Genomics-First Evaluation of Heart Disease Associated With Titin-Truncating Variants

• DOI: 10.1161/circulationaha.119.039573
• Publication Date: 2019-06-20T09:00:36Z
• Authors: Christopher M. Ha...; Scott M. Damrauer; Michael G. Levin; David Birtwell; David J. Carey; Alicia M. Golden; Dustin N. Hartzel; Yirui Hu; Renae Judy; Melissa A. Kelly; Rachel L. Kember; H. Lester Kirchner; Joseph B. Leader; Lusha Liang; Chris McDermott-Roe; Apoorva Babu; Michael Morley; Zachariah Nealy; Thomas N. Person; Arichanah Pulenth...; Aeron Small; Diane T. Smelser; Richard C. Stahl; Amy C. Sturm; Heather Williams; Aris Baras; Kenneth B. Margulies; Thomas P. Cappola; Frederick E. Dewey; Anurag Verma; Xinyuan Zhang; Adolfo Correa; Michael E. Hall; James G. Wilson; Marylyn D. Ritchie; Daniel J. Rader; Michael F. Murray; Brandon K. Fornwalt; Zoltan Arany
• Keywords: Odds; Exome; Dilated Cardiomyopathy

Background: Truncating variants in the Titin gene (TTNtvs) are common individuals with idiopathic dilated cardiomyopathy (DCM). However, a comprehensive genomics-first evaluation of impact TTNtvs different clinical contexts, and modifiers such as genetic ancestry, has not been performed. Methods: We reviewed whole exome sequence data for >71 000 (61 040 from Geisinger MyCode Community Health Initiative (2007 to present) 10 273 PennMedicine BioBank (2013 identify anyone TTNtvs. further selected exons highly expressed heart (proportion spliced [PSI] >0.9). Using linked electronic health records, we evaluated associations diagnoses quantitative echocardiographic measures, including subanalyses without DCM diagnoses. also Jackson Heart Study validate specific analyses African ancestry. Results: Identified TTNtv exon (hiPSI) were 1.2% 0.6% at Geisinger. The presence hiPSI was associated increased odds European ancestry (odds ratio [95% CI]: 18.7 [9.1–39.4] {PennMedicine BioBank} 10.8 [7.0–16.0] {Geisinger}). despite high prevalence ratio, 1.8 [0.2–13.7]; P =0.57). Among 244 BioBank, carriers had lower left ventricular ejection fraction (β=–12%, =3×10 –7 ), diameter (β=0.65 cm, =9×10 –3 ). In cohort, diagnosis more atrial fibrillation 2.4 [1.6–3.6]) failure 3.8 [2.4–6.0]), (β=–3.4%, =1×10 Conclusions: Individuals have an abnormal cardiac phenotype characterized by fraction, irrespective manifestation cardiomyopathy. Associations arrhythmias, fibrillation, observed even when controlling diagnosis. contrast, no association between discerned among Given these findings, identification may alter management strategies.