A Titin Truncation Variant Co-segregating with Dilated Cardiomyopathy in a Large Maori Kindred

Abstract

Aim: Next Generation sequencing (NGS) has recently identified Titin truncation variants (TTNtv) to be causative in numerous cases of familial dilated cardiomyopathy (DCM). Identifying the underlying molecular cause aids in cascade screening, risk stratification and a pathway for future therapeutic options. Phenotypic characteristics of patients with TTNtv are not fully described. We present a large Maori kindred with a highly penetrant TTNtv causing DCM. Method: 7 male family members affected by early onset DCM were identified. 28 inherited heart disease genes were sequenced on an Illumina MiSeq in the proband. Cardioclassifier https://www.cardioclassifier.org/ (Imperial College London, 2017) was used for variant calling. Advanced ECG (A-ECG) analysis was used to compare TTNtv carriers and a DCM cohort with unknown TTNtv status. Results: The proband was heterozygote for a nonsense TTNtv in the I band (Chr2 c.41880G > A), identified by Cardioclassifier as likely pathogenic. This co-segregated with family members with DCM and was absent in unaffected individuals. Paroxysmal atrial fibrillation and a rate related cardiomyopathy was the presenting hallmark in several family members. The proband had a ventricular fibrillation arrest at the time of pulmonary vein isolation. Two family members have undergone cardiac transplantation and one has been listed for transplantation. A-ECG Spatial QRS-T angle indicated a higher risk for ventricular arrhythmia, in family members with arrhythmic events. Conclusion: TTNtv presented as a highly penetrant pathogenic variant associated with DCM in this kindred. Both atrial and ventricular arrhythmias were common in carriers. TTNtv population frequencies should be further explored in indigenous Maori populations, who have high burden of unexplained DCM and possible founder effects.