Exome sequencing and systems biology converge to identify novel mutations in the L-type calcium channel, CACNA1C, linked to autosomal dominant long QT syndrome

Nicole J. Boczek, Jabe M. Best, David J. Tester, John R. Giudicessi, Sumit Middha, Jared M. Evans, Timothy J. Kamp, Michael J. Ackerman

Research output: Contribution to journalArticle

65 Scopus citations

Abstract

Background-Long QT syndrome (LQTS) is the most common cardiac channelopathy with 15 elucidated LQTSsusceptibility genes. Approximately 20% of LQTS cases remain genetically elusive. Methods and Results-We combined whole-exome sequencing and bioinformatic/systems biology to identify the pathogenic substrate responsible for nonsyndromic, genotype-negative, autosomal dominant LQTS in a multigenerational pedigree, and we established the spectrum and prevalence of variants in the elucidated gene among a cohort of 102 unrelated patients with "genotype-negative/phenotype-positive" LQTS. Whole-exome sequencing was used on 3 members within a genotype-negative/phenotype-positive family. Genomic triangulation combined with bioinformatic tools and ranking algorithms led to the identification of a CACNA1C mutation. This mutation, Pro857Arg-CACNA1C, cosegregated with the disease within the pedigree, was ranked by 3 disease-network algorithms as the most probable LQTS-susceptibility gene and involves a conserved residue localizing to the proline, gltamic acid, serine, and threonine (PEST) domain in the II-III linker. Functional studies reveal that Pro857Arg-CACNA1C leads to a gain of function with increased I Ca,L and increased surface membrane expression of the channel compared to wild type. Subsequent mutational analysis identified 3 additional variants within CACNA1C in our cohort of 102 unrelated cases of genotype-negative/phenotype-positive LQTS. Two of these variants also involve conserved residues within Cav1.2's PEST domain. Conclusions-This study provides evidence that coupling whole-exome sequencing and bioinformatic/systems biology is an effective strategy for the identification of potential disease-causing genes/mutations. The identification of a functional CACNA1C mutation cosegregating with disease in a single pedigree suggests that CACNA1C perturbations may underlie autosomal dominant LQTS in the absence of Timothy syndrome.

Original languageEnglish (US)
Pages (from-to)279-289
Number of pages11
JournalCirculation: Cardiovascular Genetics
Volume6
Issue number3
DOIs
StatePublished - Jun 1 2013

Keywords

  • Arrhythmia
  • Calcium
  • Genetics
  • Ion channel
  • Long QT syndrome

ASJC Scopus subject areas

  • Genetics
  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)

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