Author + information
- Received November 7, 2016
- Revision received February 9, 2017
- Accepted February 14, 2017
- Published online April 24, 2017.
- Najim Lahrouchi, MDa,
- Hariharan Raju, MBChB, PhDb,c,
- Elisabeth M. Lodder, PhDa,
- Efstathios Papatheodorou, MDb,c,
- James S. Ware, PhDd,e,
- Michael Papadakis, MBBS, MDb,c,
- Rafik Tadros, MD, PhDa,f,
- Della Cole, BScb,c,
- Jonathan R. Skinner, MBChB, MDg,
- Jackie Crawfordg,
- Donald R. Love, PhDg,
- Chee J. Pua, PhDh,
- Bee Y. Soh, PhDh,
- Jaydutt D. Bhalshankar, PhDh,
- Risha Govind, MScd,e,
- Jacob Tfelt-Hansen, MD, DMSci,
- Bo G. Winkel, MD, PhDi,
- Christian van der Werf, MD, PhDa,
- Yanushi D. Wijeyeratne, BMBSb,c,
- Greg Mellor, MBChB, MDb,c,
- Jan Till, MDc,d,e,
- Marta C. Cohen, MD, DMJ (Pathol)j,
- Maria Tome-Esteban, MD, PhDb,c,
- Sanjay Sharma, MBChB, MDb,c,
- Arthur A.M. Wilde, MD, PhDa,k,
- Stuart A. Cook, MD, PhDd,h,l,
- Connie R. Bezzina, PhDa,
- Mary N. Sheppard, MB, BCh, BAO, MDb,c and
- Elijah R. Behr, MBBS, MDb,c,∗ ()
- aHeart Centre, Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands
- bMolecular and Clinical Sciences Research Institute, St. George's, University of London, London, United Kingdom
- cCardiology Clinical Academic Group, St. George’s University Hospitals NHS Foundation Trust, London, United Kingdom
- dNational Heart and Lung Institute, Sydney Street, Imperial College London, London, United Kingdom
- eRoyal Brompton & Harefield Hospitals NHS Foundation Trust, London, United Kingdom
- fCardiovascular Genetics Center, Department of Medicine, Montreal Heart Institute and Université de Montréal, Montreal, Canada
- gCardiac Inherited Disease Group New Zealand, Green Lane Paediatric and Congenital Cardiac Services, Starship Children's Hospital, Auckland New Zealand; The University of Auckland, Department of Paediatrics Child and Youth Health, Auckland, New Zealand
- hNational Heart Centre Singapore, Singapore
- iDepartment of Cardiology, Rigshospitalet, Copenhagen, Denmark
- jSheffield Children's NHS Foundation Trust, Sheffield, United Kingdom
- kPrincess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Kingdom of Saudi Arabia
- lDuke-National University of Singapore, Singapore
- ↵∗Address for correspondence:
Dr. Elijah R. Behr, Cardiology Clinical Academic Group, Molecular and Clinical Sciences Research Institute, St. George's, University of London, Cranmer Terrace, London SW17 0RE, United Kingdom.
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.
This study was funded in part by Cardiac Risk in the Young (to Drs. Raju, Papadakis, Mellor, Sharma, Sheppard, and Behr); the British Heart Foundation (to Drs. Raju, Cook, and Behr) including BHF Clinical Research Training Fellowship FS/11/71/28918: Future diagnostic role and novel genetic loci in SADS; NMRC Singapore (to Dr. Cook); Leducq Foundation (to Dr. Cook); MRC UK (to Drs. Ware and Cook); Tanoto Foundation (to Dr. Cook); SingHealth/Duke-NUS Precision Medicine Institute (PRISM) (to Dr. Cook); Cure Kids (New Zealand) (to Drs. Skinner, Crawford, and Love); NIHR Royal Brompton Cardiovascular Biomedical Research Unit (to Dr. Ware); Wellcome Trust (to Dr. Ware) and the Dutch Heart Foundation CVON-PREDICT project (CVON2012-10) (to Drs. Lahrouchi, Lodder, Wilde, and Bezzina). Dr. Wilde has consulted for Sorin. Dr. Behr has received unrestricted research funds from Biotronik and St. Jude Medical. Dr. Cook is a consultant for Illumina.
- Received November 7, 2016.
- Revision received February 9, 2017.
- Accepted February 14, 2017.
- 2017 The Authors