Identification and Functional Characterization of a Novel CACNA1C -Mediated Cardiac Disorder Characterized by Prolonged QT Intervals with Hypertrophic Cardiomyopathy, Congenital Heart Defects, and Sudden Cardiac Death

Nicole J. Boczek, Dan Ye, Fang Jin, David J. Tester, April Huseby, J. Martijn Bos, Aaron J. Johnson, Ronald Kanter, Michael J. Ackerman

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

Background - A portion of sudden cardiac deaths can be attributed to structural heart diseases, such as hypertrophic cardiomyopathy (HCM) or cardiac channelopathies such as long-QT syndrome (LQTS); however, the underlying molecular mechanisms are distinct. Here, we identify a novel CACNA1C missense mutation with mixed loss-of-function/gain-of-function responsible for a complex phenotype of LQTS, HCM, sudden cardiac death, and congenital heart defects. Methods and Results - Whole exome sequencing in combination with Ingenuity variant analysis was completed on 3 affected individuals and 1 unaffected individual from a large pedigree with concomitant LQTS, HCM, and congenital heart defects and identified a novel CACNA1C mutation, p.Arg518Cys, as the most likely candidate mutation. Mutational analysis of exon 12 of CACNA1C was completed on 5 additional patients with a similar phenotype of LQTS plus a personal or family history of HCM-like phenotypes and identified 2 additional pedigrees with mutations at the same position, p.Arg518Cys/His. Whole cell patch clamp technique was used to assess the electrophysiological effects of the identified mutations in Ca V 1.2 and revealed a complex phenotype, including loss of current density and inactivation in combination with increased window and late current. Conclusions - Through whole exome sequencing and expanded cohort screening, we identified a novel genetic substrate p.Arg518Cys/His-CACNA1C, in patients with a complex phenotype including LQTS, HCM, and congenital heart defects annotated as cardiac-only Timothy syndrome. Our electrophysiological studies, identification of mutations at the same amino acid position in multiple pedigrees, and cosegregation with disease in these pedigrees provide evidence that p.Arg518Cys/His is the pathogenic substrate for the observed phenotype.

Original languageEnglish (US)
Pages (from-to)1122-1132
Number of pages11
JournalCirculation: Arrhythmia and Electrophysiology
Volume8
Issue number5
DOIs
StatePublished - Oct 1 2015

Keywords

  • Timothy syndrome
  • calcium channels, L-type
  • cardiomyopathy, hypertrophic
  • death, sudden, cardiac
  • genetics
  • long QT syndrome

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Fingerprint Dive into the research topics of 'Identification and Functional Characterization of a Novel CACNA1C -Mediated Cardiac Disorder Characterized by Prolonged QT Intervals with Hypertrophic Cardiomyopathy, Congenital Heart Defects, and Sudden Cardiac Death'. Together they form a unique fingerprint.

  • Cite this