title: A novel heterozygous mutation in cardiac calsequestrin causes autosomal dominant catecholaminergic polymorphic ventricular tachycardia.
abstract: 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.
  
  
  
  The aim of this study was to clinically and genetically evaluate a large family with severe autosomal dominant CPVT.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Cardiology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia; Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia; Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, New South Wales, Australia.
authors.forename: Belinda
authors.initials: B
authors.lastname: Gray
authors.affiliation: Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia; Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, New South Wales, Australia.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Bagnall
authors.affiliation: Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia; Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, New South Wales, Australia.
authors.forename: Lien
authors.initials: L
authors.lastname: Lam
authors.affiliation: Department of Cardiology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia; Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia; Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, New South Wales, Australia.
authors.forename: Jodie
authors.initials: J
authors.lastname: Ingles
authors.affiliation: Department of Cardiology, Westmead Children's Hospital, Sydney, New South Wales, Australia.
authors.forename: Christian
authors.initials: C
authors.lastname: Turner
authors.affiliation: Adult Genetics Unit, South Australian Clinical Genetics Service, SA Pathology and School of Medicine, University of Adelaide, Adelaide, New South Wales, Australia.
authors.forename: Eric
authors.initials: E
authors.lastname: Haan
authors.affiliation: Department of Cardiology, The Royal Children's Hospital Melbourne, Melbourne, New South Wales, Victoria, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Davis
authors.affiliation: Department of Pharmacology, University of California, Davis, California, USA.
authors.forename: Pei-Chi
authors.initials: PC
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, University of California, Davis, California, USA.
authors.forename: Colleen E
authors.initials: CE
authors.lastname: Clancy
authors.affiliation: Department of Cardiology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia; Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Raymond W
authors.initials: RW
authors.lastname: Sy
authors.affiliation: Department of Cardiology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia; Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia; Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, New South Wales, Australia. Electronic address: c.semsarian@centenary.org.au.
authors.forename: Christopher
authors.initials: C
authors.lastname: Semsarian
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002155:Calsequestrin / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D004562:Electrocardiography; D005260:Female; D005820:Genetic Testing; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D011817:Rabbits; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics* / Q000378:metabolism; D017180:Tachycardia, Ventricular / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D055815:Young Adult; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
chemical_list: C443109:CASQ2 protein, human; D002155:Calsequestrin; D019837:Ryanodine Receptor Calcium Release Channel; D004247:DNA
keywords: Autosomal dominant; CPVT; Cardiac calsequestrin; Heterozygous