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

• DOI: 10.1038/s41467-018-06618-y
• Publication Date: 2018-10-11T12:11:29Z
• Authors: 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
• Keywords: Exome

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