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 and Morten S. Olesen ()
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Gustav Ahlberg: University Hospital of Copenhagen
Lena Refsgaard: University Hospital of Copenhagen
Pia R. Lundegaard: University Hospital of Copenhagen
Laura Andreasen: University Hospital of Copenhagen
Mattis F. Ranthe: Statens Serum Institute
Nora Linscheid: University of Copenhagen
Jonas B. Nielsen: University of Copenhagen
Mads Melbye: Statens Serum Institute
Stig Haunsø: University Hospital of Copenhagen
Ahmad Sajadieh: Copenhagen University Hospital, Bispebjerg
Lu Camp: The Lundbeck Foundation Centre for Applied Medical Genomics in Personalized Disease Prediction, Prevention and Care
Søren-Peter Olesen: University of Copenhagen
Simon Rasmussen: Technical University of Denmark
Alicia Lundby: University of Copenhagen
Patrick T. Ellinor: Cardiovascular Research Centre, Massachusetts General Hospital
Anders G. Holst: University Hospital of Copenhagen
Jesper H. Svendsen: University Hospital of Copenhagen
Morten S. Olesen: University Hospital of Copenhagen

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06618-y

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