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. 2019 Feb;12(2):e002419.
doi: 10.1161/CIRCGEN.118.002419.

International Triadin Knockout Syndrome Registry

Daniel J Clemens  1 , David J Tester  2 , John R Giudicessi  1 , J Martijn Bos  1 , Ram K Rohatgi  1 , Dominic J Abrams  2 , Seshadri Balaji  3 , Lia Crotti  4   5   6 , Julien Faure  7   8 , Carlo Napolitano  9   10 , Silvia G Priori  9   10 , Vincent Probst  11   12 , Caroline Rooryck-Thambo  13 , Nathalie Roux-Buisson  7   8 , Frederic Sacher  13 , Peter J Schwartz  4 , Michael J Silka  14 , Mark A Walsh  15 , Michael J Ackerman  1
Affiliations
Free article

International Triadin Knockout Syndrome Registry

Daniel J Clemens et al. Circ Genom Precis Med. 2019 Feb.
Free article

Abstract

Background: Triadin knockout syndrome (TKOS) is a rare, inherited arrhythmia syndrome caused by recessive null mutations in TRDN-encoded cardiac triadin. Based previously on 5 triadin null patients, TKOS has been characterized by extensive T-wave inversions, transient QT prolongation, and severe disease expression of exercise-induced cardiac arrest in early childhood refractory to conventional therapy.

Methods: We have established the International Triadin Knockout Syndrome Registry to include patients who have genetically proven homozygous/compound heterozygous TRDN null mutations. Clinical/genetic data were collected using an online survey generated through REDCap.

Results: Currently, the International Triadin Knockout Syndrome Registry includes 21 patients (11 males, average age of 18 years) from 16 families. Twenty patients (95%) presented with either cardiac arrest (15, 71%) or syncope (5, 24%) at an average age of 3 years. Mild skeletal myopathy/proximal muscle weakness was noted in 6 (29%) patients. Of the 19 surviving patients, 16 (84%) exhibit T-wave inversions, and 10 (53%) have transient QT prolongation > 480 ms. Eight of 9 patients had ventricular ectopy on exercise stress testing. Thirteen (68%) patients have received implantable defibrillators. Despite various treatment strategies, 14 (74%) patients have had recurrent breakthrough cardiac events.

Conclusion: TKOS is a potentially lethal disease characterized by T-wave inversions in the precordial leads, transient QT prolongation in some, and recurrent ventricular arrhythmias at a young age despite aggressive treatment. Patients displaying this phenotype should undergo TRDN genetic testing as TKOS may be a cause for otherwise unexplained cardiac arrest in young children. As gene therapy advances, enrollment into the International Triadin Knockout Syndrome Registry is encouraged to better understand TKOS and to ready a well-characterized cohort for future TRDN gene therapy trials.

Keywords: genetics; human; long QT syndrome; pediatrics; phenotype.

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