Whole-Exome Molecular Autopsy After Exertion-Related Sudden Unexplained Death in the Young.
BACKGROUND
Targeted postmortem genetic testing of the 4 major channelopathy-susceptibility genes (KCNQ1, KCNH2, SCN5A, and RYR2) have yielded putative pathogenic mutations in ≤30% of autopsy-negative sudden unexplained death in the young (SUDY) cases with highest yields derived from the subset of exertion-related SUDY. Here, we evaluate the role of whole-exome sequencing in exertion-related SUDY cases.


RESULTS
From 1998 to 2010, 32 cases of exertion-related SUDY were referred by Medical Examiners for a cardiac channel molecular autopsy. A mutational analysis of the major long-QT syndrome-susceptibility genes (KCNQ1, KCNH2, and SCN5A) and catecholaminergic polymorphic ventricular tachycardia-susceptibility gene (RYR2) identified a putative pathogenic mutation in 11 cases. Whole-exome sequencing was performed on the remaining 21 targeted gene-negative SUDY cases. After whole-exome sequencing, a gene-specific surveillance of all genes (N=100) implicated in sudden death was performed to identify putative pathogenic mutation(s). Three of these 21 decedents had a clinically actionable, pathogenic mutation (CALM2-F90L, CALM2-N98S, and PKP2-N634fs). Of the 18 remaining cases, 7 hosted at least 1 variant of unknown significance with a minor allele frequency <1:20 000. The overall yield of pathogenic mutations was higher among decedents aged 1 to 10 years (10/11, 91%) than those aged 11 to 19 years (4/21, 19%, P=0.0001).


CONCLUSIONS
Molecular screening in this clinical scenario is appropriate with a pathogenic mutation detection rate of 44% using direct DNA sequencing followed by whole-exome sequencing. Only 5 of the 100 interrogated sudden death genes hosted actionable pathogenic mutations for more than one third of these exertion-related, autopsy-negative SUDY cases.
From the Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine (J.H.A., M.J.A.), Department of Molecular Pharmacology and Experimental Therapeutics/Windland Smith Rice Sudden Death Genomics Laboratory (D.J.T., M.L.W., M.J.A.), and Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic, Rochester, MN (M.J.A.).
Jason H
JH
Anderson
From the Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine (J.H.A., M.J.A.), Department of Molecular Pharmacology and Experimental Therapeutics/Windland Smith Rice Sudden Death Genomics Laboratory (D.J.T., M.L.W., M.J.A.), and Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic, Rochester, MN (M.J.A.).
David J
DJ
Tester
From the Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine (J.H.A., M.J.A.), Department of Molecular Pharmacology and Experimental Therapeutics/Windland Smith Rice Sudden Death Genomics Laboratory (D.J.T., M.L.W., M.J.A.), and Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic, Rochester, MN (M.J.A.).
Melissa L
ML
Will
From the Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine (J.H.A., M.J.A.), Department of Molecular Pharmacology and Experimental Therapeutics/Windland Smith Rice Sudden Death Genomics Laboratory (D.J.T., M.L.W., M.J.A.), and Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic, Rochester, MN (M.J.A.). ackerman.michael@mayo.edu.
Michael J
MJ
Ackerman
D000293:Adolescent; D000367:Age Factors; D001145:Arrhythmias, Cardiac / Q000150:complications / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D001344:Autopsy; D002423:Cause of Death; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D016757:Death, Sudden, Cardiac / Q000209:etiology* / Q000473:pathology; D000072237:ERG1 Potassium Channel / Q000235:genetics; D059472:Exome; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D051657:KCNQ1 Potassium Channel / Q000235:genetics; D008297:Male; D008910:Minnesota; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics; D057089:Pathology, Molecular / Q000379:methods*; D010641:Phenotype; D005082:Physical Exertion; D011237:Predictive Value of Tests; D012307:Risk Factors; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics; D055815:Young Adult
D000072237:ERG1 Potassium Channel; C000606913:KCNH2 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D062554:NAV1.5 Voltage-Gated Sodium Channel; C000621072:RyR2 protein, human; D019837:Ryanodine Receptor Calcium Release Channel; C568320:SCN5A protein, human
autopsy; exome; genetic testing; mutation; phenotype