Abstract 19858: The Promise and Peril of the Molecular Autopsy: Genetic Testing in a Sibling of a Sudden Death in the Young Victim Leads to Misdiagnosis of Long QT Syndrome and ICD Implantation
Introduction: Recent guidelines advise that postmortem genetic testing be considered as the new standard of care in the evaluation of sudden death in the young (SDY) cases. While postmortem testing has serious promise for elucidating a genetic cause of death, there may also be grave peril if used improperly. Here, we illustrate the work necessary to reverse course following the identification of a KCNQ1 variant interpreted erroneously as long QT syndrome (LQTS)-causing and to identify the true cause for the case of SDY.
Methods: Surrogate genetic testing of a decedent’s living brother identified a rare KCNQ1-V133I variant, prompting placement of an ICD and consequent diagnosis of LQTS in other family members. Subsequently, this presumed LQT1 family came to our institution for clinical evaluation and research-based investigations including KCNQ1-V133I variant specific analysis of the decedent, heterologous expression studies of KCNQ1-V133I, and a whole exome molecular autopsy (WEMA) along with genomic triangulation using his unaffected parents’ DNA.
Results: After evaluating several V133I-positive family members, clinical doubt was cast on the veracity of the previous diagnosis of LQT1 resulting in a re-opening of the case and an intense pursuit of the lethal substrate. Furthermore, the decedent tested negative for V133I and heterologous expression studies demonstrated a normal cellular phenotype for V133I-containing Kv7.1 channels. Instead, WEMA identified a de novo pathogenic variant (p. R454W) in DES-encoded desmin as the most likely disease-susceptibility gene. This gene has been implicated in HCM, and this precise variant was described as a sporadic pathogenic mutation in a 15-year-old male who developed exercise intolerance and HCM, corresponding with the autopsy findings of an enlarged heart and microscopic myocyte disarray found in this sudden death victim.
Conclusions: The forensic evaluation of SDY requires an exquisite focus on the decedent followed by a careful and deliberate assessment of the decedent’s relatives. Surrogate genetic testing can have disastrous consequences and should be avoided. Genetic test results require precise interpretation otherwise precision medicine, like the SDY victim, will be dead on arrival.
Author Disclosures: J. Ackerman: None. D. Bartos: None. J. Kapplinger: None. D. Tester: None. B. Delisle: None. M. Ackerman: Research Grant; Modest; Sheikh Zayed Saif Mohammed Al Nahyan Fund in Pediatric Cardiology Research, Dr. Scholl Fund, hannah M. Wernke Memorial Fund. Other Research Support; Modest; Mayo Clinic’s Center for Individualized Medicine. Consultant/Advisory Board; Modest; Boston Scientific, Gilead Sciences, Medtronic, St. Jude Medical.
- © 2016 by American Heart Association, Inc.