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Genetic analysis of sick sinus syndrome in a family harboring compound CACNA1C and TTN mutations

  • Authors:
    • Yao‑Bin Zhu
    • Jie‑Wei Luo
    • Fen Jiang
    • Gui Liu
  • View Affiliations / Copyright

    Affiliations: Department of Traditional Chinese Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian 350005, P.R. China, Provincial Clinical Medical College, Fujian Medical University, Fuzhou, Fujian 350001, P.R. China, Pharmacogenomics Research Center, Inje University College of Medicine, Busan 614‑715, Republic of Korea, Department of Traditional Chinese Medicine, Fujian Provincial Hospital, Fuzhou, Fujian 350001, P.R. China
    Copyright: © Zhu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 7073-7080
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    Published online on: March 16, 2018
       https://doi.org/10.3892/mmr.2018.8773
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Abstract

Sick sinus syndrome (SSS) is a sinus node dysfunction characterized by severe sinus bradycardia. SSS results in insufficient blood supply to the brain, heart, kidneys, and other organs and is associated with the increased risk of sudden cardiac death. Bradyarrhythmia appears in the absence of any associated cardiac pathology and displays a genetic legacy. The present study identified a family with primary manifestation of sinus bradycardia (five individuals) along with early repolarization (four individuals) and atrial fibrillation (one individual). Targeted exome sequencing was used to screen exons and adjacent splice sites of 61 inherited arrhythmia‑associated genes, to detect pathogenic genes and variant sites in the proband. Family members were sequenced by Sanger sequencing and protein functions predicted by Polyphen‑2 software. A total of three rare variants were identified in the family, including two missense variants in calcium voltage‑gated channel subunit alpha1 C (CACNA1C) (gi:193788541, NM_001129843), c.1786G>A (p.V596M) and c.5344G>A (p.A1782T), and one missense variant in titin (TTN) c.49415G>A (p.R16472H) (gi:291045222, NM_003319). The variants p.V596M and p.R16472H were predicted to be deleterious and resulted in alterations in the amino acid type and sequence of the polypeptide chain, which may partially or completely inactivate the encoded protein. The comparison of literature, gene database, and pedigree phenotype analysis suggests that p.V596M or p.R16472H variants are pathogenic. The complex overlapping variants at three loci lead to a more severe phenotype in the proband, and may increase the susceptibility of individuals to atrial fibrillation. The simultaneous occurrence of V596M and R16472H may increase the severity of early repolarization. Various family members may have carried heterozygous mutants of p.A1782T and p.R16472H due to genetic heterogeneity, however did not exhibit clinical signs of cardiac electrophysiological alterations, potentially attributable to the low vagal tone. To the best of the author's knowledge, this is the first study to suggest the involvement of the novel missense CACNA1C c.1786G>A and TTN c.49415G>A variants in the inheritance of symptomatic bradycardia and development of SSS.
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Copy and paste a formatted citation
Spandidos Publications style
Zhu YB, Luo JW, Jiang F and Liu G: Genetic analysis of sick sinus syndrome in a family harboring compound CACNA1C and TTN mutations. Mol Med Rep 17: 7073-7080, 2018.
APA
Zhu, Y., Luo, J., Jiang, F., & Liu, G. (2018). Genetic analysis of sick sinus syndrome in a family harboring compound CACNA1C and TTN mutations. Molecular Medicine Reports, 17, 7073-7080. https://doi.org/10.3892/mmr.2018.8773
MLA
Zhu, Y., Luo, J., Jiang, F., Liu, G."Genetic analysis of sick sinus syndrome in a family harboring compound CACNA1C and TTN mutations". Molecular Medicine Reports 17.5 (2018): 7073-7080.
Chicago
Zhu, Y., Luo, J., Jiang, F., Liu, G."Genetic analysis of sick sinus syndrome in a family harboring compound CACNA1C and TTN mutations". Molecular Medicine Reports 17, no. 5 (2018): 7073-7080. https://doi.org/10.3892/mmr.2018.8773
Copy and paste a formatted citation
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Spandidos Publications style
Zhu YB, Luo JW, Jiang F and Liu G: Genetic analysis of sick sinus syndrome in a family harboring compound CACNA1C and TTN mutations. Mol Med Rep 17: 7073-7080, 2018.
APA
Zhu, Y., Luo, J., Jiang, F., & Liu, G. (2018). Genetic analysis of sick sinus syndrome in a family harboring compound CACNA1C and TTN mutations. Molecular Medicine Reports, 17, 7073-7080. https://doi.org/10.3892/mmr.2018.8773
MLA
Zhu, Y., Luo, J., Jiang, F., Liu, G."Genetic analysis of sick sinus syndrome in a family harboring compound CACNA1C and TTN mutations". Molecular Medicine Reports 17.5 (2018): 7073-7080.
Chicago
Zhu, Y., Luo, J., Jiang, F., Liu, G."Genetic analysis of sick sinus syndrome in a family harboring compound CACNA1C and TTN mutations". Molecular Medicine Reports 17, no. 5 (2018): 7073-7080. https://doi.org/10.3892/mmr.2018.8773
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