title: Novel calmodulin mutations associated with congenital arrhythmia susceptibility.
abstract: BACKGROUND
  Genetic predisposition to life-threatening cardiac arrhythmias such as congenital long-QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) represent treatable causes of sudden cardiac death in young adults and children. Recently, mutations in calmodulin (CALM1, CALM2) have been associated with severe forms of LQTS and CPVT, with life-threatening arrhythmias occurring very early in life. Additional mutation-positive cases are needed to discern genotype-phenotype correlations associated with calmodulin mutations.
  
  
  RESULTS
  We used conventional and next-generation sequencing approaches, including exome analysis, in genotype-negative LQTS probands. We identified 5 novel de novo missense mutations in CALM2 in 3 subjects with LQTS (p.N98S, p.N98I, p.D134H) and 2 subjects with clinical features of both LQTS and CPVT (p.D132E, p.Q136P). Age of onset of major symptoms (syncope or cardiac arrest) ranged from 1 to 9 years. Three of 5 probands had cardiac arrest and 1 of these subjects did not survive. The clinical severity among subjects in this series was generally less than that originally reported for CALM1 and CALM2 associated with recurrent cardiac arrest during infancy. Four of 5 probands responded to β-blocker therapy, whereas 1 subject with mutation p.Q136P died suddenly during exertion despite this treatment. Mutations affect conserved residues located within Ca(2+)-binding loops III (p.N98S, p.N98I) or IV (p.D132E, p.D134H, p.Q136P) and caused reduced Ca(2+)-binding affinity.
  
  
  CONCLUSIONS
  CALM2 mutations can be associated with LQTS and with overlapping features of LQTS and CPVT.
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mesh_terms: D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D000328:Adult; D017668:Age of Onset; D000595:Amino Acid Sequence; D002118:Calcium / Q000737:chemistry / Q000378:metabolism; D002147:Calmodulin / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004562:Electrocardiography; D005260:Female; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D008133:Long QT Syndrome / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D011485:Protein Binding; D017422:Sequence Analysis, DNA; D017180:Tachycardia, Ventricular / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
chemical_list: D000319:Adrenergic beta-Antagonists; C488659:CALM2 protein, human; D002147:Calmodulin; D002118:Calcium
keywords: calmodulin; long QT syndrome