Research
Print page Print page
Switch language
Rigshospitalet - a part of Copenhagen University Hospital
Published

Utility of Post-Mortem Genetic Testing in Cases of Sudden Arrhythmic Death Syndrome

Research output: Contribution to journalJournal articleResearchpeer-review

  1. Natural History and Clinical Characteristics of the First 10 Danish Families With Familial ST-Depression Syndrome

    Research output: Contribution to journalLetterResearchpeer-review

  2. Long-Term Cardiovascular Outcomes in Systemic Lupus Erythematosus

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. Prognostic Value of Coronary CT Angiography in Patients With Non-ST-Segment Elevation Acute Coronary Syndromes

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. Effect of Empagliflozin on Hemodynamics in Patients With Heart Failure and Reduced Ejection Fraction

    Research output: Contribution to journalJournal articleResearchpeer-review

  5. Risk Factors for Morbidity and Mortality Following Hospitalization for Pericarditis

    Research output: Contribution to journalJournal articleResearchpeer-review

  1. Witnessed and unwitnessed sudden cardiac death: a nationwide study of persons aged 1-35 years

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Cardiac arrhythmias in patients hospitalized with COVID-19: The ACOVID study

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. Natural History and Clinical Characteristics of the First 10 Danish Families With Familial ST-Depression Syndrome

    Research output: Contribution to journalLetterResearchpeer-review

  4. Detection of atrial fibrillation with implantable loop recorders in horses

    Research output: Contribution to journalJournal articleResearchpeer-review

  5. Familial Evaluation in Idiopathic Ventricular Fibrillation: Diagnostic Yield and Significance of J-Wave Syndromes

    Research output: Contribution to journalJournal articleResearchpeer-review

  • Najim Lahrouchi
  • Hariharan Raju
  • Elisabeth M Lodder
  • Efstathios Papatheodorou
  • James S Ware
  • Michael Papadakis
  • Rafik Tadros
  • Della Cole
  • Jonathan R Skinner
  • Jackie Crawford
  • Donald R Love
  • Chee J Pua
  • Bee Y Soh
  • Jaydutt D Bhalshankar
  • Risha Govind
  • Jacob Tfelt-Hansen
  • Bo G Winkel
  • Christian van der Werf
  • Yanushi D Wijeyeratne
  • Greg Mellor
  • Jan Till
  • Marta C Cohen
  • Maria Tome-Esteban
  • Sanjay Sharma
  • Arthur A M Wilde
  • Stuart A Cook
  • Connie R Bezzina
  • Mary N Sheppard
  • Elijah R Behr
View graph of relations

BACKGROUND: Sudden arrhythmic death syndrome (SADS) describes a sudden death with negative autopsy and toxicological analysis. Cardiac genetic disease is a likely etiology.

OBJECTIVES: This study investigated the clinical utility and combined yield of post-mortem genetic testing (molecular autopsy) in cases of SADS and comprehensive clinical evaluation of surviving relatives.

METHODS: We evaluated 302 expertly validated SADS cases with suitable DNA (median age: 24 years; 65% males) who underwent next-generation sequencing using an extended panel of 77 primary electrical disorder and cardiomyopathy genes. Pathogenic and likely pathogenic variants were classified using American College of Medical Genetics (ACMG) consensus guidelines. The yield of combined molecular autopsy and clinical evaluation in 82 surviving families was evaluated. A gene-level rare variant association analysis was conducted in SADS cases versus controls.

RESULTS: A clinically actionable pathogenic or likely pathogenic variant was identified in 40 of 302 cases (13%). The main etiologies established were catecholaminergic polymorphic ventricular tachycardia and long QT syndrome (17 [6%] and 11 [4%], respectively). Gene-based rare variants association analysis showed enrichment of rare predicted deleterious variants in RYR2 (p = 5 × 10-5). Combining molecular autopsy with clinical evaluation in surviving families increased diagnostic yield from 26% to 39%.

CONCLUSIONS: Molecular autopsy for electrical disorder and cardiomyopathy genes, using ACMG guidelines for variant classification, identified a modest but realistic yield in SADS. Our data highlighted the predominant role of catecholaminergic polymorphic ventricular tachycardia and long QT syndrome, especially the RYR2 gene, as well as the minimal yield from other genes. Furthermore, we showed the enhanced utility of combined clinical and genetic evaluation.

Original languageEnglish
JournalJournal of the American College of Cardiology
Volume69
Issue number17
Pages (from-to)2134-2145
Number of pages12
ISSN0735-1097
DOIs
Publication statusPublished - 2 May 2017

    Research areas

  • Adolescent, Adult, Child, Death, Sudden, Cardiac, Female, Genetic Testing, Humans, Male, Young Adult, Journal Article

ID: 52685626