An Inherited Arrhythmia Syndrome with Long QT, Sudden Death and Depolarization Disorder Due to an In-Frame Deletion in Exon 16 of the CACNA1C Gene
- *Corresponding Author:
- Robert M Hamilton
Physiology and Experimental Medicine The Hospital
for Sick Children and Research Institute Toronto, Ontario, M5G 0A4, Canada
E-mail: [email protected]
Received date: February 24, 2017; Accepted date: April 10, 2017; Published date: April 12, 2017
Citation: Rafiq MA, Koopmann TT, Zahavich LA, Fatah M, Hamilton RM (2017) An Inherited Arrhythmia Syndrome with Long QT, Sudden Death and Depolarization Disorder Due to an In-Frame Deletion in Exon 16 of the CACNA1C Gene. Next Generat Sequenc & Applic 4:144. doi:10.4172/2469-9853.1000144
Copyright: © 2017 Rafiq MA, et al. This is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Mutations of the gene encoding the L-type voltage gated calcium channel alpha-1C subunit (CACNA1C) underlie long QT phenotypes as part of Timothy syndrome. Milder phenotypes, as well as isolated cardiac phenotypes, including Brugada syndrome have been observed. To date, CACNA1C mutations have typically been missense mutations on limited number of sites that result in either gain of function (Timothy syndrome with a prolonged QT) or loss of function (short QT and/or Brugada pattern on ECG). We report a multiplex four-generation family with 3 individuals affected by QT prolongation, sudden cardiac death and conduction abnormalities, segregating with a novel heterozygous in-frame deletion mutation in exon 16 of CACNA1C resulting in a single amino acid deletion (p.Lys773del) discovered by using clinical gene panel testing at Invitae Corporation. Affected members are present in 3 consecutive generations (II, III and IV), and demonstrate only the cardiac rhythm phenotype segregating in an autosomal dominant fashion, with normal intellect, socialization and absence of syndactyly. The implicated in-frame deletion mutation of CACNA1C is absent from the exome aggregation consortium (ExAC) database, predicted to be disease causing by Mutation Taster, and removed an evolutionarily conserved lysine amino acid residue at position 773. Three-dimensional modelling demonstrated a marked effect of the mutation on the predicted protein structure.