Deep sequencing of atrial fibrillation patients with mitral valve regurgitation shows no evidence of mosaicism but reveals novel rare germline variants

Research output: Contribution to journalJournal articleResearchpeer-review

Emilie Gregers, Gustav Ahlberg, Thea Christensen, Javad Jabbari, Kirstine O Larsen, Cecilie B Herfelt, Kristoffer M Henningsen, Laura Andreasen, Jens J Thiis, Jens Lund, Susanne Holme, Stig Haunsø, Bo H Bentzen, Nicole Schmitt, Jesper H Svendsen, Morten S Olesen

BACKGROUND: Atrial fibrillation (AF) is the most common cardiac arrhythmia. Valvular heart disease is a strong predictor, yet the underlying molecular mechanisms are unknown.

OBJECTIVE: The purpose of this study was to investigate the prevalence of somatic variants in AF candidate genes in an AF patient population undergoing surgery for mitral valve regurgitation (MVR) to determine whether these patients are genetically predisposed to AF.

METHODS: DNA was extracted from blood and left atrial tissue from 44 AF patients with MVR. Using next-generation sequencing, we investigated 110 genes using the HaloPlex Target Enrichment System. MuTect software was used for identification of somatic point variants. We functionally characterized selected variants using electrophysiologic techniques.

RESULTS: No somatic variants were identified in the cardiac tissue. Thirty-three patients (75%) had a rare germline variation in ≥1 candidate genes. Fourteen variants were novel. Fifteen variants were predicted damaging or likely damaging in ≥6 in silico predictions. We identified rare variants in genes never directly associated with AF: KCNE4, SCN4B, NEURL1, and CAND2. Interestingly, 7 patients (16%) had variants in genes involved in cellular potassium handling. The variants KCNQ1 (p.G272S) and KCNH2 (p.A913V) resulted in gain of function due to faster activation (KCNQ1) and slowed deactivation kinetics (KCNQ1, KCNH2).

CONCLUSION: We did not find any somatic variants in patients with AF and MVR. Surprisingly, we found that our cohort of non-lone AF patients might, like lone AF patients, be predisposed to AF by rare germline variants. Our findings emphasize the extent of still unknown factors in the pathogenesis of AF.

Original languageEnglish
JournalHeart Rhythm
Volume14
Issue number10
Pages (from-to)1531-1538
ISSN1547-5271
DOIs
Publication statusPublished - Oct 2017

    Research areas

  • Journal Article

ID: 183763006