Homozygous/compound heterozygous triadin mutations associated with autosomal-recessive long-QT syndrome and pediatric sudden cardiac arrest: Elucidation of the triadin knockout syndrome

Helene M. Altmann, David J. Tester, Melissa L. Will, Sumit Middha, Jared M. Evans, Bruce W. Eckloff, Michael J. Ackerman

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

Background - Long-QT syndrome (LQTS) may result in syncope, seizures, or sudden cardiac arrest. Although 16 LQTS-susceptibility genes have been discovered, 20% to 25% of LQTS remains genetically elusive. Methods and Results - We performed whole-exome sequencing child-parent trio analysis followed by recessive and sporadic inheritance modeling and disease-network candidate analysis gene ranking to identify a novel underlying genetic mechanism for LQTS. Subsequent mutational analysis of the candidate gene was performed with polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing on a cohort of 33 additional unrelated patients with genetically elusive LQTS. After whole-exome sequencing and variant filtration, a homozygous p.D18fs∗13 TRDN-encoded triadin frameshift mutation was discovered in a 10-year-old female patient with LQTS with a QTc of 500 milliseconds who experienced recurrent exertion-induced syncope/cardiac arrest beginning at 1 year of age. Subsequent mutational analysis of TRDN revealed either homozygous or compound heterozygous frameshift mutations in 4 of 33 unrelated cases of LQTS (12%). All 5 TRDN-null patients displayed extensive T-wave inversions in precordial leads V1 through V4, with either persistent or transient QT prolongation and 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 of 10, 50%) compared with older patients (0 of 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.

Original languageEnglish (US)
Pages (from-to)2051-2060
Number of pages10
JournalCirculation
Volume131
Issue number23
DOIs
StatePublished - 2015

Keywords

  • Arrhythmias
  • Cardiac
  • Genetics
  • Heart arrest
  • Humans
  • Long QT syndrome
  • Pediatrics

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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