Rare truncating variants in the sarcomeric protein titin associate with familial and early-onset atrial fibrillation

Gustav Ahlberg, Lena Refsgaard, Pia R Lundegaard, Laura Andreasen, Mattis F Ranthe, Nora Linscheid, Jonas B Nielsen, Mads Melbye, Stig Haunsø, Ahmad Sajadieh, Lu Camp, Søren-Peter Olesen, Simon Rasmussen, Alicia Lundby, Patrick T Ellinor, Anders G Holst, Jesper H Svendsen, Morten S Olesen*

*Corresponding author for this work

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    Abstract

    A family history of atrial fibrillation constitutes a substantial risk of developing the disease, however, the pathogenesis of this complex disease is poorly understood. We perform whole-exome sequencing on 24 families with at least three family members diagnosed with atrial fibrillation (AF) and find that titin-truncating variants (TTNtv) are significantly enriched in these patients (P = 1.76 × 10-6). This finding is replicated in an independent cohort of early-onset lone AF patients (n = 399; odds ratio = 36.8; P = 4.13 × 10-6). A CRISPR/Cas9 modified zebrafish carrying a truncating variant of titin is used to investigate TTNtv effect in atrial development. We observe compromised assembly of the sarcomere in both atria and ventricle, longer PR interval, and heterozygous adult zebrafish have a higher degree of fibrosis in the atria, indicating that TTNtv are important risk factors for AF. This aligns with the early onset of the disease and adds an important dimension to the understanding of the molecular predisposition for AF.
    Original languageEnglish
    Article number4316
    JournalNature Communications
    Volume9
    Number of pages11
    ISSN2041-1723
    DOIs
    Publication statusPublished - 2018

    Cite this

    Ahlberg, G., Refsgaard, L., Lundegaard, P. R., Andreasen, L., Ranthe, M. F., Linscheid, N., Nielsen, J. B., Melbye, M., Haunsø, S., Sajadieh, A., Camp, L., Olesen, S-P., Rasmussen, S., Lundby, A., Ellinor, P. T., Holst, A. G., Svendsen, J. H., & Olesen, M. S. (2018). Rare truncating variants in the sarcomeric protein titin associate with familial and early-onset atrial fibrillation. Nature Communications, 9, [4316]. https://doi.org/10.1038/s41467-018-06618-y