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Targeted Deep Sequencing Reveals No Definitive Evidence for Somatic Mosaicism in Atrial Fibrillation
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Details:
  • Pubmed ID:
    25406240
  • Pubmed Central ID:
    PMC4334693
  • Description:
    Background

    Studies of ≤15 atrial fibrillation (AF) patients have identified atrial-specific mutations within connexin genes, suggesting that somatic mutations may account for sporadic cases of the arrhythmia. We sought to identify atrial somatic mutations among patients with and without AF using targeted deep next-generation sequencing of 560 genes, including genetic culprits implicated in AF, the Mendelian cardiomyopathies and channelopathies, and all ion channels within the genome.

    Methods and Results

    Targeted gene capture and next generation sequencing were performed on DNA from lymphocytes and left atrial appendages of 34 patients (25 with AF). Twenty AF patients had undergone cardiac surgery exclusively for pulmonary vein isolation, and 17 had no structural heart disease. Sequence alignment and variant calling were performed for each atrial-lymphocyte pair using the Burrows-Wheeler Aligner, the Genome Analysis Toolkit, and MuTect packages. Next generation sequencing yielded a median 265-fold coverage depth (IQR 164–369). Comparison of the 3 million base pairs from each atrial-lymphocyte pair revealed a single potential somatic missense mutation in 3 AF patients and 2 in a single control (12 vs. 11%; p=1). All potential discordant variants had low allelic fractions (range: 2.3–7.3%) and none were detected with conventional sequencing.

    Conclusions

    Using high-depth next generation sequencing and state-of-the art somatic mutation calling approaches, no pathogenic atrial somatic mutations could be confirmed among 25 AF patients in a comprehensive cardiac arrhythmia genetic panel. These findings indicate that atrial specific mutations are rare and that somatic mosaicism is unlikely to exert a prominent role in AF pathogenesis.

  • Document Type:
  • Collection(s):
  • Funding:
    DP2 HL123228/DP/NCCDPHP CDC HHS/United States
    DP2 HL123228/HL/NHLBI NIH HHS/United States
    K08 HL093861/HL/NHLBI NIH HHS/United States
    K08 HL098361/HL/NHLBI NIH HHS/United States
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