title: 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.
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.
  
  
  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 CaV1.2 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.
authors.affiliation: From the Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (N.J.B., D.Y., D.J.T., J.M.B., M.J.A.), Division of Immunology and Neurology (F.J., A.H., A.J.J.), and Departments of Medicine (Division of Cardiovascular Diseases) and Pediatrics (Division of Pediatric Cardiology) (M.J.A.), Mayo Clinic, Rochester, MN; Division of Cardiology, Nicklaus Children's Hospital, Miami, FL (R.K.).
authors.forename: Nicole J
authors.initials: NJ
authors.lastname: Boczek
authors.affiliation: From the Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (N.J.B., D.Y., D.J.T., J.M.B., M.J.A.), Division of Immunology and Neurology (F.J., A.H., A.J.J.), and Departments of Medicine (Division of Cardiovascular Diseases) and Pediatrics (Division of Pediatric Cardiology) (M.J.A.), Mayo Clinic, Rochester, MN; Division of Cardiology, Nicklaus Children's Hospital, Miami, FL (R.K.).
authors.forename: Dan
authors.initials: D
authors.lastname: Ye
authors.affiliation: From the Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (N.J.B., D.Y., D.J.T., J.M.B., M.J.A.), Division of Immunology and Neurology (F.J., A.H., A.J.J.), and Departments of Medicine (Division of Cardiovascular Diseases) and Pediatrics (Division of Pediatric Cardiology) (M.J.A.), Mayo Clinic, Rochester, MN; Division of Cardiology, Nicklaus Children's Hospital, Miami, FL (R.K.).
authors.forename: Fang
authors.initials: F
authors.lastname: Jin
authors.affiliation: From the Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (N.J.B., D.Y., D.J.T., J.M.B., M.J.A.), Division of Immunology and Neurology (F.J., A.H., A.J.J.), and Departments of Medicine (Division of Cardiovascular Diseases) and Pediatrics (Division of Pediatric Cardiology) (M.J.A.), Mayo Clinic, Rochester, MN; Division of Cardiology, Nicklaus Children's Hospital, Miami, FL (R.K.).
authors.forename: David J
authors.initials: DJ
authors.lastname: Tester
authors.affiliation: From the Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (N.J.B., D.Y., D.J.T., J.M.B., M.J.A.), Division of Immunology and Neurology (F.J., A.H., A.J.J.), and Departments of Medicine (Division of Cardiovascular Diseases) and Pediatrics (Division of Pediatric Cardiology) (M.J.A.), Mayo Clinic, Rochester, MN; Division of Cardiology, Nicklaus Children's Hospital, Miami, FL (R.K.).
authors.forename: April
authors.initials: A
authors.lastname: Huseby
authors.affiliation: From the Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (N.J.B., D.Y., D.J.T., J.M.B., M.J.A.), Division of Immunology and Neurology (F.J., A.H., A.J.J.), and Departments of Medicine (Division of Cardiovascular Diseases) and Pediatrics (Division of Pediatric Cardiology) (M.J.A.), Mayo Clinic, Rochester, MN; Division of Cardiology, Nicklaus Children's Hospital, Miami, FL (R.K.).
authors.forename: J Martijn
authors.initials: JM
authors.lastname: Bos
authors.affiliation: From the Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (N.J.B., D.Y., D.J.T., J.M.B., M.J.A.), Division of Immunology and Neurology (F.J., A.H., A.J.J.), and Departments of Medicine (Division of Cardiovascular Diseases) and Pediatrics (Division of Pediatric Cardiology) (M.J.A.), Mayo Clinic, Rochester, MN; Division of Cardiology, Nicklaus Children's Hospital, Miami, FL (R.K.).
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Johnson
authors.affiliation: From the Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (N.J.B., D.Y., D.J.T., J.M.B., M.J.A.), Division of Immunology and Neurology (F.J., A.H., A.J.J.), and Departments of Medicine (Division of Cardiovascular Diseases) and Pediatrics (Division of Pediatric Cardiology) (M.J.A.), Mayo Clinic, Rochester, MN; Division of Cardiology, Nicklaus Children's Hospital, Miami, FL (R.K.).
authors.forename: Ronald
authors.initials: R
authors.lastname: Kanter
authors.affiliation: From the Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (N.J.B., D.Y., D.J.T., J.M.B., M.J.A.), Division of Immunology and Neurology (F.J., A.H., A.J.J.), and Departments of Medicine (Division of Cardiovascular Diseases) and Pediatrics (Division of Pediatric Cardiology) (M.J.A.), Mayo Clinic, Rochester, MN; Division of Cardiology, Nicklaus Children's Hospital, Miami, FL (R.K.). ackerman.michael@mayo.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
mesh_terms: D000293:Adolescent; D000328:Adult; D001321:Autistic Disorder / Q000235:genetics*; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics; D002648:Child; D004252:DNA Mutational Analysis; D016757:Death, Sudden, Cardiac; D005091:Exons; D005260:Female; D006330:Heart Defects, Congenital / Q000235:genetics; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D018408:Patch-Clamp Techniques; D010375:Pedigree; D010641:Phenotype; D013576:Syndactyly / Q000235:genetics*
keywords: Timothy syndrome; calcium channels, L-type; cardiomyopathy, hypertrophic; death, sudden, cardiac; genetics; long QT syndrome