Homozygous/Compound Heterozygous Triadin Mutations Associated with Autosomal Recessive Long QT Syndrome and Pediatric Sudden Cardiac Arrest: Elucidation of Triadin Knockout Syndrome
Background—LQTS may result in syncope, seizures, or sudden cardiac arrest. Although 17 LQTS-susceptibly genes have been discovered, 20-25% of LQTS remains genetically elusive.
Methods and Results—Whole exome sequencing (WES) child-parent trio analysis followed by recessive and sporadic inheritance modelling and disease-network candidate analysis gene ranking was performed to identify a novel underlying genetic mechanism for LQTS. Subsequent mutational analysis of the candidate gene was performed using PCR, DHPLC, and DNA sequencing on a cohort of 33 additional unrelated patients with genetically elusive LQTS. Following WES and variant filtration, a homozygous p.D18fs*13 TRDN-encoded triadin frame-shift mutation was discovered in a 10 year-old female LQTS patient with a QTc of 500 ms who experienced recurrent exertion-induced syncope/cardiac arrest beginning at age 1 year. Subsequent mutational analysis of TRDN revealed either homozygous or compound heterozygous frame-shift mutations in 4/33 (12%) unrelated cases of LQTS. All five TRDN null patients displayed extensive T-wave inversions in precordial leads V1-V4, with either persistent or transient QT-prolongation, severe disease expression of exercise-induced cardiac arrest in early childhood (≤ 3 years of age), and required aggressive therapy. The overall yield of TRDN mutations was significantly greater in patients ≤ 10 years of age (5/10, 50%) compared to older patients (0/24, 0%, p = 0.0009).
Conclusions—We identified TRDN as a novel underlying genetic basis for recessively inherited LQTS. All TRDN null patients had strikingly similar phenotypes. Given the recurrent nature of potential lethal arrhythmias, patients fitting this phenotypic profile should undergo cardiac TRDN genetic testing.
- Received January 9, 2015.
- Revision received April 13, 2015.
- Accepted April 17, 2015.