors could correct catecholaminergic polymorphic ventricular tachycardia arrhythmias in mice heterozygous for RyR2 mutation R176Q (R176Q/+).Methods and resultsGuide RNAs were designed to specifically disrupt the R176Q allele in the R176Q/+ mice using the SaCas9 ( Staphylococcus aureus Cas9) genome editing system. AAV serotype 9 was used to deliver Cas9 and guide RNA to neonatal mice by single subcutaneous injection at postnatal day 10. Strikingly, none of the R176Q/+ mice treated with AAV-CRISPR developed arrhythmias, compared with 71% of R176Q/+ mice receiving control AAV serotype 9. Total Ryr2 mRNA and protein levels were significantly reduced in R176Q/+ mice, but not in wild-type littermates. Targeted deep sequencing confirmed successful and highly specific editing of the disease-causing R176Q allele. No detectable off-target mutagenesis was observed in the wild-type Ryr2 allele or the predicted putative off-target site, confirming high specificity for SaCas9 in vivo. In addition, confocal imaging revealed that gene editing normalized the enhanced Ca2+ spark frequency observed in untreated R176Q/+ mice without affecting systolic Ca2+ transients.ConclusionsAAV serotype 9-based delivery of the SaCas9 system can efficiently disrupt a disease-causing allele in cardiomyocytes in vivo. This work highlights the potential of somatic genome editing approaches for the treatment of lethal autosomal-dominant inherited cardiac disorders, such as catecholaminergic polymorphic ventricular tachycardia.

Dataset Information

Three cases of catecholaminergic polymorphic ventricular tachycardia with prolonged QT intervals including two cases of compound mutations.

Publications

Three cases of catecholaminergic polymorphic ventricular tachycardia with prolonged QT intervals including two cases of compound mutations.

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