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

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

来源：Heart Rhythm, 2017, 14(10): 1531-1538.

DOI：10.1016/j.hrthm.2017.05.027

• Atrial fibrillation
• Genetics
• Bioinformatics
• Cardiac tissue
• Mitral valve regurgitation
• Somatic mutations
• Somatic variants

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.

• 出版日期2017-10