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


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.
From Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (H.M.A., D.J.T., M.L.W., M.J.A.), Department of Medicine/Division of Cardiovascular Diseases (D.J.T., M.L.W., M.J.A.), Medical Genome Facility (B.W.E.), and Department of Pediatrics/Division of Pediatric Cardiology (M.J.A.), Mayo Clinic, Rochester, MN; and Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo College of Medicine, Rochester, MN (S.M., J.M.E.).
Helene M
HM
Altmann
From Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (H.M.A., D.J.T., M.L.W., M.J.A.), Department of Medicine/Division of Cardiovascular Diseases (D.J.T., M.L.W., M.J.A.), Medical Genome Facility (B.W.E.), and Department of Pediatrics/Division of Pediatric Cardiology (M.J.A.), Mayo Clinic, Rochester, MN; and Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo College of Medicine, Rochester, MN (S.M., J.M.E.).
David J
DJ
Tester
From Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (H.M.A., D.J.T., M.L.W., M.J.A.), Department of Medicine/Division of Cardiovascular Diseases (D.J.T., M.L.W., M.J.A.), Medical Genome Facility (B.W.E.), and Department of Pediatrics/Division of Pediatric Cardiology (M.J.A.), Mayo Clinic, Rochester, MN; and Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo College of Medicine, Rochester, MN (S.M., J.M.E.).
Melissa L
ML
Will
From Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (H.M.A., D.J.T., M.L.W., M.J.A.), Department of Medicine/Division of Cardiovascular Diseases (D.J.T., M.L.W., M.J.A.), Medical Genome Facility (B.W.E.), and Department of Pediatrics/Division of Pediatric Cardiology (M.J.A.), Mayo Clinic, Rochester, MN; and Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo College of Medicine, Rochester, MN (S.M., J.M.E.).
Sumit
S
Middha
From Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (H.M.A., D.J.T., M.L.W., M.J.A.), Department of Medicine/Division of Cardiovascular Diseases (D.J.T., M.L.W., M.J.A.), Medical Genome Facility (B.W.E.), and Department of Pediatrics/Division of Pediatric Cardiology (M.J.A.), Mayo Clinic, Rochester, MN; and Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo College of Medicine, Rochester, MN (S.M., J.M.E.).
Jared M
JM
Evans
From Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (H.M.A., D.J.T., M.L.W., M.J.A.), Department of Medicine/Division of Cardiovascular Diseases (D.J.T., M.L.W., M.J.A.), Medical Genome Facility (B.W.E.), and Department of Pediatrics/Division of Pediatric Cardiology (M.J.A.), Mayo Clinic, Rochester, MN; and Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo College of Medicine, Rochester, MN (S.M., J.M.E.).
Bruce W
BW
Eckloff
From Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (H.M.A., D.J.T., M.L.W., M.J.A.), Department of Medicine/Division of Cardiovascular Diseases (D.J.T., M.L.W., M.J.A.), Medical Genome Facility (B.W.E.), and Department of Pediatrics/Division of Pediatric Cardiology (M.J.A.), Mayo Clinic, Rochester, MN; and Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo College of Medicine, Rochester, MN (S.M., J.M.E.). ackerman.michael@mayo.edu.
Michael J
MJ
Ackerman
D000293:Adolescent; D000328:Adult; D000368:Aged; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D017147:Defibrillators, Implantable; D059472:Exome; D005260:Female; D016368:Frameshift Mutation; D005808:Genes, Recessive; D006323:Heart Arrest / Q000175:diagnosis / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D008133:Long QT Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D017422:Sequence Analysis, DNA; D013562:Sympathectomy; D013575:Syncope / Q000175:diagnosis / Q000235:genetics; D013577:Syndrome; D016896:Treatment Outcome; D055815:Young Adult
D002352:Carrier Proteins; D009124:Muscle Proteins; C498269:TRDN protein, human
arrhythmias, cardiac; genetics; heart arrest; humans; long QT syndrome; pediatrics