Homozygous/Compound Heterozygous Triadin Mutations Associated With Autosomal-Recessive Long-QT Syndrome and Pediatric Sudden Cardiac Arrest: Elucidation of the Triadin Knockout Syndrome

Circulation. 2015 Jun 9;131(23):2051-60. doi: 10.1161/CIRCULATIONAHA.115.015397. Epub 2015 Apr 28.


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.

Keywords: arrhythmias, cardiac; genetics; heart arrest; humans; long QT syndrome; pediatrics.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Carrier Proteins / genetics*
  • Child
  • Child, Preschool
  • Defibrillators, Implantable
  • Exome
  • Female
  • Frameshift Mutation
  • Genes, Recessive
  • Heart Arrest / diagnosis
  • Heart Arrest / genetics*
  • Heterozygote
  • Homozygote
  • Humans
  • Infant
  • Long QT Syndrome / diagnosis
  • Long QT Syndrome / genetics*
  • Long QT Syndrome / therapy
  • Male
  • Middle Aged
  • Muscle Proteins / genetics*
  • Pedigree
  • Phenotype
  • Sequence Analysis, DNA
  • Sympathectomy
  • Syncope / diagnosis
  • Syncope / genetics
  • Syndrome
  • Treatment Outcome
  • Young Adult


  • Carrier Proteins
  • Muscle Proteins
  • TRDN protein, human