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 John Ackerman

Research output: Contribution to journalArticle

37 Citations (Scopus)

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<sup>∗</sup>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 V<inf>1</inf> through V<inf>4</inf>, 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

Fingerprint

Long QT Syndrome
Sudden Cardiac Death
Pediatrics
Mutation
Exome
Induced Heart Arrest
Frameshift Mutation
Syncope
Genetic Association Studies
triadin
Genetic Testing
DNA Sequence Analysis
Cardiac Arrhythmias
Seizures
High Pressure Liquid Chromatography
Exercise
Phenotype
Polymerase Chain Reaction

Keywords

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

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Homozygous/compound heterozygous triadin mutations associated with autosomal-recessive long-QT syndrome and pediatric sudden cardiac arrest elucidation of the triadin knockout syndrome. / Altmann, Helene M.; Tester, David J.; Will, Melissa L.; Middha, Sumit; Evans, Jared M.; Eckloff, Bruce W.; Ackerman, Michael John.

In: Circulation, Vol. 131, No. 23, 2015, p. 2051-2060.

Research output: Contribution to journalArticle

Altmann, Helene M. ; Tester, David J. ; Will, Melissa L. ; Middha, Sumit ; Evans, Jared M. ; Eckloff, Bruce W. ; Ackerman, Michael John. / Homozygous/compound heterozygous triadin mutations associated with autosomal-recessive long-QT syndrome and pediatric sudden cardiac arrest elucidation of the triadin knockout syndrome. In: Circulation. 2015 ; Vol. 131, No. 23. pp. 2051-2060.
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T1 - Homozygous/compound heterozygous triadin mutations associated with autosomal-recessive long-QT syndrome and pediatric sudden cardiac arrest elucidation of the triadin knockout syndrome

AU - Altmann, Helene M.

AU - Tester, David J.

AU - Will, Melissa L.

AU - Middha, Sumit

AU - Evans, Jared M.

AU - Eckloff, Bruce W.

AU - Ackerman, Michael John

PY - 2015

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N2 - 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.

AB - 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.

KW - Arrhythmias

KW - Cardiac

KW - Genetics

KW - Heart arrest

KW - Humans

KW - Long QT syndrome

KW - Pediatrics

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