Abstract 13310: TTN Variants and Arrhythmic Risk Among Countywide Sudden Deaths: From the San Francisco Postmortem Systematic Investigation of Sudden Cardiac Death Study

Abstract

Background: Titin, encoded by TTN , is a sarcomeric protein necessary for normal cardiac and skeletal muscle function. Truncating variants in the A-band are a frequent cause of isolated and familial dilated cardiomyopathy (DCM) in living cohorts. Whether variants outside of the A-band confer arrhythmic risk remains unclear. We investigated the yield and distribution of TTN variants in a postmortem study of presumed sudden cardiac deaths (pSCDs) in San Francisco County. Methods: From 2/1/2011 to 12/31/2017, the Postmortem Systematic Investigation of Sudden Cardiac Death study performed complete autopsies on 889 incident deaths (age 16-90) meeting World Health Organization criteria for SCD (pSCD). Using clinical records, autopsy findings, and family history, we performed deep phenotyping to adjudicate underlying arrhythmic “SAD” (potentially rescuable with defibrillation) or non-arrhythmic “non-SAD” (tamponade, overdose, etc.) cause of pSCD. We performed clinical whole exome testing on cases with next of kin consent. Results: Of the 322 pSCDs tested (196 SAD, 126 non-SAD), we detected 5 truncating/splice variants located in non-A-band regions (p=0.03 vs. none found in the A-band) in 4 cases, all SAD. No truncating/splice variants were detected in 47 cases with autopsy evidence of DCM (cardiomegaly and short axis > 3.5cm). Overall, 89 cases had at least 1 TTN variant of uncertain significance (VUS): 61 (68.5%) SADs and 28 (31.5%) non-SADs, with a trend towards more TTN VUSs among SADs (p =0.10). A total of 110 VUSs were found: 10 (9.1%) in the Z-disc, 38 (34.5%) in the I-band, 50 (45.5%) in the A-band, and 12 (10.9%) in the M-band. TTN VUSs clustered similarly throughout the gene in SADs and non-SADs. Conclusion: In this 7-year postmortem genetic study of unselected countywide sudden deaths using autopsy to adjudicate arrhythmic cause, we found TTN truncating/splice variants in non-A-band regions were associated with SAD and a trend toward association with SAD among TTN VUS carriers. In contrast to living cohorts with diagnosed DCM, no cases meeting autopsy criteria for DCM had a truncating/splice variant. Since non-survivors (i.e., SCDs) are underrepresented in DCM cohorts, our results suggest a potential role for non-A band TTN variants in arrhythmic risk.