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

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 heterozy

SUBMITTER: Ahlberg G 

PROVIDER: S-EPMC6193003 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature