A novel heterozygous mutation in cardiac calsequestrin causes autosomal dominant catecholaminergic polymorphic ventricular tachycardia

Belinda Gray, Richard D. Bagnall, Lien Lam, Jodie Ingles, Christian Turner, Eric Haan, Andrew Davis, Pei Chi Yang, Colleen E Clancy, Raymond W. Sy, Christopher Semsarian

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Background Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal inherited arrhythmia syndrome characterized by adrenergically stimulated ventricular tachycardia. Mutations in the cardiac ryanodine receptor gene (RYR2) cause an autosomal dominant form of CPVT, while mutations in the cardiac calsequestrin 2 gene (CASQ2) cause an autosomal recessive form. Objective The aim of this study was to clinically and genetically evaluate a large family with severe autosomal dominant CPVT. Methods Clinical evaluation of family members was performed, including detailed history, physical examination, electrocardiogram, exercise stress test, and autopsy review of decedents. We performed genome-wide linkage analysis in 12 family members and exome sequencing in 2 affected family members. In silico models of mouse and rabbit myocyte electrophysiology were used to predict potential disease mechanisms. Results Severe CPVT with dominant inheritance in 6 members was diagnosed in a large family with 2 sudden deaths, 2 resuscitated cardiac arrests, and multiple appropriate implantable cardioverter-defibrillator shocks. A comprehensive analysis of cardiac arrhythmia genes did not reveal a pathogenic variant. Exome sequencing identified a novel heterozygous missense variant in CASQ2 (Lys180Arg) affecting a highly conserved residue, which cosegregated with disease and was absent in unaffected family members. Genome-wide linkage analysis confirmed a single linkage peak at the CASQ2 locus (logarithm of odds ratio score 3.01; θ = 0). Computer simulations predicted that haploinsufficiency was unlikely to cause the severe CPVT phenotype and suggested a dominant negative mechanism. Conclusion We show for the first time that a variant in CASQ2 causes autosomal dominant CPVT. Genetic testing in dominant CPVT should include screening for heterozygous CASQ2 variants.

Original languageEnglish (US)
Pages (from-to)1652-1660
Number of pages9
JournalHeart Rhythm
Volume13
Issue number8
DOIs
StatePublished - Aug 1 2016

Fingerprint

Calsequestrin
Mutation
Genes
Exome
Exercise Test
Computer Simulation
Cardiac Arrhythmias
Genome
Haploinsufficiency
Ryanodine Receptor Calcium Release Channel
Implantable Defibrillators
Electrophysiology
Genetic Testing
Ventricular Tachycardia
Sudden Death
Polymorphic catecholergic ventricular tachycardia
Heart Arrest
Muscle Cells
Physical Examination
Autopsy

Keywords

  • Autosomal dominant
  • Cardiac calsequestrin
  • CPVT
  • Heterozygous

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

A novel heterozygous mutation in cardiac calsequestrin causes autosomal dominant catecholaminergic polymorphic ventricular tachycardia. / Gray, Belinda; Bagnall, Richard D.; Lam, Lien; Ingles, Jodie; Turner, Christian; Haan, Eric; Davis, Andrew; Yang, Pei Chi; Clancy, Colleen E; Sy, Raymond W.; Semsarian, Christopher.

In: Heart Rhythm, Vol. 13, No. 8, 01.08.2016, p. 1652-1660.

Research output: Contribution to journalArticle

Gray, B, Bagnall, RD, Lam, L, Ingles, J, Turner, C, Haan, E, Davis, A, Yang, PC, Clancy, CE, Sy, RW & Semsarian, C 2016, 'A novel heterozygous mutation in cardiac calsequestrin causes autosomal dominant catecholaminergic polymorphic ventricular tachycardia', Heart Rhythm, vol. 13, no. 8, pp. 1652-1660. https://doi.org/10.1016/j.hrthm.2016.05.004
Gray, Belinda ; Bagnall, Richard D. ; Lam, Lien ; Ingles, Jodie ; Turner, Christian ; Haan, Eric ; Davis, Andrew ; Yang, Pei Chi ; Clancy, Colleen E ; Sy, Raymond W. ; Semsarian, Christopher. / A novel heterozygous mutation in cardiac calsequestrin causes autosomal dominant catecholaminergic polymorphic ventricular tachycardia. In: Heart Rhythm. 2016 ; Vol. 13, No. 8. pp. 1652-1660.
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abstract = "Background Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal inherited arrhythmia syndrome characterized by adrenergically stimulated ventricular tachycardia. Mutations in the cardiac ryanodine receptor gene (RYR2) cause an autosomal dominant form of CPVT, while mutations in the cardiac calsequestrin 2 gene (CASQ2) cause an autosomal recessive form. Objective The aim of this study was to clinically and genetically evaluate a large family with severe autosomal dominant CPVT. Methods Clinical evaluation of family members was performed, including detailed history, physical examination, electrocardiogram, exercise stress test, and autopsy review of decedents. We performed genome-wide linkage analysis in 12 family members and exome sequencing in 2 affected family members. In silico models of mouse and rabbit myocyte electrophysiology were used to predict potential disease mechanisms. Results Severe CPVT with dominant inheritance in 6 members was diagnosed in a large family with 2 sudden deaths, 2 resuscitated cardiac arrests, and multiple appropriate implantable cardioverter-defibrillator shocks. A comprehensive analysis of cardiac arrhythmia genes did not reveal a pathogenic variant. Exome sequencing identified a novel heterozygous missense variant in CASQ2 (Lys180Arg) affecting a highly conserved residue, which cosegregated with disease and was absent in unaffected family members. Genome-wide linkage analysis confirmed a single linkage peak at the CASQ2 locus (logarithm of odds ratio score 3.01; θ = 0). Computer simulations predicted that haploinsufficiency was unlikely to cause the severe CPVT phenotype and suggested a dominant negative mechanism. Conclusion We show for the first time that a variant in CASQ2 causes autosomal dominant CPVT. Genetic testing in dominant CPVT should include screening for heterozygous CASQ2 variants.",
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AU - Ingles, Jodie

AU - Turner, Christian

AU - Haan, Eric

AU - Davis, Andrew

AU - Yang, Pei Chi

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N2 - Background Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal inherited arrhythmia syndrome characterized by adrenergically stimulated ventricular tachycardia. Mutations in the cardiac ryanodine receptor gene (RYR2) cause an autosomal dominant form of CPVT, while mutations in the cardiac calsequestrin 2 gene (CASQ2) cause an autosomal recessive form. Objective The aim of this study was to clinically and genetically evaluate a large family with severe autosomal dominant CPVT. Methods Clinical evaluation of family members was performed, including detailed history, physical examination, electrocardiogram, exercise stress test, and autopsy review of decedents. We performed genome-wide linkage analysis in 12 family members and exome sequencing in 2 affected family members. In silico models of mouse and rabbit myocyte electrophysiology were used to predict potential disease mechanisms. Results Severe CPVT with dominant inheritance in 6 members was diagnosed in a large family with 2 sudden deaths, 2 resuscitated cardiac arrests, and multiple appropriate implantable cardioverter-defibrillator shocks. A comprehensive analysis of cardiac arrhythmia genes did not reveal a pathogenic variant. Exome sequencing identified a novel heterozygous missense variant in CASQ2 (Lys180Arg) affecting a highly conserved residue, which cosegregated with disease and was absent in unaffected family members. Genome-wide linkage analysis confirmed a single linkage peak at the CASQ2 locus (logarithm of odds ratio score 3.01; θ = 0). Computer simulations predicted that haploinsufficiency was unlikely to cause the severe CPVT phenotype and suggested a dominant negative mechanism. Conclusion We show for the first time that a variant in CASQ2 causes autosomal dominant CPVT. Genetic testing in dominant CPVT should include screening for heterozygous CASQ2 variants.

AB - Background Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal inherited arrhythmia syndrome characterized by adrenergically stimulated ventricular tachycardia. Mutations in the cardiac ryanodine receptor gene (RYR2) cause an autosomal dominant form of CPVT, while mutations in the cardiac calsequestrin 2 gene (CASQ2) cause an autosomal recessive form. Objective The aim of this study was to clinically and genetically evaluate a large family with severe autosomal dominant CPVT. Methods Clinical evaluation of family members was performed, including detailed history, physical examination, electrocardiogram, exercise stress test, and autopsy review of decedents. We performed genome-wide linkage analysis in 12 family members and exome sequencing in 2 affected family members. In silico models of mouse and rabbit myocyte electrophysiology were used to predict potential disease mechanisms. Results Severe CPVT with dominant inheritance in 6 members was diagnosed in a large family with 2 sudden deaths, 2 resuscitated cardiac arrests, and multiple appropriate implantable cardioverter-defibrillator shocks. A comprehensive analysis of cardiac arrhythmia genes did not reveal a pathogenic variant. Exome sequencing identified a novel heterozygous missense variant in CASQ2 (Lys180Arg) affecting a highly conserved residue, which cosegregated with disease and was absent in unaffected family members. Genome-wide linkage analysis confirmed a single linkage peak at the CASQ2 locus (logarithm of odds ratio score 3.01; θ = 0). Computer simulations predicted that haploinsufficiency was unlikely to cause the severe CPVT phenotype and suggested a dominant negative mechanism. Conclusion We show for the first time that a variant in CASQ2 causes autosomal dominant CPVT. Genetic testing in dominant CPVT should include screening for heterozygous CASQ2 variants.

KW - Autosomal dominant

KW - Cardiac calsequestrin

KW - CPVT

KW - Heterozygous

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