Abstract 13546: Putative Titin Mutations Associated With Both Long QT Syndrome and Left Ventricular Noncompaction

Abstract

Introduction: Inherited long QT Syndrome (LQTS) is characterized by prolonged QTc intervals on electrocardiogram (EKG), ventricular arrhythmias and sudden death (SCD), and is caused by mutations in ion channel or ion-channel related genes. Inherited forms of dilated cardiomyopathy (DCM) and left ventricular noncompaction (LVNC), on the other hand, are caused by mutations in sarcomeric and structural genes including titin. Methods: Two unrelated families with histories of SCD presented to us for clinical evaluation of LQTS. Clinical genetic testing covering arrhythmia and cardiomyopathy genes was performed on each proband, with carrier testing on other family members. Results (Figure): The proband of family 1 had a strong family history of SCD, carried the clinical diagnosis of LQTS treated with propranolol, and had normal cardiac function by echocardiography. Following chemotherapy with adriamycin for breast cancer, evaluation showed a QTc of 514 ms on EKG, non-sustained VT on Holter, and LVNC with an LVEF=43% on cardiac MRI (cMRI). Genetic testing identified a likely pathogenic nonsense TTN variant (p.W18202*) along with a benign TTN polymorphism (p.E689K). Her clinically normal daughter did not carry the p.W18202* variant. The proband of family 2 had a strong family history of LQTS and SCD and was diagnosed with LQTS in her 20s after her mother suffered a cardiac arrest. Evaluation showed a QTc of 500 ms on EKG and biventricular LVNC with an LVEF=48% on cMRI. Genetic testing identified a likely pathogenic frameshift TTN variant (p.E18038Rfs*47). Three of her children carried the variant and had borderline or prolonged QTc intervals; one had hypertrabeculation on cMRI. Conclusion: We have identified two truncating TTN variants in close proximity to each other in unrelated families with overlapping LQTS/LVNC/DCM syndromes. Mutations in TTN may play a previously unappreciated role in the pathogenesis of inherited arrhythmia syndromes.